- Record: found
- Abstract: found
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Strongyloides stercoralis and hookworm co-infection: spatial distribution and determinants in Preah Vihear Province, Cambodia
research-article
Author(s):
Armelle Forrer
1
,
2 ,
Virak Khieu
3 ,
Fabian Schär
1
,
2 ,
Penelope Vounatsou
1
,
2 ,
Frédérique Chammartin
1
,
2 ,
Hanspeter Marti
1
,
2 ,
Sinuon Muth
3 ,
Peter Odermatt
1
,
2
,
Publication date (Electronic):
12 January 2018
Journal:
Parasites & Vectors
Publisher:
BioMed Central
Keywords:
Strongyloidiasis,
Hookworm,
Co-infection,
Spatial,
Bayesian,
Helminths,
Control,
Risk profiling,
Cambodia
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Abstract
Background
Strongyloides stercoralis and hookworm are two soil-transmitted helminths (STH) that are highly prevalent in Cambodia. Strongyloides stercoralis causes long-lasting infections and significant morbidity but is largely neglected, while hookworm causes the highest public health burden among STH. The two parasites have the same infection route, i.e. skin penetration. The extent of co-distribution, which could result in potential high co-morbidities, is unknown in highly endemic settings like Cambodia. The aim of this study was to predict the spatial distribution of S. stercoralis-hookworm co-infection risk and to investigate determinants of co-infection in Preah Vihear Province, North Cambodia.
Methods
A cross-sectional survey was conducted in 2010 in 60 villages of Preah Vihear Province. Diagnosis was performed on two stool samples, using combined Baermann technique and Koga agar culture plate for S. stercoralis and Kato-Katz technique for hookworm. Bayesian multinomial geostatistical models were used to assess demographic, socioeconomic, and behavioural determinants of S. stercoralis-hookworm co-infection and to predict co-infection risk at non-surveyed locations.
Results
Of the 2576 participants included in the study, 48.6% and 49.0% were infected with S. stercoralis and hookworm, respectively; 43.8% of the cases were co-infections. Females, preschool aged children, adults aged 19–49 years, and participants who reported regularly defecating in toilets, systematically boiling drinking water and having been treated with anthelmintic drugs had lower odds of co-infection. While S. stercoralis infection risk did not appear to be spatially structured, hookworm mono-infection and co-infection exhibited spatial correlation at about 20 km. Co-infection risk was positively associated with longer walking distances to a health centre and exhibited a small clustering tendency. The association was only partly explained by climatic variables, suggesting a role for underlying factors, such as living conditions and remoteness.
Conclusions
Both parasites were ubiquitous in the province, with co-infections accounting for almost half of all cases. The high prevalence of S. stercoralis calls for control measures. Despite several years of school-based de-worming programmes, hookworm infection levels remain high. Mebendazole efficacy, as well as coverage of and compliance to STH control programmes should be investigated.
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Most cited references55
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- Abstract: found
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Strongyloides stercoralis: Global Distribution and Risk Factors
Fabian Schär, Ulf Trostdorf, Federica Giardina … (2013)
Introduction The threadworm Strongyloides stercoralis is a soil-transmitted nematode and one of the most overlooked helminth among the neglected tropical diseases (NTDs) [1]. It occurs almost world-wide, excluding only the far north and south, yet estimates about its prevalence are often little more than educated guesses [2], [3]. Compared to other major soil-transmitted helminths (STHs), namely Ascaris lumbricoides (roundworm), Necator americanus and Ancylostoma duodenale (hookworms) and Trichuris trichiura (whipworm), information on S. stercoralis is scarce [3]. The diagnostic methods most commonly used for STH detection, such as direct fecal smear or Kato-Katz, have low sensitivity for S. stercoralis or fail to detect it altogether [4]–[6]. Especially the parasitological diagnostic tools for S. stercoralis infection like the Koga Agar plate culture consume more resources and time than the most commonly applied methods [7] and hence, are rarely used in potentially endemic settings of resource poor countries. S. stercoralis was first described in 1876. The full life cycle, pathology and clinical features in humans were fully disclosed in the 1930s (Figure 1). The rhabditiform larvae are excreted in the stool of infected individuals. The larvae mold twice and then develop into infective 3rd stage filariform larvae (L3), which can infect a new host by penetrating intact skin. The larvae thrive in warm, moist/wet soil. Walking barefoot and engaging in work involving skin contact with soil, as well as low sanitary standards are risk factors for infection. Hence, many resource poor tropical and subtropical settings provide ideal conditions for transmission [8]–[10]. 10.1371/journal.pntd.0002288.g001 Figure 1 The life-cycle of S. stercoralis (based on http://www.dpd.cdc.gov/dpdx). S. stercoralis is an exception among helminthic parasites in that it can reproduce within a human host (endogenous autoinfection), which may result in long-lasting infection. Some studies report individuals with infections sustained for more than 75 years [9]–[13]. Two other species, closely related to S. stercoralis, also infect humans, namely S. fulleborni and S. cf fulleborni, which are of minor importance and geographically restricted [14], [15]. S. stercoralis' ability to cause systemic infection is another exceptional feature of the threadworm. Particularly in immunosuppressed individuals with a defective cell-mediated immunity, spread from the intestinal tract of one or more larval stages may lead to hyperinfection syndrome and disseminated strongyloidiasis, in which several organs may be involved [16]. The outcome is often fatal [5], [17], [18]. In contrast, uncomplicated intestinal strongyloidiasis may include a spectrum of unspecific gastro-intestinal symptoms such as diarrhea, abdominal pain and urticaria [16], [19]. However, most infections, chronic low-intensity infections in particular, remain asymptomatic. Asymptomatic infections are particularly dangerous. In cases of immunosuppressive treatment, especially with corticosteroids, they have the potential to develop fatal disseminated forms. Proper screening of potentially infected individuals before immunosuppressive treatment (coprologically over several days and/or serologically) is essential, though often not carried out. This asymptomatic infection, coupled with diagnostic difficulties, (often due to irregular excretion of parasite larvae) leads to under-diagnosis of the threadworm. Assessing the clinical consequences of infection remains challenging, thus, little is known about the S. stercoralis burden in endemic countries. In 1989, Genta [2] summarized information on global distribution of this parasite for the first time. He found S. stercoralis to be highly prevalent in Latin America and sub-Saharan Africa. He further pointed out that many reports suggested high infection rates in South-East Asia and described several risk groups, including refugees and immigrants. The objectives of our study are to obtain country-wide estimates of S. stercoralis infection risk in the general population, and to assess the association between S. stercoralis prevalence and different risk groups. We reviewed the available literature and carried out a Bayesian meta-analysis taking into account the sensitivity of the different diagnostic tools. The models allowed estimation of the diagnostic sensitivity for different study types and risk groups. Materials and Methods Literature search and data extraction We conducted a systematic literature review of all research papers published between January 1989 and October 2011 and listed in PubMed. Papers were filtered using the search terms “Strongyloides” or “Strongyloides stercoralis” or “Strongyloidiasis”. Studies were included if they contained information on prevalence and/or risk of S. stercoralis infection, either in the general population or in risk groups, i.e. patients with HIV/AIDS, immuno-deficiencies, HTLV-1-infection, alcoholism, and diarrhea. We excluded articles (i) that were not written in English, Spanish, Portuguese, French or German language; (ii) that referred to specific bio-molecular research aspects of S. stercoralis; (iii) on infection in animals, and (iv) that did not provide additional information on the prevalence and/or risk of S. stercoralis infection. For each selected paper, the following information was recorded: number of infected individuals, number of examined individuals, risk factors (specific risk group or control group), study area (country or geographic coordinates, when available) and WHO world region (Region of the Americas, European region, African region, Eastern Mediterranean region, South East Asia region and the Western Pacific region), study type (cross-sectional, case-control etc.), place of implementation (community- or hospital-based studies, and studies on refugees and immigrants), and diagnostic procedures used (copro-diagnostic, serological methods etc.). Statistical analysis The main outcome of the analysis is S. stercoralis prevalence in the general population for each country as well as in specific risk groups, namely HIV/AIDS patients, HTLV-1 patients, alcoholics and patients with diarrhea. A Bayesian model for meta-analysis that included the diagnostic-test sensitivity was formulated and implemented in WinBUGS 1.4 [20]. Information about the sensitivity of the different diagnostic tools used was derived from the literature and led to the division of diagnostic procedures into three sensitivity groups. We assigned a range of sensitivity using the lowest and the highest sensitivity reported, respectively [21]–[43]. 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%); (iii) serological diagnostic procedures with high sensitivity (68.0–98.2%). Beta prior distributions were specified for the different diagnostic-test group sensitivities. A more detailed description of the prior elicitation can be found in the appendix. Estimating country-wide prevalence in the general population The retrieved data was analyzed separately in the three different subsets: community-based studies, hospital-based studies, and studies on refugees and immigrants, as prevalence rates from these subsets cannot be directly compared. Model-based prevalence estimates for each study type and country were plotted on a world map, using ArcGIS (version 9.3). The prevalence estimates for refugee and immigrant studies were displayed in the country where the study was undertaken and not in the country from where the refugees and immigrants originated. Further details regarding model specification can be found in appendix. Association with specific risk factors To analyze the association between S. stercoralis and specific risk factors, namely HIV/AIDS, Human T-lymphotropic virus 1 (HTLV-1) infected individuals, diarrhea, and alcoholism, the studies were grouped into case-control studies and cross-sectional studies. We used case-control studies conducted on each risk group with complete information about individuals screened (tested) and infected with S. stercoralis, as well as the diagnostic method used, to model specific Odds Ratios (OR) and pool them into an overall estimate using a logistic model taking into account the prior information available on diagnostic test sensitivity. In the appendix, we describe the formulation of the Bayesian model for OR estimations of the risk factors mentioned above. The same model without the inclusion of the sensitivity was implemented and run. Results are shown, for comparison purposes, in the appendix (Figure A1a–A1d). Forest plots were produced using R software (version 2.13.1). Diagnostic test sensitivity The Bayesian models employed in this study estimate the disease prevalence (or ORs) together with the diagnostic sensitivity. We run the models under different prior specifications, to assess the robustness of the estimates. Results Study identification We identified and reviewed 354 studies (Figure 2). Of those, 194 (54.8%) used a cross-sectional design and were conducted in communities: 121 (62.4%) used diagnostic methods with low sensitivity, 56 (28.9%) with moderate sensitivity, and 17 (8.8%) with high sensitivity. Out of 121 hospital-based studies, 75 (61.5%) used low, 36 (29.8%) used moderate and 10 (8.3%) used high sensitivity methods. Of the 39 studies on refugees and immigrants, 28 (71.8%) used low, three (7.7%) used moderate, and eight (20.5%) used high sensitivity diagnostic methods. 10.1371/journal.pntd.0002288.g002 Figure 2 Flowchart of the literature review. Prevalence Available information Figure 3 indicates the number of reports per country that provided information on infection rates. Tables 1–3 report the calculated prevalence rates per country. Information is notably scarce for those African countries where environmental and socioeconomic conditions are most favorable for transmission. S. stercoralis infection data is only available for 20 (43.5%) of the 46 African countries. The distribution of infection rate information is heterogeneous. Almost a quarter of the studies (18, 23.4%) were undertaken in densely populated Nigeria alone. Some studies reported on tropical West and East Africa. However, infection rate data is scarce for Sahelian, Central and Southern Africa. Most of the available studies used low sensitivity diagnostic methods. Adequate diagnostic techniques, such as the Baermann method and Koga Agar plate culture, were employed in only 19.0% of the studies in African countries. 10.1371/journal.pntd.0002288.g003 Figure 3 Number of studies undertaken per country since 1989, with geo-location if indicated; Thailand and Brazil displayed separately. 10.1371/journal.pntd.0002288.t001 Table 1 Country-wide prevalence rates for Strongyloides stercoralis in countries A–F, divided by type of study. References Community-based surveys Hospital-based surveys Refugees & Immigrants Country Total Number of surveys for prevalence calculation Total Number Prevalence 95% CI Total Number Prevalence 95% CI Total Number Prevalence 95% CI Argentina 8 w1–8 4 52.8% 42.42%–64.6% 4 63.0% 53.6%–72.9% Australia 15 w9–22 6 15.0% 13.52%–16.8% 3 28.9% 26.2%–31.6% 6 25.3% 22.3%–28.5% Austria 1 w23 1 5.2% 1.0%–15.7% Bangladesh 1 w24 1 29.8% 21.7%–39.8% Belize 1 w25 1 7.7% 3.3%–14.8% Bolivia 2 w26, 27 2 21.1% 11.2%–36.1% Brazil 43 w28–70 26 13.0% 12.0%–14.2% 16 17.0% 15.8%–18.2% 1 35.0% 9.8%–85.4% Burundi 2 w71 1 1.9% 0.4%–5.6% 1 21.6% 11.2%–36.4% Cambodia 4 w72–75 3 17.5% 15.7%–19.6% 1 13.9% 12.1%–16.0% Cameroon 1 w76 1 10.0% 3.6%–21.2% Canada 3 w77–79 3 67.5% 61.3%–73.5% Central African Republic 2 w80 1 0.1% 0.0%–1.2% 1 1.9% 0.4%–5.5% China 4 w81–84 1 14.0% 9.0%–20.4% 3 17.1% 15.2%–19.2% Colombia 2 w85, 86 1 56.2% 48.0%–65.7% 1 20.2% 6.7%–45.1% Costa Rica 1 w87 1 6.9% 2.9%–13.6% Côte d'Ivoire 5 w88–92 4 24.3% 20.7%–28.4% 1 67.7% 41.4%–98.7% DR of the Congo 1 w93 1 32.7% 20.6%–48.6% Dominica 1 w94 1 97.6% 78.4%–100% Ecuador 2 w95, 96 2 27.1% 19.3%–36.9% Egypt 12 w97–108 5 2.5% 2.0%–3.2% 7 11.1% 9.4%–13.1% Ethiopia 12 w109–120 7 15.9% 14.1%–17.9% 5 31.0% 23.6%–40.0% Fiji 1 w121 1 9.3% 2.5%–23.1% France 2 w122, 123 1 31.1% 22.7%–40.7% 1 5.6% 3.7%–8.9% 10.1371/journal.pntd.0002288.t002 Table 2 Country-wide prevalence rates for Strongyloides stercoralis for countries G-M, divided by type of study. References Community-based surveys Hospital-based surveys Refugees & Immigrants Country Total Number of surveys for prevalence calculation Total Number Prevalence 95% CI Total Number Prevalence 95% CI Total Number Prevalence 95% CI Gabon 1 w124 1 91.8% 44.6%–100.0% Ghana 2 w125, 126 1 69.5% 63.2%–76.9% 1 13.6% 1.1%–53.4% Grenada 1 w127 1 3.3% 0.3%–13.0% Guadeloupe 2 w128, 129 1 18.7% 14.5%–23.5% 1 8.3% 7.7%–8.9% Guatemala 1 w130 1 2.0% 1.5%–2.6% Guinea 2 w131, 132 2 43.8% 34.7%–54.9% Guinea-Bissau 2 w133, 134 1 23.7% 18.3%–30.0% 1 84.2% 42.1%–100.0% Haiti 1 w135 1 1.0% 0.5%–1.8% Honduras 4 w136–139 1 3.2% 1.5%–6.2% 3 29.8% 24.1%–36.0% India 14 w140–153 5 6.6% 4.4%–9.4% 9 11.2% 8.6%–14.4% Indonesia 6 w154–159 6 7.6% 6.2%–9.3% Iran 3 w160–162 1 0.3% 0.1%–0.5% 2 0.6% 0.1%–1.7% Iraq 1 w163 1 24.2% 14.1%–38.1% Israel 3 w164–166 1 94.9% 86.4%–100.0% 2 31.0% 27.0%–35.1% Italy 5 w167–171 4 1.8% 1.4%–2.3% 1 3.3% 0.6%–9.6% Jamaica 3 w172–174 2 27.1% 22.8%–32.1% 1 1.8% 0.9%–3.2% Japan 14 w63, 175–186 9 18.7% 17.4%–20.4% 5 13.6% 12.7%–14.5% Jordan 1 w187 1 0.03% 0.0%–0.1% Kenya 4 w188–191 2 80.2% 61.1%–99.4% 2 7.8% 5.0%–11.5% Kuwait 1 w192 1 16.3% 14.1%–18.7% Lao PDR 4 w193–196 3 26.2% 22.5%–30.4% 1 55.8% 37.0%–81.4% Libya 1 w197 1 1.1% 0.1%–4.5% Madagascar 1 w198 1 52.2% 42.6%–61.6% Martinique 2 w199, 200 1 3.8% 3.3%–4.4% 1 9.6% 8.1%–11.4% Mexico 2 w201, 202 1 1.6% 0.2%–6.3% 1 5.7% 1.1%–16.5% Mozambique 1 w203 1 6.2% 2.5%–12.1% 10.1371/journal.pntd.0002288.t003 Table 3 Country-wide prevalence rates for Strongyloides stercoralis for countries N-Z, divided by type of study. References Community-based surveys Hospital-based surveys Refugees & Immigrants Country Total Number of surveys for prevalence calculation Total Number Prevalence 95% CI Total Number Prevalence 95% CI Total Number Prevalence 95% CI Namibia 3 w204–206 2 99.3% 92.2%–100.0% 1 14.3% 11.6%–17.6% Nepal 3 w207–209 1 22.8% 10.1%–43.4% 2 5.8% 2.5%–11.2% Nicaragua 1 w210 1 2.0% 0.6%–4.5% Nigeria 18 w211–229 13 48.1% 43.3%–53.8% 5 17.6% 15.2%–20.3% Occ. Palestinian Territ. 1 w230 1 4.2% 0.4%–16.7% Oman 1 w231 1 3.0% 0.6%–8.7% Papua New Guinea 1 w232 1 99.0% 90.0%–100.0% Peru 6 w233–238 4 75.3% 70.8%–82.0% 2 69.3% 61.1%–77.9% Puerto Rico 2 w239, 240 1 16.0% 3.0%–47.5% 1 33.5% 13.7%–66.6% Republic of Korea 2 w241, 242 2 0.1% 0.0%–0.1% Romania 1 w243 1 48.8% 31.1%–72.1% Saint Lucia 1 w244 1 58.5% 44.1%–76.4% Saudi Arabia 3 w245–247 1 12.5% 3.3%–31.2% 2 7.1% 5.5%–9.0% Sierra Leone 3 w248–250 3 27.4% 21.5%–34.4% South Africa 2 w251, 252 2 27.5% 21.3%–34.7% Spain 5 w253–257 1 14.8% 10.3%–20.3% 1 1.9% 1.6%–2.2% 3 4.2% 2.8%–6.1% Sudan 3 w258–260 2 3.7% 1.9%–6.4% 1 98.9% 89.2%–100.0% Suriname 1 w261 1 63.2% 50.3%–78.2% Sweden 1 w262 1 1.0% 0.4%–2.1% Thailand 40 w63,263–300 32 23.7% 21.8%–26.1% 8 34.7% 31.6%–38.3% Tunisia 1 w301 1 0.5% 0.3%–0.9% Turkey 3 w302–304 1 0.6% 0.4%–0.8% 2 4.1% 2.1%–7.2% Uganda 6 w305–310 4 19.3% 17.1%–21.9% 2 30.3% 25.1%–36.5% UK 1 w311 1 12.7% 11.1%–14.5% UR of Tanzania 8 w312–317 4 7.9% 6.6%–9.5% 4 9.3% 6.1%–13.7% US of America 22 w318–337 3 2.7% 2.4%–3.0% 5 49.2% 0.1%–99.9% 14 40.4% 37.8%–43.0% Venezuela 3 w338–340 1 2.3% 0.2%–9.1% 2 48.4% 0.2%–99.8% Viet Nam 1 w341 1 0.02% 0.0%–0.3% Zambia 3 w342–344 1 6.6% 1.3%–19.4% 2 50.6% 0.2%–99.9% The Americas are well covered, with studies in 21 (60.0%) of the 35 countries in this region. Data is mostly missing for smaller countries, such as the Caribbean island nations (Antigua, Barbuda, Bahamas, Barbados, etc.). A large amount of information is available for Brazil, where 43 (37.4%) studies were undertaken. Most investigations were conducted in communities (26, 60.5%) rather than in hospitals (16, 37.2%). For the United States of America, 22 (19.1%) studies were identified. Almost two thirds of them (14, 63.6%) focused on refugees and immigrants. For Europe, comparably fewer reports (24) were found. Most of them focused on refugees, immigrants and travelers. South-East Asia and the Western Pacific region are reasonably represented, with 40 investigations conducted in Thailand (36.4%), 15 in Australia (13.6%), 14 in Japan (12.7%), and 14 in India (12.7%). Yet, in many other Asian countries where high prevalence of S. stercoralis is likely to occur, information on infection rates is limited, and studies often lack the use of high sensitivity methods. Global prevalence of S. stercoralis The global prevalence picture is as diverse and heterogeneous as the type and number of studies undertaken. The existing information suggests that S. stercoralis infections affect between 10% and 40% of the population in many tropical and subtropical countries. In resource-poor countries with ecological and socioeconomic settings conducive to the spread of S. stercoralis, high infection rates of up to 60% can be expected. The majority of the studies reviewed were undertaken at community-level (Figure 4). Yelifari and colleagues [44] conducted one of the biggest studies in Africa, in Northern Ghana, sampling 20,250 persons across 216 villages and therefore covering different settings. The infection rate was 11.6%. They found a slightly higher statistically significant infection rate in men (12.7%) than women (10.6%). 10.1371/journal.pntd.0002288.g004 Figure 4 Prevalence of S. stercoralis infection by country based community-based studies. Studies based on health services data often focus on the number of patients reporting symptoms or suffering from conditions other than helminthiasis. If stool samples are analyzed, high sensitivity methods are only applied if the patient is suspected of having an intestinal parasitic infection, i.e. might be infected with S. stercoralis. A study from Guadeloupe [45] analyzed 17,660 hospital records from the university hospital in Pointe-à-Pitre, reporting 708 cases of S. stercoralis (4.0%). Yet in Guatemala, where 14,914 pregnant women were tested using a single stool sample and where low-sensitivity diagnostic methods were applied, the reported prevalence was as low as 0.4% [46]. This is an example for the difficulties comparing studies using different diagnostic approaches (Figure 5). 10.1371/journal.pntd.0002288.g005 Figure 5 Prevalence of S. stercoralis infection by country based on health services studies. Studies on refugees and immigrants were mostly conducted, with a few exceptions, in developed countries (Figure 6). Most found high infection rates in immigrants and refugees, reaching prevalence rates of up to 75%. Infection rates varied substantially depending on the refugees' country of origin. In Canada in 1990, Gyorkos and colleagues [40] used high sensitivity diagnostic tools and found a prevalence rate of 11.8% in Vietnamese refugees versus 76.6% in Cambodian refugees. In many countries, immigrants are routinely screened for helminthiasis if they attend a hospital. A study in Saudi Arabia by al-Madani and colleagues [47] analyzed 5,518 female housekeepers originating from different Asian countries. The overall prevalence reported was 0.6%; 0.4% in Filipinos, 0.5% in Indonesians, 1.5% in Sri Lankans, 2.6% in Indians and 3.4% in Thais, respectively. 10.1371/journal.pntd.0002288.g006 Figure 6 Prevalence of S. stercoralis in refugees and immigrants by country. Hotspots: Brazil and Thailand Brazil and Thailand are S. stercoralis endemic countries where reliable and consistent data on infection is available. For Brazil, we found 43 studies (12.1% of all studies world-wide) that qualified for inclusion. Using data from the community-based studies, our model showed a prevalence of 13.0% (95% Bayesian Confidence Interval (BCI): 12.0–14.2%). The Baermann method was used in nine (34.6%) of these studies, and the Koga Agar plate culture in just four (15.4%). Analyzing data from the 16 hospital-based studies yielded a prevalence of 17.0% (95% BCI: 15.8–18.2%). The Baermann method was used in 15 (93.8%) studies, most often in combination with other methods, yet the Koga Agar plate culture was not used in any of the hospital-based studies in Brazil. Most hospital-based studies were undertaken in the big cities of Rio de Janeiro and São Paolo. Rossi and colleagues [48] reported analyzing 37,621 laboratory specimens over a period of two years in the university hospital in the Campinas City region. The patients examined originated from all over Campinas City. The infection rate was estimated to be 10.8%. In Thailand, a quarter to a third of the study participants tested positive for S stercoralis. In all studies conducted directly in the community, the overall prevalence was 23.7% (95% BCI: 21.8–26.1%). In contrast to Brazil, the main diagnostic approach used for the Thai studies was the Koga Agar plate culture, which was used in 10 (31.3%) of the studies. In hospitals (8, 20.0%), the infection prevalence was considerably higher and reached 34.7% (95% BCI: 31.6–38.3%). Five (62.5%) of these studies were undertaken in the capital Bangkok, four of which (50.0%) focused on HIV/AIDS-infected patients. Other regional highlights and concerns For Japan, all 14 studies were undertaken on the Okinawa islands. S. stercoralis is only endemic in Okinawa prefecture and the cases reported are mostly among older persons with sustained infection due to auto-infection. This was demonstrated in a study of Arakaki and colleagues [49] which showed an overall infection rate of 16.4%; yet for individuals aged 10–39 years, the prevalence was only 5.5% whereas in individuals older than 40 years of age, the prevalence was 30.2%. Our country estimate of infection rates based on community data was 18.7% (95% BCI: 17.4–20.4%) and 13.6% (95% BCI: 12.7–14.5%) based on hospital investigations. All the studies from Japan employed a highly sensitive Koga Agar plate culture diagnostic method and often analyzed several stool samples per person. Arakaki and colleagues [50] undertook a study of six different endemic regions in Okinawa, and reported a significant difference between infection rates in males (14.0%) and females (6.8%). European studies principally focused on refugees, immigrants and travelers to endemic countries. A good example of this is found in a recent report on two Italian tourists returning from Southeast-Asia, presenting acute strongyloidiasis [51]. As an exception, in a study from Spain [52], infections were reported in farm workers in Gandia (south of Valencia, eastern Spain). The Koga Agar plate culture was used on three stool samples taken on consecutive days to diagnose a threadworm infection. Of the 250 farm workers, 12.4% were S. stercoralis positive. When adjusted for the sensitivity of the diagnostic method, our model found a prevalence of 14.8% (95% BCI: 10.3–20.3%). Another study from Gill and colleagues [53] of World War II veterans undertaken in 2004 in the United Kingdom showed that S. stercoralis infection might be sustained over a long time. Most participants had not left the UK since returning from their deployment in Southeast Asia and were evaluated some 60 years later. The study reported 248 cases from 2,072 veterans screened for S. stercoralis (12.0%); the adjusted prevalence was 12.7% (95% BCI: 11.1–14.5%). Little information is available from countries with the largest populations, namely China and India. Studies on Mainland China are scarce or could not be included due to the language limitations of this review. Our calculation from a study of communities in Yunnan province resulted in a prevalence of 14.0% (95% BCI: 9.0–20.4%). The three other studies identified were conducted on immigrants, mainly from South-East Asian countries, working in Taiwan and presented an infection prevalence of 17.1% (95% BCI: 15.2–19.2%). For India, 14 studies were identified, nine of which were conducted on hospitalized persons, and reporting an infection rate of 11.2% (95% BCI: 8.6–14.4%). Five of these reports focus on HIV/Aids patients. For the five community-level studies, an infection rate of 6.6% was reported (95% BCI: 4.4–9.4%). For other countries with large populations, such as Indonesia, Pakistan and Bangladesh, which combined account for over half a billion inhabitants, only seven studies were available (Indonesia: 6, Bangladesh: 1, Pakistan: 0). All seven studies were conducted at community-level, and infection rates of 7.6% (95% BCI: 6.2–9.3%) in Indonesia and 29·8% (95% BCI: 21.7–39.8%) in Bangladesh, respectively, suggest a considerable burden of infection in these populous countries. High risk groups for Strongyloides stercoralis infection HIV/AIDS patients Many countries with high HIV-prevalence rates are also highly S. stercoralis endemic, and co-infection may occur. S. stercoralis no longer constitutes an AIDS-defining, opportunistic infection [54] as it did during the onset of the HIV-pandemic. For 29 cross-sectional studies focusing on HIV-positive individuals, we calculated S. stercoralis prevalence rates per country. The rates varied substantially from 1.0% (95% BCI: 0.0–2.0%) in Iran to as high as 43.0% (95% BCI: 20.0–83.0%) in Ethiopia. The overall prevalence for HIV-positive individuals was 10.0% (95% BCI: 5.0–20.0%). We identified 16 case-control studies comparing HIV-positive individuals with sero-negative controls. Four reported a lower or similar prevalence in the two groups [55]–[58]. All other studies showed an increased S. stercoralis infection risk for HIV-positive individuals; three showed a statistically significant risk [59]–[61]. Our meta-analysis resulted in a pooled OR of 2.17 (95% BCI: 1.18–4.01) for HIV-positive individuals [28], [55], [56], [58]–[70] (Figure 7) compared to the HIV-negative controls. 10.1371/journal.pntd.0002288.g007 Figure 7 Risk of S. stercoralis infection in HIV/AIDS patients (meta-analysis of case-control studies). HTLV-1 patients Persons infected with human T-lymphotropic virus 1 (HTLV-1) tend to be significantly co-infected with S. stercoralis in comparison with HTLV-1-seronegative controls [71]–[74]. Our meta-analysis resulted in a pooled OR of 2.48 (95% BCI: 0.70–9.03) for the infection with HTLV-1 [75]–[78] (Figure 8), showing no statistically significant difference. In HTLV-1 infected patients, eradication of the parasite by conventional drug therapy is hindered [79]. S. stercoralis hyperinfection syndrome, including its fatal outcome, is particularly common in these patients [80]. S. stercoralis co-infection appears to shorten the latency period until the onset of adult T-cell leukaemia in HTLV-1 positive subjects [81]. 10.1371/journal.pntd.0002288.g008 Figure 8 Risk of S. stercoralis infection in patients with HTLV-1 infection (meta-analysis of case-control studies). Alcoholics Four studies (three case-control studies, and one cross-sectional study) focused on patients with an alcohol addiction. The case-control studies, all from Brazil, showed higher infection rates in alcoholics than in the control groups [82]–[84]. The meta-analysis resulted in a pooled OR of 6.69 (95% BCI: 1.47–33.8, Figure 9). The study by Zago-Gomes and colleagues [83] showed that only S. stercoralis infection rates differed between alcoholics and control groups. Contrastingly, other nematodes showed the same prevalence in alcoholics and control groups. Zago-Gomes and colleagues argue that alcoholics' regular ethanol intake might lead to an immune modulation and/or alteration in corticosteroid metabolism, favoring S. stercoralis infection. 10.1371/journal.pntd.0002288.g009 Figure 9 Risk of S. stercoralis infection in alcoholics (meta-analysis of case-control studies). Patients with diarrhea Studies undertaken in patients with diarrhea showed a wide range of infection prevalences. The lowest infection rate was 1.0% (95% CI: 0.0–3.0%) found in a tertiary care hospital in Andhra Pradesh in India [85], while the highest reported was 76.0% (95% CI: 39.0–99.0%) in a study on Cambodian children in a refugee camp at the Thai-Cambodian border [86]. Comparing case-control studies lead to a pooled OR of 1.82 (95% BCI 0.19–12.2), showing no statistically significant difference [87]–[90]. Case-control studies on patients with and without diarrhea are relatively scarce, especially studies reporting on S. stercoralis, of which we could only identify four. Because diarrhea is one of the symptoms associated with S. stercoralis infection, as well as with other STH-infections, it remains unclear whether diarrhea can be considered as a risk factor, or if infection with STHs leads to a higher prevalence of diarrhea (Figure 10). 10.1371/journal.pntd.0002288.g010 Figure 10 Risk of S. stercoralis infection in patients with diarrhea (meta-analysis of case-control studies). Patients with malignancies and/or immuno-compromising conditions Case-control studies often focus on the infestation rates among patients with haematologic neoplastic diseases and/or immuno-suppressing conditions, arising, for instance, as a consequence of treatment. Two studies from Egypt show that S. stercoralis is found more often in patients with malignant diseases undergoing immuno-suppressive treatment [91], [92]. In Japan, Hirata and colleagues [93] found the parasite more often in patients diagnosed with biliary tract or pancreatic cancer. The infection rate was 7.5% among the 1,458 controls, 18.4% in the biliary tract cancer group, and 15.4% in the pancreatic cancer group. The liver cancer group reported the same infection rate (7.5%) of strongyloidiasis as the control group. One case-control study from Brazil found S. stercoralis to be more prevalent in immuno-compromised children in comparison with an immuno-competent control population by using serological techniques only. Four different serological approaches were used, each reporting higher infection rates in immuno-compromised children (e.g. ELISA-IgG: 12.1% versus 1.5%) than in the control group. No differences could be demonstrated (2.4% versus 4.4%) when based on parasitological examinations of stool samples, using the Baermann method, for three consecutive days [94]. The malignancies and immuno-comprising conditions reported in the literature are manifold, leading to a very heterogeneous set of data. This makes meta-analysis virtually impossible. Children Of the 354 studies, 84 (23.7%) were conducted specifically on children, adolescents and young adults (aged 0–20 years). One third of them 29 (34.5%) were conducted in Africa, followed by 22 (26.2%) in the Americas and 19 (22.6%) in South-East Asia. The Western Pacific region (9), Middle East (4) and Europe (1) make up the remaining 14 (16.7%) studies. Almost all of these studies are cross-sectional and focus on children only. Seven studies compared children with adults, but their comparison is challenged by very heterogeneous age grouping and matching. Two studies were conducted in Indonesia; Mangali and colleagues [95] reported a prevalence of 4.4% in the group aged 2–14 years, and 6.7% in all participants aged 15 or older. The study by Toma and colleagues [96] reported similar trends with a prevalence of 0% in the group aged 4–14 years and 1.2% in all participants aged 15 years or older. The study by Dancesco and colleagues [97] in Côte d'Ivoire presented a prevalence of 12.2% in children aged 4–15 years, and 17.7% in adults, also underlining the trend of children having lower prevalence rates than adults. In contrast, the study by Gaburri and colleagues [84] showed a prevalence of 1.9% in adults, and 13.2% in children. The Gaburri study, however, focused on hepatic cirrhosis patients, and the prevalence rates are derived from only partially matched control groups. In Nepal, the study by Navitsky and colleagues [98] found a prevalence of 2.0% in 292 pregnant women (aged 15–40 years) and 0% in 129 infants (aged 10–20 weeks). The study by Wongjindanon and colleagues [99] found a prevalence of 9.7% in adult volunteers in Surin (rural), Thailand, while the prevalence in schoolchildren from Samut Sakhon (suburban) was 2.0%. Due to the heterogeneity of the reported data, meta-analysis was not performed. Diagnostic test sensitivity estimation Estimations of the three diagnostic test sensitivity groups (low, moderate and high) are presented in the Appendix (Table A1–A3). Medians and 95% credible intervals are shown under two different prior specifications and divided according to the study type. Estimates were robust to the prior specification, however they varied among the different study types. Hospital-based surveys led to higher sensitivity estimates than the community-based ones. Sensitivity estimates in the low sensitivity group range from 0.15 to 0.18 in the community-based surveys and from 0.17 to 0.21 in the hospital-based surveys. Sensitivity in the moderate sensitivity group is estimated between 0.77 and 0.90 in the community-based surveys. Higher uncertainty is observed in the estimation of the same diagnostic tools in hospital-based surveys, probably due to a smaller sample sizes. Sensitivity estimates in serological tests vary between 0.88 and 0.98 in community-based studies whereas they are more precise in the hospital-based surveys (0.94–0.98). The meta-analysis included limited number of surveys on immigrants and therefore the corresponding sensitivity estimates can not be compared to those from community- or hospital-based surveys. Discussion Prevalence rates of S. stercoralis World-wide prevalence rates of S. stercoralis have been estimated on several occasions. Values vary from three million to one-hundred million infected individuals [2], [21], [100]–[102]. In 1989, after having examined the epidemiological evidence, Genta [2] called these estimates “little more than inspired guesses” and cast doubts on the “practical value” of those numbers. In fact, knowledge on country and regional S. stercoralis infection rates and risks in specific population groups is of increasing clinical and epidemiological importance. Infected individuals are at risk of developing complicated strongyloidiasis as soon as cell-mediated immunity is compromised. The widespread and increasing use of corticosteroids for immuno-suppressive treatment, especially in S. stercoralis endemic areas, exacerbates the risk for severe complications associated with this infection. Our findings provide an overview of the global prevalence of S. stercoralis, drawn from published infection reports since 1989. For the first time, we report prevalence rates on a country-by-country basis, based on published infection rates and taking into account the sensitivity of the diagnostic methods used. In Africa, the range of infection rates in the communities varies from 0.1% in the Central African Republic to up to 91.8% in Gabon. In South- and Central-America, Haiti reports a prevalence of 1.0%, while in Peru the infection rate is as high as 75.3%. Interestingly, in South-East Asia, another highly endemic part of the world, several countries report infection rates within a comparably small range. In Cambodia, the infection rate is 17.5%, Thailand 23.7% and Lao PDR 26.2%. Only Vietnam, with a prevalence of 0.02% - based on only one study - falls out of this picture. In general, information on infection rates/prevalence of the parasite is scarce, and the studies we analyzed suggest that infection with S. stercoralis is highly underreported, especially in Sub-Saharan Africa and Southeast Asia. The main reason is that almost no studies focusing on S. stercoralis were conducted. Therefore, studies reporting S. stercoralis prevalence most often used low-sensitivity diagnostic methods for S. stercoralis and only samples from one day were analyzed. Furthermore, information about at-risk groups and affected populations is missing, as few studies focus on strongyloidiasis and possible at-risk groups. S. stercoralis has a very low prevalence in societies where fecal contamination of soil is rare. Hence, it is a very rare infection in developed countries and is less prevalent in urban than in rural areas of resource poor countries, with the exception of slum areas in the bigger cities. In Europe and in the United States the infection occurs in pockets and predominantly affects individuals pursuing farming activities or miners. In Germany, S. stercoralis is recognized as a parasitic professional disease in miners [103]. Moreover, in developed countries, strongyloidiasis remains an issue for immigrants [33], [104], tourists [51] and military [53] returning from deployment in endemic areas. This fact has implications for medical services in developed countries, and may call for systematic screening after visits to endemic countries and before initiation of immuno-suppressive treatment. While information on S. stercoralis infection rate is patchy, information on incidence is virtually non-existent. None of the identified studies offered evidence on first or new infections. Incidence rates would give insight into how often and how quickly people are re-infected after successful treatment. Further, it could establish how often first-time infections are sustained over a longer period. We showed that prevalence rates in children are often lower than in adults, yet the incidence might be a lot higher if in fact many adult patients acquired the infection during childhood. In addition, risk for infection might be different in children than in adults. Longitudinal studies, particularly at community level, are required to address this knowledge gap. Comparing the infection rates from hospitalized patients and infection rates in the communities in the same countries often shows great differences. Venezuela and Zambia are good examples, reporting infection rates of 48.4% and 50.6% in hospitalized persons, respectively; yet in the communities the reported infection rates are as low as 2.3% and 6.6%, respectively. One reason for this discrepancy comes from the use of low-sensitivity methods in community-based studies versus use of moderate- and high-sensitivity methods in the hospitals. Furthermore, hospitalized persons are more likely to belong to an at-risk group or have underlying risk factors for infection with S. stercoralis. Additionally, in the hospitals, patients are sampled for more than one day. Another factor is the small number of studies contributing to the calculation of the infection rates. For countries with many studies available (most notably Brazil and Thailand), the differences between the infection rates in communities and in hospitals are considerably smaller (Brazil 13.0% vs. 17.0% and Thailand 23.7% vs. 34.7%). These findings imply that countries with few community-level studies that report high infection rates in the hospitals are likely to be highly endemic. Examples might include DR Congo and Madagascar, both of which lack studies undertaken at community-level yet report infection rates of 32.7% and 52.2% in hospitalized persons, respectively. Here, cross-sectional studies at community level that apply high-sensitivity diagnostic methods and that preferably investigate several stool samples per person over consecutive days are desperately needed to identify possible hotspots of S. stercoralis transmission and to quantify the infection rates and risks. With our approach, we can for the first time report country-wide infection rates. Yet, sometimes a large part of the studies were conducted in a comparatively small area in a specific country. This presents a limitation to our analysis, as do countries with only one or a few studies from a specific location, as it is not possible to make a general statement about prevalence that encompasses all parts of the country. It is very likely that the studies were conducted in areas where S. stercoralis infection was already suspected. This is especially true for bigger countries that often have a wide variety of ecological and economic environments, different standards of sanitation, and big differences between rural and urban environments. A major challenge of giving an overview of prevalence data for S. stercoralis world-wide lies in the low comparability of the studies reporting infection rates. Most studies that we identified did not focus on S. stercoralis specifically, but on other STHs. Therefore, S. stercoralis is mostly reported as an additional outcome and the diagnostic methods used possess only a low sensitivity for S. stercoralis. Direct smears and the Kato-Katz method were most commonly used, both of which show a very low sensitivity for the diagnosis of S. stercoralis [5], [6], [23]. The more sensitive and Strongyloides specific methods, such as the Baermann method and Koga Agar plate culture are more cumbersome and/or time- and resource intensive [7]. In our model for estimating country-wide infection rates, we addressed this limitation by taking into account the sensitivity of the diagnostic methods used, summarized as a range derived from the literature. To further increase diagnostic sensitivity, more than one stool sample should be examined from the same individual over consecutive days [105]–[108]. This is also true for superior methods like Baermann or Koga Agar plate culture [109], [110]. This is necessary because of the irregular excretion pattern of S. stercoralis larvae. Especially for low-intensity infections, there is a big risk that a one-day examination will miss the infection altogether. However, in most studies, only one stool sample was examined. Therefore, the reported infection rates are very likely underestimations. The challenges outlined above lead to a very heterogeneous set of prevalence data. Today, many countries (including some of the most populous ones) with ecologically and socio-economic conditions favorable to S. stercoralis transmission are lacking prevalence data entirely. More data is required for almost all countries and for various socio-economic/cultural settings. Further large-scale surveys that sample the general population, and use highly sensitive methods over three consecutive days would help to narrow this gap. Finally, as comprehensive as the collection of information on global S. stercoralis infection rates was, important information might have been missed due to language restrictions and the choice of databases searched. Risk groups for S. stercoralis infection Several possible risk factors for S. stercoralis infection are reported in the literature. However, studies that focus specifically on risk groups are very rare. We conducted a meta-analysis of case-control studies that provided information on risk and control groups. Most studies were related to HIV/AIDS infection. Our analysis showed an S. stercoralis infection risk for HIV/AIDS patients that was twice as high as the risk for individuals without HIV/AIDS (OR: 2.17, 95% BCI: 1.18–4.01). Most studies used the same diagnostic methods for cases and controls, yet the study of Feitosa and colleagues [59] used additional high sensitivity methods in the HIV-positive group. Another significant highly increased risk for S. stercoralis infection was alcoholism (OR: 6.69, 95% BCI: 1.47–33.8). The well-established risk factors HTLV-1 infection as well as diarrhea both showed an increased risk, but without statistical significance (OR: 2.48, 95% BCI: 0.70–9.03 and OR: 1.82, 95% BCI: 0.19–12.2, respectively). Cases for which strongyloidiasis would cause severe complications in HIV-infected persons are rare. As Keiser & Nutman [11] pointed out, less than 30 cases of hyperinfection in HIV-infected individuals have been reported in the literature thus far. The modulation of the immune system by the HIV appears to be the main reason for this. The increase of TH2 cytokines and the decrease of TH1 cytokines [111]–[113] leads to a pattern that may favor bacterial and viral opportunistic infections rather than helminthic infections [9]. Further, it has been proposed that indirect larval development is promoted in patients that are immuno-compromised by advancing AIDS and therefore, the possibility of increased auto-infection is reduced [114]. All case-control studies included in the meta-analysis for HTLV-1 [75]–[78] showed an increased risk for S. stercoralis co-infection for individuals with an HTLV-1 infection. The result of the meta-analysis however showed no statistically significant risk increase in HTLV-1 infected individuals. As there were only four studies that could be included in the meta-analysis, which is a possible limitation, further case-control studies would be needed to come to a unifying conclusion. Alcohol-addiction is another potential risk factor for S. stercoralis infection. Studies undertaken in Brazil [82], [83], [115] showed evidence of this. It is argued that the regular ethanol intake modulates immune response, making survival and reproduction of the larvae in the duodenum easier. Consequently, there is a higher frequency of larvae present in the stools of alcoholic patients, yet an increased infection rate is not necessarily observed. For patients with malignancies and/or immuno-compromising conditions, case-control studies are also scarce. De Paula and colleagues [94] showed a higher prevalence of S. stercoralis in immuno-compromised children compared to immuno-competent children, although these differences could only be shown with serological diagnostic methods. Using coprological methods, there was no difference in prevalence found between the two groups. This might be because serological diagnostic methods are known to cross-react with other helminth infections or because of the higher sensitivity. Three other case control studies showed a higher prevalence in patients with malignant diseases or undergoing immuno-supressive treatment [91]–[93]. Age-related findings suggest that children are not generally at a higher risk for S. stercoralis infection. However, behavioral factors might increase the risk of infection, and many of the infected adults might have picked up an infection during childhood and sustained it through auto-infection. The infection rates in children lower than or equal to those in adults suggests that due to the persistence of S. stercoralis, infections are accumulated over time. Longitudinal studies are needed to get more insight into the incidence and possible accumulation, following the same individuals over longer time periods. Discerning the risk factors or possible risk factors for S. stercoralis infection is hindered by the small amount of research on S. stercoralis in general. Therefore, for most risk factors, only a few case-control studies exist, making it difficult to present clear statements. However, these studies can point to trends and lead the way for further and more detailed research. Diagnostic test sensitivity Diagnostic tests with low or moderate sensitivity underestimate disease prevalence. The inclusion of the diagnostic test sensitivity in the models allowed us to properly evaluate prevalence and OR for the risk factors under study. The sensitivity adjusted OR for each risk factor have larger uncertainty (wider BCI) most likely due to the added variability of the detection. Furthermore, the intensity of infection influences the sensitivity estimates [5]. Higher sensitivity estimates in hospital based surveys may reflect high intensity probably due to co-infection. Test-specific diagnostic sensitivity could not be obtained because of the variety of tests employed in the studies reviewed and relatively small sample size for each test. What should be done next? We showed that in many countries, prevalence of S. stercoralis infection is high. The results are based on studies that often do not focus on S. stercoralis specifically, but on other STHs. Therefore, the results are mostly based on low-sensitivity diagnostic methods and likely underestimate prevalence. It is necessary to conduct further studies using high sensitivity diagnostic methods, coprologically the Koga Agar plate culture or the Baermann or the ELISA in serology, to achieve a more comprehensive and detailed picture of the global prevalence of S. stercoralis. Especially in countries with favorable conditions for S. stercoralis transmission, studies conducted on STHs should not neglect to include S. stercoralis. This would help to establish more detailed data on regional and country-wide prevalence rates. The results obtained in these studies and of our analysis show many countries with a high estimation of the prevalence rate of S. stercoralis. In many of these countries the current policy guidelines neglect or are unclear about how to address S. stercoralis. We conclude that S. stercoralis is of high importance in global helminth control and should therefore not be neglected. Supporting Information Checklist S1 PRISMA Checklist. (DOCX) Click here for additional data file. Diagram S1 PRISMA Flow diagram. (DOCX) Click here for additional data file. References S1 Web-based reference list. (DOC) Click here for additional data file. Text S1 Appendix: Estimation of country-specific prevalence and estimation of prevalence in specific risk groups. (DOC) Click here for additional data file.
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Model-based geostatistics
P J Diggle, J. Tawn, R. A. Moyeed (1998)
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Hookworm-Related Anaemia among Pregnant Women: A Systematic Review
Simon J. Brooker, Peter Hotez, Donald Bundy (2008)
Introduction Anaemia is a major factor in women's health, especially reproductive health in developing countries. Severe anaemia during pregnancy is an important contributor to maternal mortality [1], as well as to the low birth weight which is in turn an important risk factor for infant mortality [2]–[3]. Even moderate anaemia makes women less able to work and care for their children [4]. The causes of anaemia are multi-factorial, including diet, infection and genetics, and for some of the commonest causes of anaemia there is good evidence of the effectiveness of simple interventions: for example, iron supplementation [5], long-lasting insecticide nets and intermittent preventive treatment for malaria [6]–[7]. Hookworm infection has long been recognized among the major causes of anaemia in poor communities [8], but understanding of the benefits of the management of hookworm infection in pregnancy has lagged behind the other major causes of maternal anaemia. An epidemiological study in 1995 highlighted the paradox presented to public health workers that an estimated one-third of all pregnant women in developing countries were infected with hookworm and yet, in the absence of safety data, the appropriate advice then current was to avoid the use of anthelmintics in pregnancy [9]. Furthermore, the lack of an acceptable intervention constrained the development of evidence-based understanding of the impact of hookworm infection on maternal anaemia [10]. These issues were addressed directly by de Silva and colleagues [11], who analysed the safety profile of some 20 years of mebendazole use in antenatal clinics in Sri Lanka. In 2002, WHO published new guidance indicating that pregnant women should be treated for hookworm infection, ideally after the first trimester [12]. This immediately provided the opportunity for improved service delivery, and also encouraged studies to assess the contribution of hookworm to anaemia in pregnancy and the impact of treatment, some of which have been undertaken since 2002. These provide a rich new source of data to help inform public health decision making, and in this paper we present a systematic review of hookworm as a risk factor for anaemia among pregnant women. We also estimate the extent of the problem of hookworm among pregnant women living in sub-Saharan Africa, where hookworm remains an intractable reproductive health problem. Methods Data sources and search strategy A systematic search of published articles was undertaken in July 2007 and repeated again in October 2007. The online databases MEDLINE (1970–2007) and EMBASE (1980–2007) were used to identify relevant studies, using the Medical Subject Headings (MSHs) pregnancy or pregnant AND hookworm, Necator americanus, Ancylostoma duodenale, intestinal parasites, geohelminths or soil-transmitted helminths AND an(a)emia, h(a)emoglobin or h(a)ematocrit. All permutations of MSHs were entered and each search was conducted twice to ensure accuracy. The search did not exclude non-English language papers. The abstracts of returned articles were then reviewed, and if they did not explicitly investigate the association between hookworm and anaemia, they were discarded. Potentially useful articles were retrieved. We also reviewed reference lists of identified articles and hand searched reviews. Where suitable papers did not provide information in a relevant format, authors were emailed and requested to provide relevant summaries of data. SB undertook the literature search and scanned the results for potentially relevant studies, retrieved the full article, and contacted authors. SB and PJH independently assessed every relevant paper, with no disagreements arising, and SB used a pre-formed database to abstract information. We followed the reporting checklist of the Meta-analysis of observational studies in epidemiology (MOOSE) group [13]. The primary outcome analysis was haemoglobin concentration (Hb), and our hypothesis was that haemoglobin concentration is associated with the intensity of hookworm infection. Data without quantitative measures of Hb and hookworm infection intensity were excluded. No distinction could be made between the two different hookworm species, Necator americanus and Ancylostoma duodenale, because none of the studies used specific methods to differentiate the species, and routine coprology is unable to do this. Studies had to be based on at least 30 individuals. No scoring of quality of studies was undertaken. However, a description of statistical methods employed, including whether adjustment for potentially confounding variables, is provided. For randomised controlled trials, information is provided on key components of study design as recommended by the CONSORT statement [14]. Data analysis Data were stratified according to the intensity of infection, based on thresholds recommended by WHO: light (1–1,999 epg); moderate (2,000–3,999 epg); and heavy (4000+ epg). Estimates of Hb were assessed for each intensity category and differences between categories were presented as a standardized mean difference (SMD) and 95% confidence interval. These were calculated with a random-effects model according to the DerSimonian and Laird method [15]. Heterogeneity was assessed by the I2 test with values greater than 50% representing significant heterogeneity. When heterogeneity between studies was found to be significant, pooled estimates were based on random-effect models and the Hedges method of pooling. Results were displayed visually in forest plots. Bias was investigated by construction of funnel plots and by the statistical tests developed by Begg & Mazumdar [16] and Egger et al. [17]. Analysis was performed using the ‘metan’ and related functions in STATA version 10 (College Station, TX). Estimating population at-risk of hookworm-related anaemia We attempted to estimate the number of pregnant women infected with hookworm in hookworm-endemic countries in sub-Saharan Africa. To estimate the number of pregnant women, we used population data from the Gridded Population of the World (GPW) version 3.0 β [18]. GPW3.0β is a global human population distribution map derived from areal weighting of census data from 364,111 administrative units to a 2.5′×2.5′ spatial resolution grid. Country-specific medium variant population growth rates and proportions of the female population aged 15–49 years available from the United Nations Population Division – World Population Prospects [UNPD-WPP] database [19] were used to project this age cohort of the population total to 2005 using ArcView (Environmental Systems Research Institute Inc., CA, USA). The number of pregnant women was estimated separately for each country from the crude birth rate (number of births over a given period divided by the person-years lived by the population over that period); this will be an under-estimate as it does not include women experiencing miscarriages and stillbirths, which are not routinely reported. Hookworm prevalence was defined on the basis of an existing model which uses satellite-derived climatic factors to predict the geographical distribution and prevalence of hookworm among school-aged children [20]. In the absence of relevant empirical data, we assume that infection prevalence is equivalent in school-aged populations and pregnant women; this is probably an under-estimate since hookworm prevalence is generally higher in adult populations [21]. We also assume that no large-scale hookworm control has been undertaken. Extractions of population at risk by prevalence of hookworm were then conducted in ArcView 3.2. Results Our literature searches identified 105 citations and from this list 30 potentially relevant research studies were identified; the remaining citations were either research studies among non-pregnant women, reviews or editorials. Of these 30 potentially relevant studies, 19 were determined to be eligible, including 13 cross-sectional studies, 2 randomised controlled trials, 2 non-randomised treatment trials and 2 observational studies. Association between hookworm infection and haemoglobin 13 studies presented observational data on the relationship between hookworm infection and haemoglobin concentration: eight from Africa, three from Asia and two from Latin America. The characteristics of the cross-sectional studies included are presented in Table 1. The data were stratified according to the intensity of infection. In four of the studies, none of the woman included had an intensity of infection that exceeded 2,000 epg; in eight studies women had an infection intensity that exceeded 4,000 epg. Comparing uninfected women and women lightly (1–1,999 epg) infected with hookworm, the standardized mean difference (SMD) in Hb was −0.72 (95% CI: −1.26 to −0.18) (n = 13), indicating that even women lightly infected with hookworm have lower Hb levels than uninfected women. However, there was variation in the differences observed and examination of forest plots suggested heterogeneity of effect, which was statistically significant (I2 score of 72.9%). This was explained by inclusion of the study by Rodríguez-Morales et al. [22] which collated data from nine states across Venezuela. Omitting this study from the analysis, the SMD between women uninfected and lightly infected was −0.24 (95% CI: −0.36 to −0.13) (Figure 1). Omission of other studies made little or no difference to the overall effect. There was slight evidence of bias using the Egger test (p = 0.008) and the Begg test (p = 0.07): the relatively small study by Ayoya et al. [23] in Mali showed evidence of effects that differed from the larger studies. Heavy hookworm infection was also significantly associated with a lower Hb level compared to light infection: the standardized mean difference in Hb was −0.57 (95% CI: −0.87 to −0.26) (n = 7) (Figure 2). No evidence of bias was observed. 10.1371/journal.pntd.0000291.g001 Figure 1 Forest plot of the difference in haemoglobin (Hb) concentration among pregnant women uninfected with hookworm and women harbouring a light (1–1,999 eggs/gram) hookworm infection. Standardised mean difference less than zero indicate lower Hb levels in lightly infected women compared to uninfected women. The diamond represents the overall pooled estimates of the effect of light hookworm infection on Hb. 10.1371/journal.pntd.0000291.g002 Figure 2 Forest plot of the difference in haemoglobin (Hb) concentration among pregnant women women harbouring a light (1–1,999 eggs/gram) hookworm infection and women harbouring a heavy (4,000+ eggs/gram) infection. Standardised mean difference less than zero indicate lower Hb levels in heavily infected women compared to lightly infected women. The diamond represents the overall pooled estimates of the effect of heavy hookworm infection on Hb. 10.1371/journal.pntd.0000291.t001 Table 1 The impact of hookworm infection on haemoglobin concentration in pregnant women. Setting Participants and year of study Prevalence of parasites (%)a Prevalence of anaemia (threshold used) Statistical methods and potential confounders adjusted fora Study Liberia 128 women attending antenatal clinic aged 14–43 y, 88% in 1st or 2nd trimester, 1985 Hw = 30.0 78% ( g/L, gestational age g/L, gestational age <18–26 weeks at baseline, and not received treatment for 6 months 500 mg MBZ 60 mg ferrous sulphate daily for 1 month No difference in maternal anaemia or mean birthweight between groups; however, lower prevalence of very low birthweight babies in MBZ group Non-randomised intervention trials [27] Cote d'Ivoire Hw = 50 Al = 78% NAc Non-randomised drug trial Women aged 15–38 y attending antenatal clinic 500 mg Pyrantel pamoate daily for three days Decrease in severe anaemia and 6-month infant mortality; increase in birthweight [28] Sri Lanka Hw = 41.4 65.4% Non-randomised intervention trial of iron supplementation and anthelmintics (n = 115) Randomly selected pregnant plantation workers Unspecified (probably MBZ) 60 mg ferrous sulphate and 0.25 mf folic acid daily for 1–2 months Anthelmintic treatment in addition to iron supplementation improved Hb more than iron supplementation alone Observational studies [29] Nepal Hw = 74% Al = 59% Tt = 5% NA Non-randomised community-based study investigating receipt of ABZ and health (No doses = 58; One dose = 543; Two doses = 2726) Pregnant women previously enrolled in a cluster-randomised trial followed up 6 months post-delivery. 400 mg ABZ Decrease in severe anaemia and 6-month infant mortality; increase in birthweight [30] India NA 68.7% Pre-post (18 months) community based evaluation (n = 828) of deworming and iron-folate supplementation. Randomly selected pregnant women from two areas (one intervention; one control). 100 mg MBZ twice daily for three days plus 60 mg ferrous sulphate from fourth month of pregnancy Improvement in Hb (6.4–8.4 g/L according to trimester) Adapted and expanded from [60]. a Hw = hookworm; Al = Ascaris lumbricoides; Tt = Trichuris trichiura; b Defined as Hb<110 g/L; c Not available. The two non-randomised intervention trials presented data on the impact of anthelmintic treatment on Hb. A study in Cote d'Ivoire included 32 pregnant women treated with pyrantel pamoate and showed that the prevalence of hookworm decreased by 93% and Hb increased by 6 g/L over the course of the pregnancy [27]. A study in Sri Lanka also showed that treatment increased Hb in pregnant women, and found that providing both mebendazole and iron supplementation had a greater impact on Hb than iron supplementation alone [28]. The observational study in Nepal compared women who had received anthelmintic treatment to those who did not, and found that treatment had significant beneficial effects on severe anaemia, birthweight and infant mortality [29]. The other observational study on pregnant women, in India, also found that co-administration of mebendazole and iron supplementation resulted in improved Hb [30]. Burden of hookworm in pregnant women in sub-Saharan Africa (SSA) Using GPW3.0β population estimates and country-specific age-sex structures, we estimate that in 2005 there were 148 million women of reproductive age (15–49 years) in hookworm endemic countries in SSA. Overlaying this surface with our model of hookworm prevalence we estimate that 37.7 million women of reproductive age are infected with hookworm. On the basis of number of live births occurring in SSA, we estimated that the number of pregnant women in SSA in 2005 was 25.9 million of which approximately 6.9 million were infected with hookworm. Discussion That human hookworm infection results in intestinal blood loss which, in turn, can contribute to anaemia is well-established [8]. What has remained unclear and hindered public health policy and planning is the extent to which hookworm is associated with anaemia during pregnancy. The results of our systematic review quantify this relationship and confirm that heavy intensities of hookworm infection are associated with lower levels of haemoglobin than light infection intensities. This finding corroborates previous studies among school-aged children that show a relationship between infection intensity and haemoglobin [31]–[33]. Over forty years ago, Roche & Layrisse [31] in their seminal study on hookworm anaemia identified four conditions necessary to show an association between hookworm infection and Hb: a large sample size; quantitative measures of haemoglobin and hookworm infection; sufficient variation in infection levels; and few other competing causes of anaemia. These conditions are also relevant to interpreting the current results: in particular, the absence of estimates of hookworm intensity resulted in the exclusion of studies, some of which, reported no association between hookworm infection and the risk of anaemia [34]–[36]; while others reported a significant association [37]–[38]. Anaemia in developing countries has multiple causes, including micro-nutrient deficiencies, infectious diseases and inherited disorders [39], and as such, the observed relationship between Hb and hookworm infection may be confounded by other causes of anaemia. Furthermore, residual confounding may exist among studies which did not adjust for socio-economic status, which may lead to an overestimation of association. However, nine of the 13 studies undertook some form of analysis which adjusted for potential confounding variables, including dietary intake, gestation age, and co-infections (Table 1), thereby adding weight to the observed associations; only four studies adjusted for socio-economic status. The contribution of hookworm infection to maternal anaemia is such that all women of child-bearing age could benefit from periodic treatment in hookworm endemic areas, and that women harbouring the heaviest infections are likely to benefit most. Previously, a systematic review of randomised controlled trials investigating the impact of anthelmintic treatment on haemoglobin among school-aged children concluded that treatment against intestinal nematode infections resulted in an increase in haemoglobin of 1.71 g/L (95% confidence intervals 0.70–2.73) [40]. However, there were a number of important omissions in the study, including the failure to distinguished between different helminth species or account for intensity of infection, which may have under-estimated the true treatment effect [41]. The treatment studies among pregnant women reported here found that albendazole was effective in reducing the decline in haemoglobin that typically occurs during pregnancy [25], but that the effect was less apparent with mebendazole [24]. This may reflect the lower efficacy of mebendazole versus albendazole in treating hookworm infection [42],[43]. However, there is a trade-off between efficacy and safety since mebendazole is poorly absorbed from the gut whereas albendazole is turned into a sulfoxide metabolite that gets widely distributed in the tissues. In addition to drugs used, there are other potential reasons accounting for the difference in the observed impact of anthelmintic treatment on haemoglobin. These include higher intensities of hookworm among women in Peru than among the women in the Sierra Leone study. In addition, different underlying aetiologies of anaemia may be relevant, such differences in iron deficiency anaemia and malaria and schistosome transmission intensity [39]. Finally, although we did not quantitatively assess the quality of the studies, reporting of the RCT in Sierra Leone was incomplete and it is possible that there were methodological differences that were associated with observed treatment effects [14]. Despite the potential benefits of anthelmintic treatment during pregnancy, few countries have included deworming in their routine antenatal care (ANC) programmes, with only Madagascar, Nepal and Sri Lanka doing so routinely. It is suggested that a fear of adverse birth outcomes as well as a lack of safety data, especially country-specific data, represents a barrier for many ministries of health including anthelmintics into their ANC programmes. The evidence from the RCTs included in this review found no evidence of an increased risk of adverse events following treatement. This is consistent with other observational studies which have investigated the safety of mebendazole in pregnant women (for a recent review of studies, see [26]). We feel that the findings of the present paper make clear that hookworm in pregnancy is prevalent and important, and we strongly encourage that a substantial review of the safety evidence is undertaken, perhaps by WHO and its partners. The finding that co-administration of deworming and iron supplements has a greater impact on haemoglobin than deworming alone supports the assertion that deworming is unlikely to replenish iron stores in the short term, and needs to be combined with iron supplementation, particularly among populations whose diets is low in bioavailable iron [10]. In addition, a review of the impact of malaria-related anaemia among pregnant women in sub-Saharan Africa suggested that over a quarter of cases of severe anaemia were attributable to malaria [44], while other evidence shows that anaemia burden can be reduced effectively by anti-malarial intermittent preventive treatment (IPT) [7]. An effective package to improve maternal anaemia should therefore ideally include IPT, iron supplementation and anthelmintic treatment. Interestingly, a recent case control study of the causation of severe anaemia in young children in Malawi also concludes that hookworm has tended to be overlooked as a causal factor [45]. The value of combining deworming with micronutrient supplementation for children has previously been emphasized [46]. We found only slight evidence of publication bias, and this is likely to be less important than the numerous other factors that may introduce heterogeneity [17], such as transmission of malaria and schistosomiasis, iron and nutritional intake, diagnostic accuracy in quantifying Hb and hookworm intensity. Furthermore, hookworm species may be important but in the reported studies, no distinction was made between N. americanus and A. duodenale because of the practical difficulties of differential diagnosis. Pathological studies indicate that A. duodenale causes greater blood loss than N. americanus [47], with epidemiological studies among Zanzibari schoolchildren suggesting that A. duodenale is associated with an increased risk of anaemia [48]. Thus, where hookworm is exclusively A.duodenale, such as in Nepal [49], the observed effect on maternal anaemia might be greater. In 1995, Bundy and colleagues estimated that in low income countries, 44 million (35.5%) out of 124 million pregnant women were infected with hookworm [9]. Here we estimate that 6.9 million (26.7%) out of 25.9 million pregnant women in SSA are infected with hookworm. Our current estimates are more precise since they are the first to explicitly include the fine spatial variation in distribution of both infection and population. They suggest that the earlier methodology may have overestimated the proportion of pregnant women infected. On the other hand, the reliance on infection prevalence data from surveys of schoolchildren, in the absence of data from adult women, means that both estimation procedures are likely to result in under-estimates. Nonetheless, the estimates suggest that between a quarter and a third of pregnant women in sub-Saharan Africa are infected with hookworm and therefore at risk of preventable hookworm-related anaemia. In conclusion, this systematic review presents evidence that increasing hookworm infection intensity is associated with lower haemoglobin levels in pregnant women in poor countries. The chronic and recurring nature of hookworm infection throughout the reproductive years means that it may have a chronic impact on the iron status of infected women, potentially contributing to their morbidity and mortality and that of their children. In many developing countries it is policy that pregnant women receive anthelmintic treatment but in practice coverage rates are often unacceptably low. We suggest that efforts are made to increase the coverage of anthelmintic treatment and iron supplementation, with, where appropriate, intermittent preventive treatment for malaria.
Author and article information
Contributors
Armelle Forrer: armelle.forrer@swisstph.ch
Virak Khieu: virak.khieu@gmail.com
Fabian Schär: f.schaer@nhm.ac.uk
Penelope Vounatsou: Penelope.vounatsou@swisstph.ch
Frédérique Chammartin: f.chammartin@unibas.ch
Hanspeter Marti: hanspeter.marti@swisstph.ch
Sinuon Muth: sinuonm@gmail.com
Peter Odermatt: peter.odermatt@swisstph.ch
Journal
Journal ID (nlm-ta): Parasit Vectors
Journal ID (iso-abbrev): Parasit Vectors
Title:
Parasites & Vectors
Publisher:
BioMed Central
(London
)
ISSN
(Electronic):
1756-3305
Publication date
(Electronic):
12
January
2018
Publication date PMC-release: 12
January
2018
Publication date Collection: 2018
Volume: 11
Electronic Location Identifier: 33
Affiliations
Article
Publisher ID: 2604DOI: 10.1186/s13071-017-2604-8
PMC ID: 5767026
PubMed ID: 29329561
SO-VID: e30a72c8-2b98-43b8-8b21-54e12c9f1dd2
Copyright © © The Author(s) 2018
License:
Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
History
Date
received
: 6
June
2017
Date
accepted
: 25
December
2017
Funding
Funded by: UBS Optimus Foundation (CH)
Categories
Subject:
Research
Custom metadata
issue-copyright-statement © The Author(s) 2018
ScienceOpen disciplines: Parasitology
Data availability:
ScienceOpen disciplines: Parasitology
Keywords: strongyloidiasis, hookworm, co-infection, spatial, bayesian, helminths, control, risk profiling, cambodia