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      Ivermectin versus albendazole or thiabendazole for Strongyloides stercoralis infection

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          Abstract

          Background

          Strongyloidiasis is a gut infection with Strongyloides stercoralis which is common world wide. Chronic infection usually causes a skin rash, vomiting, diarrhoea or constipation, and respiratory problems, and it can be fatal in people with immune deficiency. It may be treated with ivermectin or albendazole or thiabendazole.

          Objectives

          To assess the effects of ivermectin versus benzimidazoles (albendazole and thiabendazole) for treating chronic strongyloides infection.

          Search methods

          We searched the Cochrane Infectious Diseases Group Specialized Register (24 August 2015); the Cochrane Central Register of Controlled Trials (CENTRAL), published in the Cochrane Library; MEDLINE (January 1966 to August 2015); EMBASE (January 1980 to August 2015); LILACS (August 2015); and reference lists of articles. We also searched the metaRegister of Controlled Trials ( mRCT) using 'strongyloid*' as a search term, reference lists, and conference abstracts.

          Selection criteria

          Randomized controlled trials of ivermectin versus albendazole or thiabendazole for treating chronic strongyloides infection.

          Data collection and analysis

          Two review authors independently extracted data and assessed risk of bias in the included trials. We used risk ratios (RRs) with 95% confidence intervals (CIs) and fixed- or random-effects models. We pooled adverse event data if the trials were sufficiently similar in their adverse event definitions.

          Main results

          We included seven trials, enrolling 1147 participants, conducted between 1994 and 2011 in different locations (Africa, Southeast Asia, America and Europe).

          In trials comparing ivermectin with albendazole, parasitological cure was higher with ivermectin (RR 1.79, 95% CI 1.55 to 2.08; 478 participants, four trials, moderate quality evidence). There were no statistically significant differences in adverse events (RR 0.80, 95% CI 0.59 to 1.09; 518 participants, four trials, low quality evidence).

          In trials comparing ivermectin with thiabendazole, there was little or no difference in parasitological cure (RR 1.07, 95% CI 0.96 to 1.20; 467 participants, three trials, low quality evidence). However, adverse events were less common with ivermectin (RR 0.31, 95% CI 0.20 to 0.50; 507 participants; three trials, moderate quality evidence).

          In trials comparing different dosages of ivermectin, taking a second dose of 200 μg/kg of ivermectin was not associated with higher cure in a small subgroup of participants (RR 1.02, 95% CI 0.94 to 1.11; 94 participants, two trials).

          Dizziness, nausea, and disorientation were commonly reported in all drug groups. There were no reports of serious adverse events or death.

          Authors' conclusions

          Ivermectin results in more people cured than albendazole, and is at least as well tolerated. In trials of ivermectin with thiabendazole, parasitological cure is similar but there are more adverse events with thiabendazole.

          Ivermectin versus benzimidazoles for treating Strongyloides stercoralis infection

          What is strongyloides infection and how might ivermectin work

          Strongyloides stercoralis is a parasite that lives in the gut of infected people. The infection is not serious for most people, but it can be fatal in people with immune deficiency. People become infected when they come in contact with soil or water contaminated with infectious worms. The chronic infection usually causes skin rash, vomiting, diarrhoea, and constipation, and respiratory problems, such as asthma-like illness. This disease may be treated with ivermectin or albendazole or thiabendazole. We wanted to know if ivermectin was better or worse than the other alternative therapies.

          What the research says

          We reviewed the evidence about the effect of ivermectin compared with albendazole and thiabendazole. After searching for relevant trials up to August 2015, we included seven randomized controlled trials, enrolling 1147 adults with chronic strongyloides infection, conducted between 1994 and 2011 in different locations (Africa, Southeast Asia, America, and Europe). Four trials assessed the effectiveness of ivermectin compared with albendazole and three trials assessed the effectiveness of ivermectin compared with thiabendazole.

          Comparison ivermectin versus albendazole

          Treatment with ivermectin probably cures more people than albendazole ( moderate quality evidence), and may be equally or better tolerated ( low quality evidence). The included trials did not report serious adverse events or death.

          Comparison ivermectin versus thiabendazole

          Treatment with ivermectin and thiabendazole may cure similar numbers of people with strongyloides infection ( low quality evidence), but ivermectin is probably better tolerated ( moderate quality evidence). The included trials did not report serious adverse events or death.

          Related collections

          Most cited references 85

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          Strongyloides stercoralis: Global Distribution and Risk Factors

          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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            The Global Programme to Eliminate Lymphatic Filariasis: Health Impact after 8 Years

            Introduction In 1997, the Global Programme to Eliminate Lymphatic Filariasis (GPELF) was created in response to a specific resolution by the World Health Assembly [1]. At that time the World health Organization (WHO), having recently devised a strategy aimed at achieving LF elimination through ‘mass drug administration’ (MDA) [2], received extraordinary pledges from two pharmaceutical companies (GlaxoSmithKline and Merck & Co., Inc.) for long-term drug donations of unprecedented size to jumpstart this nascent program. The impressive programmatic progress made by the GPELF has been documented in a number of valuable reviews and updates [1], [3]–[7]; however, what is most needed now – for donors who are supporting this effort, for the Ministries of Health and health workers who are laboring on its behalf and for endemic communities who continue to invest their energies and resources towards its success – is to understand not just the technical achievements, but especially what difference it all has made to the health and welfare of the at-risk populations. What impact has 10 years of focus on LF – long recognized as one of the most debilitating and economically-draining of the neglected tropical diseases – really had? To answer this question requires not just a tabulation of the GPELF's programmatic achievements in providing necessary drugs to the targeted at-risk populations, but also, importantly, a projection of the public health gain from this effort, using estimates based on the most accurate data and most reasonable assumptions available. Methods Data sources Specific sources for the data are identified as they are presented; in general, however: Numbers related to LF endemicity, populations at-risk (Table 1) and treatments delivered were derived from publications by WHO in the Weekly Epidemiological Record (WER) and WHO Annual Reports between 2000 and 2008 [4]–[10]; this information is also recorded at www.who.int/lymphatic_filariasis. Information on the quantities of albendazole, ivermectin (Mectizan) and diethylcarbamazine (DEC) used in the GPELF came from these same WER reports [4]–[7], from WHO's Annual Reports (available at www.who.int/lymphatic_filariasis) and from records of GlaxoSmithKline and the Mectizan Donation Program. Population demographic figures used to calculate age or gender subpopulations of the total at-risk populations were taken from the Population Reference Bureau [11] and the World Bank Health, Nutrition and Population Statistics [12]. Disability weights and formulas for calculating Disability Adjusted Life Years (DALYs) were derived from the Global Burden of Disease [13]. Information on the clinical profiles and the effectiveness of treatment for both LF and soil transmitted helminth (STH) infections has been taken from scientific publications [3], [14]–[16]. Estimates of the epidemiology of STH infections (number and distribution of affected individuals worldwide) came from published information [17]. 10.1371/journal.pntd.0000317.t001 Table 1 Population at Risk [5] Region # of Endemic Countries At-Risk Population (millions) Children at Risk (millions) Africa (AFRO) 39 394 176 Americas (AMRO) 7 8.87 3.39 Eastern Mediterranean (EMRO) 3 14.9 6.50 South-east Asia (SEARO) 9 851 297 Western Pacific (WPRO) 25 31.6 11.1 TOTAL: 83 1,300 494 Impact Projections The assumptions made and the rationale behind the projections are outlined below and summarized in Tables 2 and 3. 10.1371/journal.pntd.0000317.t002 Table 2 Projected Health Impact – LF Related. Impact #1 Individuals Protected Disease Prevented DALYs Averted 6.6 million newborns 1.4 million cases of hydrocele 3.2 million DALYs 800,000 cases of lymphedema 2.8 million DALYs 4.4 million cases of subclinical disease ? Assumptions and Reasoning 1) 66 million babies born into at-risk areas under MDA 2000–2007 (discounted for infant mortality) [11] 2) LF infections occur in 10% of at-risk population [3] 3) 12.5% of LF infections result in lymphedema, 20.8% in hydrocele, 66.7% in subclinical damage [3] 4) Disability weights (based on Global Burden of Disease methods): 0.105 for lymphedema, 0.073 for hydrocele; onset at age 20; life span is Region-specific 5) LF transmission (estimated by mosquito infection rates) falls progressively to 50%, 25%, 12%, 6%, and 0% pre-MDA levels after each of the first 5 MDAs, respectively Impact #2 Individuals Protected Disease Prevented DALYs Averted 9.5 million people 6.0 million cases of hydrocele 14 million DALYs 3.5 million cases of lymphedema 12 million DALYs Assumptions and Reasoning 1) 570 million individuals (at minimum) treated under MDAs 2000–2007. The maximal number of individuals treated in any single MDA was determined for each country. The sum of these numbers indicates the minimum total number of individuals treated. 2) LF infections occur in 10% of at-risk (i.e., treated) population [3] (here 57 million) with 1/3 having clinical manifestations and 2/3 having subclinical disease [3] (here 38 million) 3) To maintain this 1/3∶2/3 ratio 50% of those with subclinical disease must progress to overt disease (62.5% manifesting hydrocele [11.9 million] and 37.5%, lymphedema [7.1 million]) [3] 4) If treatment halts progression in only 50% of the subclinical cases (a conservative estimate [19]), 9.5 million people would have been protected from developing overt disease (6 million hydrocele; 3.5 million lymphedema) 5) Disability weights**: 0.105 for lymphedema, 0.073 for hydrocele; onset at age 20; life span, Region-specific 6) Treated individuals will not become re-infected in context of diminished LF transmission in MDA-covered areas 10.1371/journal.pntd.0000317.t003 Table 3 Projected Health Impact – Beyond LF. Impact #3 Individuals Reached Target Health Benefits 56.6 million children -minimal estimate- Soil-transmitted helminthes (intestinal parasites: hookworm, roundworm, whipworm) Weight/height gain, learning ability, cognitive testing, school attendance, fitness, activity [14], [26]–[28] Assumptions and Reasoning 1) 172 million treatments of albendazole given to children (age 2–15 in countries treated with DEC+albendazole; 5–15 in countries using ivermectin+albendazole) in 48 countries during MDAs 2000–2007 [4]–[7]. 2) The maximal number of children treated in any single MDA was determined for each country. The sum of these numbers indicates the minimum total number of children treated (56.6 million) [4]–[7]. 3) Uncertainty of STH prevalence estimates limits the specific quantification of health benefits despite their description in published studies [14], [26]–[28]. Impact #4 Individuals Reached Target Health Benefits 44.5 million women of childbearing age (not pregnant) -minimal estimate- Soil-transmitted helminthes (intestinal parasites: hookworm, roundworm, whipworm) Decreased anemia [16], maternal mortality, infant mortality; increased infant birth-weight [29] Assumptions and Reasoning 1) 140 million treatments of albendazole given to non-pregnant women-of-childbearing-age (15–49 years old) in 48 countries during MDAs 2000–2007 [4]–[7],[12]. 2) The maximal number of such women treated in any single MDA was determined for each country [4]–[7]. The sum of these numbers indicates the minimum total number of women-of-childbearing-age treated (44.5 million). 3) Uncertainty of STH prevalence estimates limits the specific quantification of health benefits despite their description in published studies [16],[27],[30]. Impact #5 Individuals Reached Target Health Benefits 45 million people in Africa -minimal estimate- Onchocerciasis, scabies, lice Decreased physical, mental discomfort (severe itching) [32]; prevention of renal complications of streptococcal superinfections [35] Assumptions and Reasoning 1) 149 million treatments of ivermectin given to communities in 12 African countries during MDAs 2000–2007 [4]–[7]. 2) The maximal number of individuals treated in any single MDA was determined for each country. The sum of these numbers indicates the minimum total number of individuals treated (45 million) [4]–[7]. 3) Uncertainty of prevalence estimates for each of these conditions limits the specific calculation of health benefits despite the descriptions reported in published studies [32]–[34]. Impact estimates: LF-related Babies protected from infection. To estimate the number of babies born into LF treatment areas between 2000 and 2007, demographic data from each country (births per 1,000 population discounted by infant mortality rates [18] were applied to those populations living in areas targeted for LF treatments. Since LF transmission might not stop immediately after MDAs begin, changes observed in mosquito infection rates post MDA were used to estimate changes in LF transmission as progressively decreasing to 50%, 25%, 12%, 6%, and 0% of pre-MDA levels after each of the first 5 MDAs. These multipliers were used on a country-by-country and MDA-by-MDA basis to discount the number of surviving babies born into MDA areas, thereby allowing an estimate of the number of newborns protected from potential LF infection (66 million). Since LF infections are estimated to occur in approximately 10% of the at-risk population [3], 6.6 million newborn babies are therefore considered protected from contracting LF. Cases of morbidity prevented in newborns. Globally, 12.5% of LF infections are estimated to result in lymphedema, 20.8% in hydrocele and the remainder, 66.7%, in subclinical disease [3]. Cases of disease averted (hydrocele, lymphedema and subclinical) were calculated by multiplying these proportions by the number of LF infections averted in babies. DALYs averted in newborns. The number of DALYs averted in newborns was calculated using methods outlined in Global Burden of Disease, utilizing disability weights, the number of cases of clinical disease averted (hydrocele and lymphedema), an estimated onset of disease at age 20 and region-specific life spans [13]. Since disability weights are not available for subclinical LF disease, DALYs associated with this manifestation were not estimated. For all of the calculations associated with the prevention of LF disease, it was assumed, based on available information, that treated individuals will not become re-infected in the context of diminished LF transmission in MDA-covered areas. Infected individuals protected from progression of subclinical disease to clinical disease. For each country the number of individuals treated in each MDA is known, but since it is not known how many unique individuals have received treatment in a program with multiple MDAs, the conservative approach to identifying this number of unique individuals treated in any one country is to identify the maximal numbers of individuals treated in any single MDA for each country. These numbers were then summed for all countries and used as the minimum total number of individuals already treated (570 million). Since LF infections are estimated to occur in approximately 10% of the at-risk population [3], 57 million would be expected to be infected with LF. Approximately two-thirds of infected individuals have subclinical disease [3] (38 million), with 50% of those expected to progress to overt disease (19 million). Approximately 62.5% of individuals with overt disease manifest hydrocele (11.9 million) and 37.5% manifest lymphedema (7.1 million). If it is assumed that treatment halts disease progression in only 50% of subclinical cases (a conservative estimate [19]), 9.5 million people would have been protected from developing overt disease (i.e., 6 million cases of hydrocele and 3.5 million cases of lymphedema averted). DALYs averted through halting progression of disease. The number of DALYs averted through progression of disease was calculated using methods outlined in Global Burden of Disease, utilizing disability weights, the number of cases of clinical disease averted (hydrocele and lymphedema; calculated as described above), an estimated onset of disease at age 20 and region-specific life spans [13]. Impact estimates: ‘Beyond-LF’ benefits Because individual country estimates of the prevalence and distribution of soil transmitted helminthiases are generally not available, it was not possible to estimate directly the number of STH infections, either in children or women of child bearing age, that have been treated as a consequence of LF MDA activities. However, since it is widely accepted that the common STH infections are distributed throughout the pan-tropical belt where lymphatic filariasis is endemic [17], we recognize that a proportion of the albendazole and ivermectin treatments delivered for LF will have had a beneficial impact for children and women of child bearing age who harbor intestinal helminth infections. The number of individual children less than 15 years of age treated with albendazole was estimated by multiplying demographic data (children under the age of 15 years, for each country [11] by that country's total treatment figures, then summing the maximal number of children treated in any single MDA for each country between 2000 and 2007 (the conservative estimate of the number of unique individuals treated; see above). Since age is an exclusion criterion for LF treatment, the annual estimates thus derived were discounted depending on the therapeutic regimen applied as follows: in ivermectin and albendazole areas of Africa and the Yemen, data for children 5 to 15 years of age only are included, whereas for the rest of the world where DEC and albendazole are utilized, data for children 3 to 15 years of age are included. Women between 15 and 49 years were considered to be of childbearing age, and the number of individuals treated in this age class was calculated by multiplying demographic data [11] for each country by that country's total treatment figures, then summing the maximal number treated in any single MDA for each country between 2000 and 2007 (the conservative estimate of the number of unique individuals treated; see above). Since pregnancy is an exclusion criterion for LF treatment, the annual estimates thus derived were discounted by subtracting the estimated percent of the female population that is pregnant at any given time: the total fertility rate for each region was multiplied by a nine month gestational period and divided by 408 months (representing the estimated average number of reproductive months in a woman's lifetime). Whilst the beneficial outcomes of treating STH infections in these population groups are listed, we do not attempt to quantify the accumulated health impact because of the uncertainty surrounding the prevalence estimates. The same rationale and argument adopted for soil transmitted helminth infections were applied when we considered the impact of ivermectin treatments on skin diseases of various etiology in Africa. Results Programmatic achievements of the GPELF 2000–2007 1. The Global Programme One hundred twenty million people are affected with LF – 40 million with limb or genital damage recognized as either lymphedema/elephantiasis (15 million) or hydrocele (25 million), and twice that number with subclinical disease principally of the lymphatics or kidneys [3]. These 120 million people live in 83 endemic countries of the tropics and subtropics where 1.3 billion people (1/5 of the world's population) comprise the total population considered ‘at risk’ for infection through their exposure to LF's mosquito-borne infective larvae (Table 1) [5]. More than a third of these are children [11]. Little more than a decade ago it was established that single doses of a 2-drug regimen (either albendazole+ivermectin or albendazole+DEC) can effectively eliminate microfilariae from the blood of infected individuals for periods often in excess of a year [20]. Once understood, this drug effectiveness permitted development of a strategy for LF elimination based on treating entire at-risk populations yearly with one of these two safe, effective 2-drug regimens in order to reduce microfilaremia (MF) below a ‘transmission threshold’ where future recrudescence would be unlikely even after population treatment was halted. From estimates of the life span of the adult parasites (Wuchereria bancrofti or Brugia malayi), from projections of the levels of ‘drug coverage’ that must be achieved in the targeted populations and from earlier experiences in countries targeting LF elimination, the average number of rounds of effectively conducted, yearly ‘mass drug administrations’ (MDAs) necessary to achieve success for national programs was estimated to be 4–6 [2]. Recent experience from both program observations and specific research studies is consistent with this notion that in most instances between 2 and 6 rounds of effective MDA are able to clear microfilaremia (see below for sentinel site data). There are, however, specific situations where more than 6 rounds might be required, since the number of MDAs necessary appears to depend principally on the pre-treatment microfilaremia levels, programmatic drug ‘coverage’ and local vector parasite complex [21]. 2. Treatments delivered Since its official inauguration in 2000 the GPELF has seen the most rapid expansion of any drug delivery program in public health history; by the end of 2007 more than 1.9 billion treatments for LF had been delivered [7], almost ¾ by the program in India (initially a program based on DEC alone; more recently, on albendazole+DEC) with the remainder distributed in the 47 other countries with active MDA programs (Fig 1). The amount of drug donated to support this Programme has been extraordinary: more than 740 million tablets of albendazole and more than 590 million tablets of ivermectin were provided between 2000–2007 by the Global Programme's partners in the pharmaceutical industry. The amount of the non-donated drug (DEC) that had to be purchased during this same period by countries that utilize DEC instead of ivermectin (which is used for LF only in Africa [3]) was more than 4.7 billion tablets (Fig 2A & B). 10.1371/journal.pntd.0000317.g001 Figure 1 Cumulative treatments in GPELF. Progressive increase in number of treatments given through 2007; distribution by WHO region is depicted in pie-chart. 10.1371/journal.pntd.0000317.g002 Figure 2 Cumulative totals of donated drugs (Panel A), albendazole and ivermectin (Mectizan), and purchased drug (Panel B) DEC, used in GPELF between 2000 and 2007. 3. Programme effectiveness in decreasing LF prevalence The effectiveness of GPELF's strategy to reduce the prevalence of microfilaremia in an endemic population to levels below that believed necessary to sustain the parasite's life cycle has been substantiated by research teams in well-controlled, large-scale initiatives (e.g. in Egypt [22] and Papua New Guinea [23]). In addition, assessment of programmatically collected data available to WHO from another 20 countries shows similar progressive declines in mf prevalence in treated communities (Fig. 3), with greater than 10-fold reduction in mf-prevalence levels seen in sentinel-site communities that have received 6 rounds of MDA and total clearance of mf (by inference, interruption of LF transmission) recorded in almost 2/3 of the communities after 5 MDA rounds (Fig. 4). 10.1371/journal.pntd.0000317.g003 Figure 3 Effect of MDA on microfilaremia prevalence. Individuals in all of the sentinel sites (approximately 500 persons per site) reporting to the Global Programme were evaluated for microfilaremia. Progressive decline in prevalence among these individuals was recorded during yearly assessments (n = 131 sentinel sites for year 1; n = 124 for year 2; n = 139 for year 3; n = 148 for year 4; n = 68 for year 5; and n = 12 for year 6). 10.1371/journal.pntd.0000317.g004 Figure 4 Clearance of microfilaremia from each sentinel site (approximately 500 persons per site) reporting to the Global Programme after 5 rounds of MDA treatment (n = 68). Health impact of the GPELF 2000–2007 As impressive as the record is for the number of treatments given, the number of albendazole and ivermectin tablets donated, the amount of DEC purchased, and the number of communities cleared of microfilaremia during the first 8 years of this Global Programme, still the most important Programme outcome is the overall health benefit that the GPELF has brought to populations at-risk for LF. This benefit must derive from projections based on the best data and most reasonable assumptions available (see below and Tables 2 & 3 for the assumptions and implications). There are two principal sources of this health benefit: LF-related benefits – i.e., those coming directly from the effects of the MDAs in preventing the acquisition of lymphatic filarial disease or in arresting its progression ‘Beyond-LF’ benefits – i.e., those coming from ancillary benefits of the highly effective, broad-spectrum anti-parasitic drugs, albendazole and ivermectin, used in the Programme. 1. Projected health impact that is LF-related Protecting newborns from LF infection and disease. Since MDAs, by decreasing and then stopping LF transmission, will prevent uninfected individuals from becoming infected, the clearest measure of the Programme's long-term health impact is the amount of disease prevented over the lifetime of babies born into areas where their likelihood of acquiring infection has become much diminished or nil. To determine this impact requires an understanding of the number of babies born (and surviving) in areas covered by LF MDAs, the number who would have acquired infection (and disease) in the absence of GPELF, the ‘disability weights’ for different manifestations of LF disease and the rate at which exposure to LF infection declines in treated populations. When these variables were assessed [see Discussion and Table 2 for fuller description], the following conclusions could be made: Impact #1 - Prevention of LF infection (and disease): Between 2000–2007, 6.6 million newborns (the fraction of all newborns who would have been expected to acquire LF) were protected by GPELF – thereby averting in their lifetimes nearly 1.4 million cases of hydrocele, more than 800,000 cases of lymphedema and 4.4 million cases of subclinical disease ( Table 2 ). Because of this disease prevention, 6.0 million Disability Adjusted Life Years (DALYs) have been averted (3.2 million from prevention of hydrocele and 2.8 million from prevention of lymphedema [Table 2]). Preventing the progression to overt disease in LF-endemic populations. With evidence now available that the MDA treatment regimens for LF can halt, or even reverse, the progression of subclinical to overt disease [19],[24],[25], it is clear that those already infected but having no overt disease also benefit directly from the yearly MDAs. To quantify this benefit requires understanding the number of individuals treated during the MDAs, the proportion of these individuals with subclinical LF disease, the number who would have progressed to each of the manifestations of LF disease and the ‘disability weights’ for each of these manifestations. When all of these were considered (see Discussion and Table 2), the following could be recognized: Impact #2 - Prevention of LF disease: Between 2000–2007, 9.5 million individuals – previously infected but without overt manifestations of disease – were protected by GPELF from developing hydrocele (6.0 million) or lymphedema 3.5 million). This disease prevention translates into 26 million DALYs averted (14 million from hydrocele prevention and 12 million from lymphedema prevention). 2. Projected health impact from ‘Beyond-LF’ benefits Preventing the consequences of intestinal parasite infections. The best drugs to control intestinal parasites (i.e., ‘soil-transmitted helminths’ [STH]: hookworm, roundworm and whipworm) are the same drugs (albendazole and ivermectin) used to eliminate LF [3],[20]. Though Mectizan (ivermectin) has formal regulatory approval only for lymphatic filariasis and onchocerciasis and is donated by Merck & Co., Inc. only for those indications, each year millions of children and women-of-childbearing-age are concomitantly treated for debilitating intestinal parasite infections (without additional cost or effort) while participating in their national programs to eliminate LF. To identify the impact of such treatment requires estimation of the number of children and the number of women-of-childbearing-age who received albendazole (with or without ivermectin) in all GPELF countries. Thus, Impact #3 - ‘Beyond-LF’ benefit for children with intestinal parasites: Between 2000–2007, more than 172 million treatments for intestinal parasite infections were given to 56.6 million children by GPELF ( Table 3 ) Based on earlier research studies, each infected child receiving treatment would be expected to develop increased appetite [26] (leading, in some settings, to 1 kg of extra weight gain and 0.6 cm extra growth in the first 5 months) [27] ; greater eye-hand coordination, learning ability and concentration [14] ; better school attendance, cognitive testing (20% improvement) [28], fitness scores and spontaneous play activity (43% increase) [26],[27]. Impact #4 - ‘Beyond-LF’ benefit for women-of-childbearing-age with intestinal parasites: Between 2000–2007 more than 140 million treatments for STH were given to 44.5 million women-of-childbearing age by GPELF ( Table 3 ). Repeated treatment of hookworm and other intestinal parasites improves both nutritional status and, most importantly, iron stores in women during their reproductive years [16],[29] . Prior studies predict that such treatment can lead to an increase in infant birth-weights by more than 50 grams and a drop in infant mortality by as much as 40% [29] . Maternal mortality should also decrease significantly in women receiving GPELF treatments, since iron deficiency anemia is a prominent cause of maternal mortality [30] . Prevention of debilitating skin diseases. Onchocerciasis, scabies, and pediculosis (lice) are all diseases of the skin caused by parasites common in resource poor communities and associated with appreciable mental and physical disability in affected populations. Ivermectin, one of the two drugs co-administered by the GPELF in Africa, is the best oral treatment for all of these debilitating skin diseases [31]–[33]; it is also the mainstay drug for onchocerciasis control programs in Africa [34]. To gauge the GPELF impact on skin diseases it is necessary first to understand the number of individuals receiving ivermectin through GPELF activities in Africa. Thus, Impact #5 - ‘Beyond-LF’ benefit for people with skin diseases in Africa: Between 2000–2007, over 149 million treatments with ivermectin were administered by GPELF or APOC (African Programme for Onchocerciasis Control) to more than 45 million people in African communities ( Table 3 ) where the prevalence of scabies skin infection may exceed 30% and the prevalence of onchocerciasis even more. Ivermectin's long lasting impact on scabies can cause community prevalence to fall dramatically after 1 cycle of treatment and to disappear almost completely after 2 or more treatments [31] . Cured individuals show improvements in sleep patterns and overall wellbeing, but also importantly, treatment of scabies in childhood can prevent the post-streptococcal renal disease induced by group B streptococcus skin infections that often complicate chronic scabies infection [35] . Because of its broad geographic range, the GPELF has brought ivermectin treatment to additional millions of people living in onchocerciasis-endemic areas not previously targeted by onchocerciasis control programs (as these programs focus only on communities where the prevalence of onchocerciasis exceeds 40%) [34] . Discussion Since WHO's Global Programme to Eliminate Lymphatic Filariasis was officially launched in 2000, its programmatic achievements [recorded here through 2007] are unparalleled (Box 1): 1.9 billion treatments delivered through yearly MDAs to over 570 million people in 48 endemic countries. These accomplishments were made possible by the enormous drug donations of albendazole (over 740 million tablets from GlaxoSmithKline through 2007) and ivermectin (over 590 million tablets of Mectizan from Merck & Co., Inc.), by the willingness of National Programs to procure 4.7 billion tablets of DEC, and by the early support from numerous other organizations – most significantly the Bill and Melinda Gates Foundation, the Arab Fund for Economic and Social Development, the international development agencies of Japan and the United Kingdom and the Ministries of Health of endemic countries. Box 1. The Global Programme to Eliminate LF – Its First 8 Years. Reach Nearly 2 billion treatments delivered to more than 560 million people in 48 countries. Dissemination More than 50% of endemic countries actively involved in annual MDA programmes. Child Protection Nearly 176 million children already treated for LF, and over 66 million babies born into areas now protected by MDA. Public Health Impact on LF More than 6 million cases of hydrocele and 4 million cases of lymphoedema prevented, translating into more than 32 million DALYs averted. Additional Health Benefits More than 310 million treatments of albendazole delivered to women of child-bearing age and school-age children, providing sustained relief from the negative consequences of soil-transmitted helminth (STH) infections that include maternal anemia, low birth weight newborns, excess infant mortality, inhibited growth and development, diminished intellectual performance. Almost 150 million treatments of ivermectin delivered to African communities, providing sustained relief from onchocercal skin disease, scabies, lice and important STH infections. Though it is without question that this Programme has had a very great impact on global health, quantifying this impact still poses difficult challenges. Principally this is because all projections must be made not just from the numbers of people treated but also from the more-difficult-to-quantify effects of such treatment. Assumptions derived from current best understanding must be linked with the available data to formulate the health impact projections, and while making such assumptions is never entirely satisfactory, the present analysis does endeavor to identify clearly both the assumptions themselves and the sources of the data used to generate the projections; it also has chosen to err on the conservative side in most estimations. For the GPELF, health benefits lie in two domains: one related to the Programme's effects on lymphatic filarial disease and its consequences, and the other related to the outcome of treating LF-endemic populations with one or both of the very safe, broad-spectrum anti-parasitic drugs used by the Programme, albendazole and ivermectin. LF-related impact To gauge the LF-related impact, this analysis has considered quantitatively only what has been accomplished by: 1) preventing infection in those born into areas where GPELF is active and 2) stopping the progression to clinical disease in previously infected individuals whose disease has not yet expressed itself overtly. 1) To identify the amount of infection prevented, the number of babies born in areas under LF MDAs between 2000–2007 who survived infancy was first determined, by country [11],[12]. Estimation of how many of these newborns would have acquired LF during their lives and what manifestations they would have developed was based on the global prevalence figures available for LF and its clinical manifestations (Table 2) [3]. Calculation of the DALYs attributable to that amount of disease during the lifetimes of those newborns assumed that clinical expression of disease (hydrocele and lymphedema) had its onset at an average age of 20 years and persisted throughout the life of the individual. Since the risk of exposure of these infants to LF depends on the level of local transmission, it is necessary to estimate the rate of decline of transmission (here using vector infection in mosquitoes as a surrogate for transmission) as MDA programs progress. While programmatic evidence exists that effective transmission of LF might cease very soon after the initiation of MDA activities [22],[23],[36], entomologic studies linked with anti-filarial single-dose treatment regimens indicate that the decline in vector infection may be more gradual [22], [23], [37]–[41]. Since the availability of such data is too limited (with respect to vector species, collection techniques, parasite assessments, LF prevalence, treatment regimens, and other variables) to give precise estimates of post-MDA changes in vector infection, data from available studies [22], [23], [37]–[41] were pooled, yielding a relationship that describes an ‘average’ rate-of-decline of vector infection; namely, declines to 50%, 25%, 12%, 6% and 0% of pre-treatment levels following each of the first 5 MDAs, respectively. (As these numbers were empirically defined, they already incorporate the influence of population ‘coverage’ on MDA effectiveness.) This information was then used to estimate the effect that each MDA had for each treated population in each country in order to approximate the exposure to LF in infants born after initiation of GPELF activities. 2) Stopping the progression of subclinical to clinical disease in those already infected contributes appreciably to the calculations of LF-related health benefits from GPELF (Table 2). Evidence for such effectiveness of MDA regimens in halting disease progression is relatively recent and has focused particularly on children with subclinical or early-stage lymphatic disease [19],[25]. Because these effects are just now being studied comprehensively, and in order to be conservative in estimating GPELF's health impact, the present calculations are based on the conservative assumption [19] that the MDA programs would arrest subclinical disease progression in only 50% of the affected individuals (Table 2). Though one cannot be completely certain of all of the calculations in Table 2, it is still hard to escape the conclusion that these values for GPELF's LF-related health impact are almost certainly gross underestimates – for at least 2 reasons. First, not considered at all in the assessments of GPELF's LF-prevention benefits are those related to any of the manifestations of LF disease other than hydrocele and lymphedema. Among those omitted, quantitatively most important would be the Programme's impact on subclinical LF disease [24],[25],[42] – especially microfilaremia, hematuria, lymphatic dilatation and lymphatic dysfunction – which affect a very large percentage of those with LF infection [3] but for which there are no ‘disability weights’ available for calculating DALYs or DALYs averted. Also overlooked are other extremely important, often debilitating overt clinical manifestations of infection – especially, the very common, recurrent acute adenolymphangitis episodes (ADL) and the progressive, crippling pulmonary disease, tropical pulmonary eosinophilia (TPE) [3]. Excluding all of these important consequences of LF infection from the calculations of GPELF's health impact from preventing LF ensures that these calculations will significantly underestimate the Programme's impact. Second, none of these quantitative calculations of GPELF's LF-related health impact has taken into consideration the direct effect that this Programme has had on arresting progression or ameliorating clinical disease of affected individuals. In addition to its delivery of essential anti-filarial drugs, the GPELF is also a program that advocates and initiates ‘morbidity management’ activities based on vigorous personal hygiene management of lymphedema or elephantiasis [43]. Dramatic improvement in both physical state and mental attitude occurs in patients following the hygiene guidelines [43],[44], but none of the health impact of this component of the GPELF has been quantified or captured in the calculations of Table 2. Similarly uncaptured is the potential direct improvement in both lymphedema and hydrocele now being reported by patients following MDA treatment alone (i.e., even in the absence of hygiene management) [23]. ‘Beyond-LF’ Health Impact If the LF-related health impact of GPELF seems difficult to quantify, the ‘beyond-LF’ impact presents an even greater challenge. A major reason is that many of the ‘beyond LF’ benefits come from the impact that the GPELF drugs have on soil transmitted helminth (STH) infections in the treated populations. The quantitative epidemiology of these infections remains poorly characterized, albeit for good reasons: not only are STH infections caused by three distinct parasites (hookworm, roundworm and whipworm), but these three infections also occur in unequal proportions in different endemic regions and cause different diseases with varying severity and health consequences. Further, while the geographic overlap of STH infections with the LF at-risk areas is felt to be almost universal [45], it is rarely known which STH infections occur or with what abundance in which areas. Thus, while general estimates of overall STH prevalence can be approximated for areas where GPELF is active, the data itself is not certain enough to be used quantitatively to project GPELF's health impact from treating STH infections. Despite such limitations, a number of very important studies have been carried out to document and measure the health consequences of STH infections – usually by monitoring changes in outcome indicators following treatment with albendazole or other drugs. These have shown, for example, that Soil transmitted helminth infections exact a severe toll on the nutritional status and growth of infected children, but intervention with albendazole and ivermectin can make an extraordinary difference in their physical development, with spectacular gains in growth parameters quantified in a number of important studies [14]–[16],[46],[47]. Lethargy and lack of physical stamina often characterize children infected with intestinal worms, but within weeks of treatment significant increases can be found in physical activity and spontaneous play. Resting heart rates, physical fitness on the Harvard step test, and measurements of spontaneous play behavior all improved in children from Kenya and Indonesia after being treated for intestinal worms [14],[26],[27],[47]. Children infected with intestinal worms are frequently seen to miss many more school days than their uninfected peers, as documented in Jamaica where children with intense Trichuris infections missed twice as many school days as their infection-free peers [48]. Treatment leads to significant reduction in school absenteeism; a 25% reduction was recorded in Kenya following school-based treatment for STH [49]. Children infected with intestinal worms perform poorly in learning ability tests, cognitive function and educational achievement, but treating school age children increases their ability to learn, as documented by improvement in children's short and long term memory, executive function language, problem solving and attention [50],[51]. These STH infections that are treated by the GPELF MDAs are not just important for children. While their effect on the health and productivity of men remains poorly defined, in women-of-childbearing-age hookworm infection is recognized as a major cause of anemia, and this anemia significantly affects both maternal and newborn morbidity and mortality. Indeed, WHO estimates that women in developing countries may be pregnant for half their reproductive lives and are at an increased risk of anemia during this time [30]. Anemia in pregnancy has been clearly associated with poor birth outcome, including low birth-weight [52]–[55] and increased maternal morbidity and mortality [30],[56],[57]. Hookworm-attributable anemia, induced by deficiencies in iron, protein and total energy, is a significant cause of intrauterine growth retardation and low birth weight [58]. It might even exacerbate the sometimes fatal effects of malaria infection in infants and young children. Treating STH infections in women-of-child-bearing-age improves both maternal health status and the status of infants born to infection-free mothers; therefore, WHO recommends that anthelminthic treatment be included in strategies to improve maternal nutrition wherever hookworm infection and anemia are prevalent [30]. (GPELF, however, currently restricts its treatment to women who are not pregnant.) In addition to its effect on certain of the STH infections, ivermectin – as GPELF's second drug with broad-spectrum anti-parasite activity – is unsurpassed for the oral treatment of both onchocerciasis [34] and ectoparasites (scabies and lice) [31]. While ivermectin has been the mainstay of onchocerciasis control programs for the past 2 decades, the control programs in Africa (where 99% of the onchocerciasis is found) have as their principal target only communities designated hyper- or meso-endemic (i.e., prevalence ≥40%), so that many communities endemic for onchocerciasis were left untreated until GPELF was initiated [34]. Since LF is distributed very much more widely than onchocerciasis, and since almost all regions of Africa where onchocerciasis is endemic are also ‘at risk’ for LF, GPELF activity in those areas has resulted in the treatment of millions of additional individuals in these onchocerciasis-endemic areas who were not covered under the older control programs. These individuals are generally not those with blinding onchocerciasis but with severe onchocercal skin disease (OSD) and “troublesome itching”; the burden of illness from this OSD, quantified in DALYS lost, is recognized as essentially equivalent to that estimated for onchocercal ocular disease and blindness [33]. GPELF's impact on improving OSD is not yet quantified, but it can be defined once the number of individuals with onchocerciasis who live in the expanded treatment areas is more well understood [34]. On the other hand, for the very important skin diseases caused by scabies and lice, the significant health benefits that GPELF brings through its use of ivermectin in affected populations will be much more difficult to quantify, since so much less is known about the epidemiology of these widespread ectoparasite diseases, and no burden-of-illness estimates have yet been established [32]. The Global Programme to Eliminate LF is not a static program; indeed, its reach continues to expand each year. In 2008 it is projected that >500 million people will be treated in that year alone. The effect on the calculated health benefits of the Programme that these progressively increasing numbers will have each year is enormous, since the number of protected children and cases of disease prevented will increase rapidly as new cohorts of treated individuals are added each year; in addition, of course, all of those benefits not currently quantified (both LF-related and beyond-LF effects) will continue to multiply as well. Already the GPELF has been described as a ‘best buy’ in global health, and the present tally of health benefits only strengthens this contention. Even during its first 8 years, almost 2 billion MDA treatments have been given and 32 million DALYs-averted have been identified by considering (conservatively) just 2 of the 5 specific impacts attributable to the Programme (Tables 2 & 3). Considering only these DALYs and estimating treatment costs at $0.10/person (a ‘high’ estimate given the fact that the preponderance of treatments were in countries where costs have been identified as being much lower [59]) suggests that, excluding the donated drug costs, $190 million will have been spent to effect the 1.9 billion treatments. If the 32 million averted DALYs were the only benefits achieved, each DALY averted by the Programme would have cost $5.90. This cost is extremely low compared to DALY averted costs of other programs [60], but even it is a gross overestimate of the true cost of DALYs-averted by GPELF activities, since so much of the Programme's benefit (Tables 2 & 3) remain unquantified and not included in this calculation. As this LF Elimination Programme continues to expand, its benefits will continue to accrue; as our ability to quantify these benefits improves, the Programme's true value will become progressively still more impressive. Supporting Information Alternative Language Abstract S1 Translation of the Abstract into French by P. J. Hooper (0.06 MB PDF) Click here for additional data file.
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              Strongyloides stercoralis: there but not seen.

              Diagnosis of Strongyloides stercoralis is often delayed owing to patients presenting with nonspecific gastrointestinal complaints, a low parasite load and irregular larval output. Although several diagnostic methods exist to detect the presence of S. stercoralis there is no gold standard. In immunocompromised hosts (patients with malignancy, organ transplantation or concurrent human T-cell-lymphocytic virus 1 infection or those on corticosteroid therapy), autoinfection can go unchecked with large numbers of invasive Strongyloides larvae disseminating widely and causing hyperinfection with dissemination, which can be fatal. This review will highlight current published research on improved diagnostic methods for S. stercoralis and the immune mechanisms thought to be responsible for hyperinfection syndrome. Recent advances in diagnosis of S. stercoralis include a luciferase immunoprecipitation system that shows increased sensitivity and specificity to detect S. stercoralis-specific antibodies and a real-time quantitative PCR method to detect S. stercoralis in fecal samples. The severe clinical manifestations of S. stercoralis observed in human T-cell-lymphocytic virus 1 coinfected patients has been associated with an increased proportion of regulatory T cells that may be responsible for blunting otherwise effective granulocyte responses. Strongyloidiasis is a major global health challenge that is underestimated in many countries. Novel diagnostic methods are expected to improve epidemiological studies and control efforts for prevention and treatment of strongyloidiasis. More studies are needed to unveil the mechanisms of severe clinical manifestations of human strongyloidiasis.
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                Author and article information

                Journal
                Cochrane Database Syst Rev
                Cochrane Database Syst Rev
                cd
                The Cochrane Database of Systematic Reviews
                John Wiley & Sons, Ltd (Chichester, UK )
                1469-493X
                18 January 2016
                : 1
                : 1-50
                Affiliations
                [1 ]Instituto de Medicina Tropical Alexander von Humboldt, Universidad Peruana Cayetano Heredia Lima, Peru
                [2 ]Internal Medicine, Hospital Universitario Fundación Alcorcón Madrid, Spain
                [3 ]Hospital Nacional Cayetano Heredia Lima, Peru
                [4 ]Department of Internal Medicine, University of Texas Medical Branch Galveston, USA
                [5 ]Tropical Medicine and Parasitology Unit, Infectious Disease Service, Hospital Ramón y Cajal Madrid, Spain
                [6 ]Cochrane Collaborating Centre, Clinical Biostatistics Unit. Ramón y Cajal Hospital (IRYCIS). Francisco de Vitoria University (UFV Madrid). CIBER Epidemiology and Public Health (CIBERESP) Madrid, Spain
                Author notes
                Instituto de Medicina Tropical Alexander von Humboldt, Universidad Peruana Cayetano Heredia, Av. Honorio Delgado 430, Lima, 31, Peru. chenriquezc@ 123456gmail.com
                Article
                10.1002/14651858.CD007745.pub3
                4916931
                26778150
                Copyright © 2016 The Authors. Cochrane Database of Systematic Reviews published by John Wiley & Sons, Ltd. on behalf of The Cochrane Collaboration.

                This is an open access article under the terms of the Creative Commons Attribution-Non-Commercial-No-Derivatives Licence, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

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                Review

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