Successful Interruption of Transmission of Onchocerca volvulus in the Escuintla-Guatemala Focus, Guatemala: e404

Abstract

Background

Elimination of onchocerciasis (river blindness) through mass administration of ivermectin in the six countries in Latin America where it is endemic is considered feasible due to the relatively small size and geographic isolation of endemic foci. We evaluated whether transmission of onchocerciasis has been interrupted in the endemic focus of Escuintla-Guatemala in Guatemala, based on World Health Organization criteria for the certification of elimination of onchocerciasis.

Methodology/Principal Findings

We conducted evaluations of ocular morbidity and past exposure to Onchocerca volvulus in the human population, while potential vectors (Simulium ochraceum) were captured and tested for O. volvulus DNA; all of the evaluations were carried out in potentially endemic communities (PEC; those with a history of actual or suspected transmission or those currently under semiannual mass treatment with ivermectin) within the focus. The prevalence of microfilariae in the anterior segment of the eye in 329 individuals (≥7 years old, resident in the PEC for at least 5 years) was 0% (one-sided 95% confidence interval [CI] 0-0.9%). The prevalence of antibodies to a recombinant O. volvulus antigen (Ov-16) in 6,432 school children (aged 6 to 12 years old) was 0% (one-sided 95% IC 0-0.05%). Out of a total of 14,099 S. ochraceum tested for O. volvulus DNA, none was positive (95% CI 0-0.01%). The seasonal transmission potential was, therefore, 0 infective stage larvae per person per season.

Conclusions/Significance

Based on these evaluations, transmission of onchocerciasis in the Escuintla-Guatemala focus has been successfully interrupted. Although this is the second onchocerciasis focus in Latin America to have demonstrated interruption of transmission, it is the first focus with a well-documented history of intense transmission to have eliminated O. volvulus.

Abstract

Background

Elimination of onchocerciasis (river blindness) through mass administration of ivermectin in the six countries in Latin America where it is endemic is considered feasible due to the relatively small size and geographic isolation of endemic foci. We evaluated whether transmission of onchocerciasis has been interrupted in the endemic focus of Escuintla-Guatemala in Guatemala, based on World Health Organization criteria for the certification of elimination of onchocerciasis.

Methodology/Principal Findings

We conducted evaluations of ocular morbidity and past exposure to Onchocerca volvulus in the human population, while potential vectors (Simulium ochraceum) were captured and tested for O. volvulus DNA; all of the evaluations were carried out in potentially endemic communities (PEC; those with a history of actual or suspected transmission or those currently under semiannual mass treatment with ivermectin) within the focus. The prevalence of microfilariae in the anterior segment of the eye in 329 individuals (≥7 years old, resident in the PEC for at least 5 years) was 0% (one-sided 95% confidence interval [CI] 0-0.9%). The prevalence of antibodies to a recombinant O. volvulus antigen (Ov-16) in 6,432 school children (aged 6 to 12 years old) was 0% (one-sided 95% IC 0-0.05%). Out of a total of 14,099 S. ochraceum tested for O. volvulus DNA, none was positive (95% CI 0-0.01%). The seasonal transmission potential was, therefore, 0 infective stage larvae per person per season.

Conclusions/Significance

Based on these evaluations, transmission of onchocerciasis in the Escuintla-Guatemala focus has been successfully interrupted. Although this is the second onchocerciasis focus in Latin America to have demonstrated interruption of transmission, it is the first focus with a well-documented history of intense transmission to have eliminated O. volvulus.

Author Summary

Brought to the Americas from Africa by the slave trade, onchocerciasis is present in six countries in Latin America. The disease is caused by a round worm and is transmitted to humans by the bite of an infected black fly. Once in a human, the adult worms produce larvae that circulate through the body, causing itching or even blindness. Ivermectin, a drug that kills the larvae, is delivered by public health authorities in countries where the disease is present. If the larvae are killed, then the disease cannot be transmitted to more people. People living in the Escuintla-Guatemala focus, a region in Guatemala where the disease was common, have been taking ivermectin for many years. The Ministry of Health of Guatemala believes that onchocerciasis is no longer being transmitted in the area. To prove that there is no more transmission of the disease, the authors examined the eyes of residents of the area to see if they could find any evidence of the worms. They also conducted analyses of blood in school children to see if they had ever been exposed to the worm, and they caught thousands of black flies and tested them to see if they were infected. These evaluations found no evidence of transmission of the disease in the Escuintla-Guatemala focus. As a result, local public health authorities can stop giving ivermectin and invest their human resources in other important diseases.

Citation: Gonzalez RJ, Cruz-Ortiz N, Rizzo N, Richards J, Zea-Flores G, et al. (2009) Successful Interruption of Transmission of Onchocerca volvulus in the Escuintla-Guatemala Focus, Guatemala. PLoS Negl Trop Dis 3(3): e404. doi:10.1371/journal.pntd.0000404

Editor: Jeffrey M. Bethony, George Washington University, United States of America

Received: June 6, 2008; Accepted: March 4, 2009; Published: March 31, 2009

This is an open-access article distributed under the terms of the Creative Commons Public Domain declaration which stipulates that, once placed in the public domain, this work may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose.

Funding: These studies were funded by the Centers for Disease Control and Prevention (CDC) (Atlanta, GA) and the Onchocerciasis Elimination Program of the Americas (OEPA) (Guatemala City, Guatemala). The OEPA funds were provided through a grant by the Bill and Melinda Gates Foundation (Seattle, WA) to The Carter Center (Atlanta, GA). Scientists from both the CDC and OEPA, but not the Gates Foundation, were involved in all aspects of study design, data collection, interpretation and manuscript preparation.

Competing interests: The authors have declared that no competing interests exist.

Introduction

Onchocerciasis (river blindness) is caused by a filarial nematode transmitted by black flies of the genus Simulium [1]. The disease may be mild (dermatitis) or severe (visual impairment and blindness) and is caused by the human immune response to microfilariae (mf) released by female adult worms as they move across subcutaneous tissue and spread throughout the body. Humans are the only known reservoir [2].

Onchocerciasis occurs throughout much of East and West Africa and Yemen, and was brought to the Americas through the slave trade [3]. It is now endemic to 6 countries in Latin America (Brazil, Colombia, Ecuador, Guatemala, Mexico and Venezuela). Foci of transmission in the Americas are relatively small and geographically delimited compared to areas of transmission in Africa [4]. In part due to the geographical isolation of foci, the goal of the Onchocerciasis Elimination Program of the Americas (OEPA) is both to eliminate ocular morbidity throughout the region, and to permanently interrupt transmission where possible [1],[5].

Control and eventual regional elimination of transmission is considered feasible due to the efficacy of ivermectin (Mectizan®, donated by Merck&Co, Inc.) as a microfilaricide, when used twice per year [6],[7]. While ivermectin used in this manner prevents transmission of infections, it does not kill adult worms [8] although it may reduce their fecundity and lifespan [9]. OEPA, along with its ministry of health counterparts, supports mass treatment with ivermectin twice per year, with the goal of reaching 85% of eligible individuals (those ≥5 years of age, ≥90 cm of height and ≥15 kg of weight; excluded are pregnant women and individuals with severe disease) living in endemic areas. Recent reanalysis of information on the effectiveness of ivermectin delivered in this strategy has suggested that six and a half years (13 treatment rounds) of such coverage can be sufficient to interrupt transmission [7].

Guatemala, with a population eligible for treatment of 175,881 (to receive 351,762 treatments) in 2006 [5] accounts for 38.5% of the endemic population eligible for treatment in Latin America. Guatemala has four endemic foci: Santa Rosa (Department of Santa Rosa), Huehuetenango (Department of Huehuetenango), Escuintla-Guatemala (Departments of Escuintla and Guatemala) and the Central Endemic Zone (Departments of Suchitepéquez, Sololá and Chimaltenango; Figure 1) [10]. The Guatemalan Ministry of Public Health and Social Welfare (MSPAS, in its Spanish acronym) has been delivering ivermectin to endemic communities, through mass drug administration (MDA), since 1988 [8] and has reached 85% of the eligible population at risk twice per year in all foci since 2001 (Figure 2) [5].

[Figure omitted, see PDF]

Figure 1. The four onchocerciasis foci in Guatemala (dark gray) in the endemic departments (light gray).

[Figure omitted, see PDF]

Figure 2. Ivermectin biannual treatment coverage from 1996 to 2007 in the Escuintla-Guatemala focus.

Beginning in 2004, the MSPAS, in partnership with OEPA, the US Centers for Disease Control and Prevention (CDC) and the Universidad del Valle de Guatemala (UVG), began evaluating three of the four endemic foci in the country to determine whether transmission had been interrupted in these areas and if semiannual treatment could be suspended. Criteria for making these determinations are based on World Health Organization (WHO) guidelines presented in the 2001 document "Certification of Elimination of Human Onchocerciasis: Criteria and Procedures" [11] as adapted for field conditions by Lindblade et al. [12] and the OEPA steering committee (the Program Coordinating Committee-PCC) [1]. In summary, the criteria to be applied in areas with historically documented onchocerciasis transmission include: 1) demonstration of a prevalence of mf in the anterior segment (MfAS) of the eye (anterior chamber and cornea) to be less than 1%; 2) a cumulative incidence of O. volvulus infection of less than 0.1% in school-age children; and 3) a prevalence of infection in vectors of less than 0.05% [11],[13]. Based on these criteria, Lindblade et al. demonstrated that transmission had been interrupted in the Santa Rosa focus; [12] subsequently, the PCC recommended to the Minister of Public Health of Guatemala that treatment be suspended in this focus. That recommendation was accepted and the Santa Rosa focus is currently under a three year post treatment surveillance phase to monitor for transmission recrudescence [5].

In this report, we evaluate the current status of transmission of O. volvulus in the Escuintla-Guatemala focus based on the adapted WHO criteria.

Methods

The Escuintla-Guatemala focus

In 2007, the Escuintla-Guatemala focus consisted of 49,616 individuals at risk, with 45,224 eligible for treatment, divided among 103 communities in the department of Escuintla (14.30°N, 90.79°W), and 14 communities in the department of Guatemala (14.62°N, 90.53°W). Historically, this focus included areas with intense transmission: between 1979-1982, the community mf prevalence ranged from 8 to 38%. [14] A larval control effort from 1979-1989 significantly reduced both biting density and community mf prevalence.

Potentially endemic communities (PEC)

To ensure that all areas with current or past evidence of onchocerciasis transmission were included in this evaluation, all communities with at least one of the following characteristics were identified using historical data, including unpublished reports from the MSPAS and published articles: a) past evidence of onchocerciasis transmission (nodules or mf in at least one community resident); b) suspicion of past transmission suggested by a documented survey, which may not have found evidence of transmission; or c) currently under semiannual ivermectin treatment by the MSPAS. A total of 155 communities satisfied at least one of these criteria) (Figure 3). These potentially endemic communities (PEC) served as the sampling frame for all evaluations of the status of transmission of onchocerciasis (Figure 3).

[Figure omitted, see PDF]

Figure 3. Potentially endemic communities and sites for the entomologic, ophthalmologic and serologic evaluations in the Escuintla-Guatemala focus.

Ophthalmologic evaluation

Because ocular morbidity is more likely to be found where onchocerciasis transmission is most intense, [15] we evaluated ocular lesions associated with onchocerciasis only in communities that historically had the highest rates of transmission. PEC with >0% nodule prevalence in the last 3 MSPAS surveys (1989, 1990 and 1991) and elevation >800 m were considered in order to maximize the possibility of finding O. volvulus related morbidity. A total of 16 communities satisfied these criteria. Two of these communities were dropped before the evaluation began because they had less than 5 inhabitants, and one was not included because it effectively serves as a bedroom community for Guatemala City, making it very difficult to locate potential participants in their homes.

The calculation of minimum sample size was based on estimating a population prevalence of MfAS of the eye of less than 1%. Finding 0 positive individuals out of 300 examined will allow a one-sided 95% confidence interval (CI) to exclude 1%. Given an estimated non-response rate of 10%, the total sample size required was 330.

All houses of the selected communities were mapped and the residents were censused using a pre-programmed hand-held personal digital assistant (PDA) with a global positioning system (GPS) attached. Eligible residents (those who were ≥7 years old and who had resided in the community for at least the last 5 years) were identified and recorded. As the ophthalmologist is capable of evaluating up to 90 individuals per day, we stratified communities into those with <90 eligible residents and those with ≥90 eligible residents. In the small communities (<90 residents), all eligible individuals (N~266) were invited to participate. In the larger communities (≥90 residents), a PDA-based algorithm was applied in the field to randomly select 12% of the households and their members for inclusion in the evaluation (N~223).

An ophthalmologist (OO) with extensive experience conducting evaluations of onchocerciasis-related eye disease performed the ophthalmologic evaluations. Visual acuity was measured with a Snellen chart using standard methods. Ocular examinations were conducted with a split-lamp in a darkened area after the patients were asked to sit with their head between their legs for 5 minutes [16]. MfAS were noted as live/coiled or dead/straightened. Data were entered in the PDA and later

[Figure omitted, see PDF]

Figure 4. Mean community prevalence of microfilaria in the skin and nodules in the Escuintla-Guatemala focus.

Unpublished Ministry of Public Health surveys from 1983 to 1991. Bars indicate the upper 95% confidence interval of the prevalence.

Santa Rosa was the first focus in the Americas to demonstrate interruption of onchocerciasis transmission, but there is evidence that transmission was extremely low to nonexistent prior to ivermectin distribution [5]. In contrast, levels of transmission in the Escuintla-Guatemala focus were historically higher than the Santa Rosa focus and transmission was well documented until at least the early 1980s. The larviciding efforts in the San Vicente Pacaya area from 1983-1989 were responsible for a significant decline in vector biting rates and, subsequently, community mf prevalence. The successful interruption of transmission after 12-13 rounds of MDA with ivermectin in San Vicente Pacaya may be at least partially due to the reduction in mf prevalence resulting from the larviciding campaign. While other areas of the Escuintla-Guatemala focus experienced a decline in mf prevalence without vector control, larviciding may be considered a complementary strategy to mass drug administration in areas of intense transmission.

Although the reported specificity of the Ov-16 ELISA test is 90%, [17] our laboratory has now tested over 9,964 samples from endemic areas with only 1 false positive, a specificity of 99.99%. However, distinguishing false from true positives is challenging. We undertook extensive interviews of the family of the child initially found positive to rule out travel to other endemic areas or potential exposure to vectors during his daily activities. We tested other family members, including a grandfather who reported a nodule that was extirpated in the past, and none was found positive. After a second blood sample from the same child tested positive, we sent the samples for testing in another laboratory against additional antigens, where the child's samples were negative in all external tests. We, therefore, feel confident reporting this finding as a false positive.

The data presented in this report were extensively reviewed by OEPA and the PCC. Based on the results, the PCC recommended to the Minister of Health of Guatemala that ivermectin treatments be suspended in the Escuintla-Guatemala focus in 2008. The recommendation was accepted, and, as in Santa Rosa, three years of surveillance for recrudescence has now begun during which a final set of evaluations to ensure that transmission has been completely eliminated will be undertaken [5].

Currently we are conducting a similar series of evaluations in the focus of Huehuetenango along the border with Chiapas, Mexico, to determine whether transmission has been interrupted there. Results from these studies are expected mid-2008. As of the writing of this article, transmission of O. volvulus continues in the Central Endemic zone of Guatemala [5].

Supporting Information

Alternative Language Abstract S1.

Translation of the Abstract into Spanish by Rodrigo Gonzalez

(0.05 MB DOC)

Acknowledgments

We would like to express our gratitude to Mario Rodriguez Perez and Cristian Lizarazo Ortega of the Centro de Biotecnologia Genómica in the Instituto Politécnico Nacional in Reynosa, Mexico, for ELISA testing of the false positive sample. Our thanks to Mynor Lopez, Jorge Sincal, Marvin Chiquitá, Auri Paniagua, Alicia Castillo and Enio Morales for their excellent field work. We are grateful to Estuardo Barrios for the programming of PDAs and map production. None of these studies would have been possible without substantial support from the administrative offices of the Centro de Estudios en Salud of the Universidad del Valle de Guatemala, especially Rosmery Garcia.

Author Contributions

Conceived and designed the experiments: FOR KAL. Performed the experiments: RJG KAL. Analyzed the data: RJG KAL. Wrote the paper: RJG KAL. Supervised data collection: RJG NC-O JR. Performed laboratory testing: NC-O. Assisted in design of the survey: NR JR. Supervised laboratory testing: NR. Evaluaton design, data collection, and publication of results: GZ-F AD MS EC. Ophthalmologic evaluations: OO. Evaluation design and publication of results: FOR. Principal investigator, evaluation design, data collection, publication of results: KAL.

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