Factors Associated with Severe Human Rift Valley Fever in ... - PLOS

RESEARCH ARTICLE

Factors Associated with Severe Human Rift Valley Fever in Sangailu, Garissa County, Kenya A. Desirée LaBeaud1,2*, Sarah Pfeil2, Samuel Muiruri3, Saidi Dahir3, Laura J. Sutherland4, Zachary Traylor4, Ginny Gildengorin2, Eric M. Muchiri3, John Morrill5, C. J. Peters5, Amy G. Hise4,6,7, James W Kazura4, Charles H. King4 1 Stanford University, Department of Pediatrics, Palo Alto, California, United States of America, 2 UCSF Benioff Children’s Hospital Oakland, Oakland, California, United States of America, 3 Division of Vector Borne and Neglected Tropical Diseases, Ministry of Health, Nairobi, Kenya, 4 Center For Global Health and Diseases, Case Western Reserve University, Cleveland, Ohio, United States of America, 5 Department of Microbiology and Immunology, The University of Texas Medical Branch at Galveston, Galveston, Texas, United States of America, 6 Department of Pathology, Case Western Reserve University, Cleveland, Ohio, United States of America, 7 Research Service, Louis Stokes Cleveland Department of Veterans Affairs, Cleveland, Ohio, United States of America * [email protected] OPEN ACCESS Citation: LaBeaud AD, Pfeil S, Muiruri S, Dahir S, Sutherland LJ, Traylor Z, et al. (2015) Factors Associated with Severe Human Rift Valley Fever in Sangailu, Garissa County, Kenya. PLoS Negl Trop Dis 9(3): e0003548. doi:10.1371/journal. pntd.0003548 Editor: Maya Williams, U.S. Naval Medical Research Unit No. 2, INDONESIA Received: July 15, 2014 Accepted: January 20, 2015 Published: March 12, 2015 Copyright: © 2015 LaBeaud et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Data Availability Statement: We ask very detailed information about age, sex, occupation and take the X and Y coordinates of the household by GPS, so in essence someone with that data could unmask all of our participants. A dataset containing data that does not contain any PHI has been uploaded as S1 Dataset. Funding: This study was supported by National Institutes of Health Midwest Regional Center of Excellence Program Project Award: U54AI057160 for ADL, AGH, CHK, and JWK. The funders had no role

Abstract Background Mosquito-borne Rift Valley fever virus (RVFV) causes acute, often severe, disease in livestock and humans. To determine the exposure factors and range of symptoms associated with human RVF, we performed a population-based cross-sectional survey in six villages across a 40 km transect in northeastern Kenya.

Methodology/Principal Findings: Methodology/Principal Findings: A systematic survey of the total populations of six Northeastern Kenyan villages was performed. Among 1082 residents tested via anti-RVFV IgG ELISA, seroprevalence was 15% (CI95%, 13–17%). Prevalence did not vary significantly among villages. Subject age was a significant factor, with 31% (154/498) of adults seropositive vs. only 2% of children 15 years (12/583). Seroprevalence was higher among men (18%) than women (13%). Factors associated with seropositivity included a history of animal exposure, non-focal fever symptoms, symptoms related to meningoencephalitis, and eye symptoms. Using cluster analysis in RVFV positive participants, a more severe symptom phenotype was empirically defined as having somatic symptoms of acute fever plus eye symptoms, and possibly one or more meningoencephalitic or hemorrhagic symptoms. Associated with this more severe disease phenotype were older age, village, recent illness, and loss of a family member during the last outbreak. In multivariate analysis, sheltering livestock (aOR = 3.5 CI95% 0.93–13.61, P = 0.065), disposing of livestock abortus (aOR = 4.11, CI95% 0.63–26.79, P = 0.14), and village location (P = 0.009) were independently associated with the severe disease phenotype.

PLOS Neglected Tropical Diseases | DOI:10.1371/journal.pntd.0003548

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Severe Human Rift Valley Fever

in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist.

Conclusions/Significance Our results demonstrate that a significant proportion of the population in northeastern Kenya has been infected with RVFV. Village and certain animal husbandry activities were associated with more severe disease. Older age, male gender, herder occupation, killing and butchering livestock, and poor visual acuity were useful markers for increased RVFV infection. Formal vision testing may therefore prove to be a helpful, low-technology tool for RVF screening during epidemics in high-risk rural settings.

Author Summary Rift Valley fever virus (RVFV) causes serious disease in both animals and humans. Largescale outbreaks result in devastating economic losses and create many urgent public health concerns. Among humans, the symptoms of RVF are variable, having a broad spectrum of disease that ranges from mild to severe fever symptoms, and can include ocular complications, encephalitis, and sometimes hemorrhagic disease. In this study, 1082 at-risk Kenyan subjects were serum antibody-tested for evidence of prior RVFV infection and their demographic, health, and exposure data were collated. Seroprevalence was moderately high across the study area (15%) but did not differ significantly among villages across the study region. Age, gender, and herding occupation were all significantly associated with being RVFV seropositive. Older age, village and certain animal husbandry activities were associated with more severe disease. Poor visual acuity was more likely in the seropositive group. This better definition of risk factors and associated symptom complexes should prove helpful for RVF screening during future outbreaks in high-risk rural settings.

Introduction Rift Valley fever virus (RVFV) is a mosquito-borne zoonotic disease that poses a significant risk to human health in endemic regions of Africa and the Middle East [1]. Epizootics usually precede epidemics and can result in large-scale abortion storms in local livestock populations [2]. These RVFV outbreaks in human and animal populations result in significant economic damage from trade embargos and significant livestock losses in affected areas [3]. Recent data also demonstrate that RVFV can be transmitted to humans during interepidemic periods [4–6]. RVFV infection is categorized as a neglected tropical disease due to the fact that RVFV disproportionately affects resource-limited semi-nomadic herding communities, is poverty promoting, and has long-lasting sequelae [5]. Additionally, RVF is expanding its range, threatening other areas of the world as an emerging infectious disease; notably, both Europe and the United States have the necessary vectors and livestock reservoirs to sustain autochthonous RVFV transmission [7,8]. The severity of RVFV manifestation, its devastating economic and public health effects, and its potential to be sustained in new regions make the study of RVFV transmission and disease a high priority. Clinically, most often RVFV causes no symptoms or a mild illness manifesting with fever and liver abnormalities [4]. More rarely, RVFV is known to cause cases of retinitis, encephalitis, or hemorrhagic diathesis with hepatitis during epidemics [9], but these manifestations are variable and currently unpredictable. Most primary infections are thought to cause only self-limited febrile illness followed by complete recovery. It is not yet clear why severe cases occur- these


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consist of patients with neurologic dysfunction (up to 8%), and hemorrhagic cases (up to 1%, which is then associated with mortality of up to 50%) [2,4]. Furthermore, RVFV causes visual disturbances including reversible anterior uveitis (up to 30% of cases), and permanent retinitis (up to 20%) [10]. This broad spectrum of human RVF disease has been most recently confirmed in investigations of the 2006–2007 epidemics in East Africa [9]. Outbreaks in NE Kenya (Garissa County) were reported during the last epidemic [2], but RVFV activity in nearby Ijara constituency (Masalani and Sangailu), was not specifically monitored. Other reports have shown evidence of interepidemic human RVFV transmission in Ijara constituency (Masalani)[5–6]. It has been suggested that clinical phenotype of disease may be in part determined by the route of RVFV transmission, with animal-related transmission likely to be more severe than mosquito borne disease [1]. To expand this knowledge, the goal of the present study was to identify the exposures and other risk factors associated with human RVFV transmission and disease severity in a typical East African endemic setting, the Ijara constituency, Sangailu location, Kenya.

Methods Ethics statement All participants provided written consent under a protocol approved by the Human Investigations Review Board of University Hospitals Case Medical Center (No. 11–09–01) and the Ethical Review Committee of the Kenya Medical Research Institute, Nairobi, Kenya (Non-SSC Protocol No. 195). Before participation, written informed consent was obtained from adult study subjects, and parents provided written informed consent for their participating children. Children over 7 years of age also provided individual assent.

Location This study was performed in the semi-arid Sangailu Location of Ijara constituency, Kenya. Six villages (Golabele, Sabenale, Gedilun, Matarba, Korahindi, and Tumtish) were sampled for demographic, epidemiological, and health information during area-wide household surveys performed from August through November of 2011, five years after the last known RVF epidemic in the area (2006–2007). The villages are located off a main road across a span of approximately 40 Km, in a transect running southwest to northeast (Fig. 1) centered around coordinates 1 deg. 19 min S, 40 deg. 44 min E. The northern-most village, Tumtish, is located 39 Km from the border with Somalia. The participating populations studied were comprised predominantly of herders and semi-nomadic pastoralists of Somali ethnicity. A typical household landscape is shown in Fig. 2. For unique identification and subsequent analysis of the spatial distribution of RVFV serostatus, participating household locations were geo-referenced by Global Positioning System with the use of a Garmin eTrex handheld device (Garmin, Schaffhausen, Switzerland).

Participants Study recruitment began after consultation and approval by local leaders and administrators. After an initial demographic census was performed to determine the current local population and its distribution, a systematic survey of the total populations of six Northeastern Kenyan villages was performed. The villages were systematically surveyed in sequence to reach the desired sample size of >1000 enrolled individuals. All residents were eligible for inclusion, except that those residing in the area for 0.25 and a PRNT titer of 1:20 were considered positive. The confirmatory plaque reduction neutralization testing (PRNT) was performed at the University of Texas, Medical Branch at Galveston.

Statistical methods Statistical analysis examined the association of subject demographic and exposure factors with two primary outcomes: i) odds of seropositivity and ii) odds of having had the more severe symptoms of RVF. Initial chi-square tests were performed to identify the association of categorical factors with RVFV seropositivity and t-tests were used for continuous variables. A series of nested multivariable logistic regression models were next developed that initially included predictors significant in bivariate comparisons, as well as those considered of biological relevance prior to conduct of the study. Bivariate results and stepwise regression models were used to aid in the selection of variables to be included in the final models. Non-significant variables (p > = 0.10) were removed in stepwise fashion to help identify the variables with the greatest multiply adjusted links to RVFV seropositivity or symptom score. For this analysis, statistical significance was set at the 0.05 level. Following analysis of individual symptoms, a relative RVF severity score was developed using the two-step cluster algorithm in SPSS v. 21 (IBM, Armonk NY, USA) to empirically define significant constellations of milder, moderate, and more severe symptom states among RVFV seropositive subjects [15]. The severe disease phenotype was defined as having somatic symptoms of acute fever plus eye symptoms and possibly one or more meningoencephalitic or hemorrhagic symptoms (S1 Fig). Mild disease phenotype was defined as RVFV seropositivity with few to no symptoms. Multivariate logistic regression models were


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run using severe vs. mild disease categories and significant variables from bivariate analysis, excluding those variables used to define disease severity. These statistical models were performed using SAS software (SAS Institute Inc. version 9.3, Cary, NC, USA). Statistical analysis of spatial patterns of seropositivity among the participating households was performed with the use of Point Pattern Analysis software [16] and Clusterseer 2.0 software (Biomedware, Ann Arbor, MI)

Results Associations with RVFV seropositivity Of the 1134 participants enrolled in the study, 1082 completed all phases of the examination and were tested for RVFV infection. Of these, 164 were RVFV seropositive (15%; CI95% 13– 17%). Males were more likely to be RVFV infected: 18% (79/433) were seropositive compared to 13% (85/646) of females (P = 0.023; Table 1). Adults (16 years old) were also more likely than children to be RVFV infected: Thirty-one percent (152/487) of adults were seropositive compared to 2% (12/595) of children (P < 0.001). The average age of seropositive people was 42 ± 19.5 years (range 6–85 years) vs. 17 ± 17 for seronegatives (range 1–84 years). No significant differences in seropositivity were seen among the six villages studied in the Sangailu region: Golabele (17.6%; 15/85), Korahindi (17.0%; 49/288); Sabenale (15.6%; 10/64); Matarba (14.3%; 33/231); Gedilun (13.9%; 32/230), and Tumtish (13.6%; 25/184). This was not surprising given the uniformity of landscape and environmental features, and the socioeconomic homogeneity within pastoralist communities of this region. From initial bivariate analysis, RVFV seropositivity was significantly associated with multiple environmental exposures, as well as certain physical signs and reported symptoms (see Table 1). After multivariable adjustment, our most parsimonious logistic model of seropositive status found that older age (4% increase per year CI95% 2–9%, p