Stable and Unstable Malaria Hotspots in Longitudinal Cohort Studies in Kenya

Background

Infectious diseases often demonstrate heterogeneity of transmission among host populations. This heterogeneity reduces the efficacy of control strategies, but also implies that focusing control strategies on “hotspots” of transmission could be highly effective.

Methods and Findings

In order to identify hotspots of malaria transmission, we analysed longitudinal data on febrile malaria episodes, asymptomatic parasitaemia, and antibody titres over 12 y from 256 homesteads in three study areas in Kilifi District on the Kenyan coast. We examined heterogeneity by homestead, and identified groups of homesteads that formed hotspots using a spatial scan statistic. Two types of statistically significant hotspots were detected; stable hotspots of asymptomatic parasitaemia and unstable hotspots of febrile malaria. The stable hotspots were associated with higher average AMA-1 antibody titres than the unstable clusters (optical density [OD] = 1.24, 95% confidence interval [CI] 1.02–1.47 versus OD = 1.1, 95% CI 0.88–1.33) and lower mean ages of febrile malaria episodes (5.8 y, 95% CI 5.6–6.0 versus 5.91 y, 95% CI 5.7–6.1). A falling gradient of febrile malaria incidence was identified in the penumbrae of both hotspots. Hotspots were associated with AMA-1 titres, but not seroconversion rates. In order to target control measures, homesteads at risk of febrile malaria could be predicted by identifying the 20% of homesteads that experienced an episode of febrile malaria during one month in the dry season. That 20% subsequently experienced 65% of all febrile malaria episodes during the following year. A definition based on remote sensing data was 81% sensitive and 63% specific for the stable hotspots of asymptomatic malaria.

Conclusions

Hotspots of asymptomatic parasitaemia are stable over time, but hotspots of febrile malaria are unstable. This finding may be because immunity offsets the high rate of febrile malaria that might otherwise result in stable hotspots, whereas unstable hotspots necessarily affect a population with less prior exposure to malaria. Please see later in the article for the Editors'' Summary     

Serological Evidence of MERS-CoV Antibodies in Dromedary Camels (Camelus dromedaries) in Laikipia County,Kenya

Middle East respiratory syndrome coronavirus (MERS-CoV) is a recently identified virus causing severe viral respiratory illness in people. Little is known about the reservoir in the Horn of Africa. In Kenya, where no human MERS cases have been reported, our survey of 335 dromedary camels, representing nine herds in Laikipia County, showed a high seroprevalence (46.9%) to MERS-CoV antibodies. Between herd differences were present (14.3%– 82.9%), but was not related to management type or herd isolation. Further research should focus on identifying similarity between MERS-CoV viral isolates in Kenya and clinical isolates from the Middle East and elsewhere.     

Waterpipe smoking as a public health risk: Potential risk for transmission of MERS-CoV

The Middle East Respiratory Syndrome (MERS-CoV) emerged in the Kingdom of Saudi Arabia in 2012 causing a critical challenge to public health. The epidemiology of MERS-CoV remain enigmatic as human-to-human transmission is not fully understood. One possible scenario that might play a role in the virus transmission is the cultural waterpipe smoking. Cafés providing waterpipe smoking in cities within Saudi Arabia have been moved to areas outside city limits that frequently place them close to camels markets. We report results of a surveillance study wherein waterpipe hoses throughout several regions in Saudi Arabia were tested for the presence of MERS-CoV. A total of 2489 waterpipe samples were collected from cities where MERS-CoV cases were continuously recorded. MERS-CoV RNA wasn’t detected in collected samples. Irrespective of the negative results of our survey, the public health risk of waterpipe smoking should not be underestimated. To avoid a possible transmission within country where MERS-CoV is prevalent, we recommend the replacement of resusable hoses with “one-time-use” hoses in addition to a close inspection of waterpipe components to assure the appropriate cleaning and sanitization.     

Predictive Factors and Risk Mapping for Rift Valley Fever Epidemics in Kenya

Background

To-date, Rift Valley fever (RVF) outbreaks have occurred in 38 of the 69 administrative districts in Kenya. Using surveillance records collected between 1951 and 2007, we determined the risk of exposure and outcome of an RVF outbreak, examined the ecological and climatic factors associated with the outbreaks, and used these data to develop an RVF risk map for Kenya.

Methods

Exposure to RVF was evaluated as the proportion of the total outbreak years that each district was involved in prior epizootics, whereas risk of outcome was assessed as severity of observed disease in humans and animals for each district. A probability-impact weighted score (1 to 9) of the combined exposure and outcome risks was used to classify a district as high (score ≥ 5) or medium (score ≥2 - <5) risk, a classification that was subsequently subjected to expert group analysis for final risk level determination at the division levels (total = 391 divisions). Divisions that never reported RVF disease (score < 2) were classified as low risk. Using data from the 2006/07 RVF outbreak, the predictive risk factors for an RVF outbreak were identified. The predictive probabilities from the model were further used to develop an RVF risk map for Kenya.

Results

The final output was a RVF risk map that classified 101 of 391 divisions (26%) located in 21 districts as high risk, and 100 of 391 divisions (26%) located in 35 districts as medium risk and 190 divisions (48%) as low risk, including all 97 divisions in Nyanza and Western provinces. The risk of RVF was positively associated with Normalized Difference Vegetation Index (NDVI), low altitude below 1000m and high precipitation in areas with solonertz, luvisols and vertisols soil types (p <0.05).

Conclusion

RVF risk map serves as an important tool for developing and deploying prevention and control measures against the disease.     

Urban Cholera Transmission Hotspots and Their Implications for Reactive Vaccination: Evidence from Bissau City,Guinea Bissau

Background

Use of cholera vaccines in response to epidemics (reactive vaccination) may provide an effective supplement to traditional control measures. In Haiti, reactive vaccination was considered but, until recently, rejected in part due to limited global supply of vaccine. Using Bissau City, Guinea-Bissau as a case study, we explore neighborhood-level transmission dynamics to understand if, with limited vaccine and likely delays, reactive vaccination can significantly change the course of a cholera epidemic.

Methods and Findings

We fit a spatially explicit meta-population model of cholera transmission within Bissau City to data from 7,551 suspected cholera cases from a 2008 epidemic. We estimated the effect reactive vaccination campaigns would have had on the epidemic under different levels of vaccine coverage and campaign start dates. We compared highly focused and diffuse strategies for distributing vaccine throughout the city. We found wide variation in the efficiency of cholera transmission both within and between areas of the city. “Hotspots”, where transmission was most efficient, appear to drive the epidemic. In particular one area, Bandim, was a necessary driver of the 2008 epidemic in Bissau City. If vaccine supply were limited but could have been distributed within the first 80 days of the epidemic, targeting vaccination at Bandim would have averted the most cases both within this area and throughout the city. Regardless of the distribution strategy used, timely distribution of vaccine in response to an ongoing cholera epidemic can prevent cases and save lives.

Conclusions

Reactive vaccination can be a useful tool for controlling cholera epidemics, especially in urban areas like Bissau City. Particular neighborhoods may be responsible for driving a city''s cholera epidemic; timely and targeted reactive vaccination at such neighborhoods may be the most effective way to prevent cholera cases both within that neighborhood and throughout the city.     

Mapping Biological Transmission: An Empirical,Dynamical, and Evolutionary Approach

The current debate over extending inheritance and its evolutionary impact has focused on adding new categories of non-genetic factors to the classical transmission of DNA, and on trying to redefine inheritance. Transmitted factors have been mainly characterized by their directions of transmission (vertical, horizontal, or both) and the way they store variations. In this paper, we leave aside the issue of defining inheritance. We rather try to build an evolutionary conceptual framework that allows for tracing most, if not all forms of transmission and makes sense of their different tempos and modes. We discuss three key distinctions that should in particular be the targets of theoretical and empirical investigation, and try to assess the interplay among them and evolutionary dynamics. We distinguish two channels of transmission (channel 1 and channel 2), two measurements of the temporal dynamics of transmission, respectively across and within generations (durability and residency), and two types of transmitted factors according to their evolutionary relevance (selectively relevant and neutral stable factors). By implementing these three distinctions we can then map different forms of transmission over a continuous space describing the combination of their varying dynamical features. While our aim is not to provide yet another model of inheritance, putting together these distinctions and crossing them, we manage to offer an inclusive conceptual framework of transmission, grounded in empirical observation, and coherent with evolutionary theory. This interestingly opens possibilities for qualitative and quantitative analyses, and is a necessary step, we argue, in order to question the interplay between the dynamics of evolution and the dynamics of multiple forms of transmission.     

The Potential for Mapping Nematode Distributions for Site-specific Management

The success of site-specific nematode management depends on a grower or advisor being able to afford to make a map of an infestation that is accurate enough for management decisions. The spatial dependence of nematode infestations and correlation of soil attributes with nematode density were assessed to investigate the scale of sampling required to obtain correlated observations of density and the use of soils data to reduce the cost of sampling. Nematodes and soil were sampled on a 76.2 × 76.2-m grid in two irrigated corn (Zea mays) fields for 2 years. Nematodes of each of three species were found in 36% to 77% of the cores from a field. Spatial dependence was detected for 10 of 16 distributions, and 22% to 67% of the variation in density within a field could be attributed to spatial correlation. Density was correlated to distances of 115 to 649 m in the directions of 0, 45, 90, and 135° from the crop row, and distances varied with direction. Correlations between nematode density and soil attributes were inconsistent between species and fields. These results indicate a potential for mapping nematode infestations for site-specific management, but provide no evidence for reducing the cost of sampling by substituting soils data for nematode counts when making a map.     

When More Transmission Equals Less Disease: Reconciling the Disconnect between Disease Hotspots and Parasite Transmission

The assumed straightforward connection between transmission intensity and disease occurrence impacts surveillance and control efforts along with statistical methodology, including parameter inference and niche modeling. Many infectious disease systems have the potential for this connection to be more complicated–although demonstrating this in any given disease system has remained elusive. Hemorrhagic disease (HD) is one of the most important diseases of white-tailed deer and is caused by viruses in the Orbivirus genus. Like many infectious diseases, the probability or severity of disease increases with age (after loss of maternal antibodies) and the probability of disease is lower upon re-infection compared to first infection (based on cross-immunity between virus strains). These broad criteria generate a prediction that disease occurrence is maximized at intermediate levels of transmission intensity. Using published US field data, we first fit a statistical model to predict disease occurrence as a function of seroprevalence (a proxy for transmission intensity), demonstrating that states with intermediate seroprevalence have the highest level of case reporting. We subsequently introduce an independently parameterized mechanistic model supporting the theory that high case reporting should come from areas with intermediate levels of transmission. This is the first rigorous demonstration of this phenomenon and illustrates that variation in transmission rate (e.g. along an ecologically-controlled transmission gradient) can create cryptic refuges for infectious diseases.     

Raccoon Social Networks and the Potential for Disease Transmission

Raccoons are an important vector of rabies and other pathogens. The degree to which these pathogens can spread through a raccoon population should be closely linked to association rates between individual raccoons. Most studies of raccoon sociality have found patterns consistent with low levels of social connectivity within populations, thus the likelihood of direct pathogen transmission between raccoons is theoretically low. We used proximity detecting collars and social network metrics to calculate the degree of social connectivity in an urban raccoon population for purposes of estimating potential pathogen spread. In contrast to previous assumptions, raccoon social association networks were highly connected, and all individuals were connected to one large social network during 15 out of 18 months of study. However, these metrics may overestimate the potential for a pathogen to spread through a population, as many of the social connections were based on relatively short contact periods. To more closely reflect varying probabilities of pathogen spread, we censored the raccoon social networks based on the total amount of time spent in close proximity between two individuals per month. As this time criteria for censoring the social networks increased from one to thirty minutes, corresponding measures of network connectivity declined. These findings demonstrate that raccoon populations are much more tightly connected than would have been predicted based on previous studies, but also point out that additional research is needed to calculate more precise transmission probabilities by infected individuals, and determine how disease infection changes normal social behaviors.     

Scanning Transmission X-Ray, Laser Scanning, and Transmission Electron Microscopy Mapping of the Exopolymeric Matrix of Microbial Biofilms

Confocal laser scanning microscopy (CLSM), transmission electron microscopy (TEM), and soft X-ray scanning transmission X-ray microscopy (STXM) were used to map the distribution of macromolecular subcomponents (e.g., polysaccharides, proteins, lipids, and nucleic acids) of biofilm cells and matrix. The biofilms were developed from river water supplemented with methanol, and although they comprised a complex microbial community, the biofilms were dominated by heterotrophic bacteria. TEM provided the highest-resolution structural imaging, CLSM provided detailed compositional information when used in conjunction with molecular probes, and STXM provided compositional mapping of macromolecule distributions without the addition of probes. By examining exactly the same region of a sample with combinations of these techniques (STXM with CLSM and STXM with TEM), we demonstrate that this combination of multimicroscopy analysis can be used to create a detailed correlative map of biofilm structure and composition. We are using these correlative techniques to improve our understanding of the biochemical basis for biofilm organization and to assist studies intended to investigate and optimize biofilms for environmental remediation applications.     

A Comprehensive Review of Animal Models for Coronaviruses: SARS-CoV-2, SARS-CoV,and MERS-CoV

The recent outbreak of coronavirus disease(COVID-19) caused by the novel severe acute respiratory syndrome coronavirus 2(SARS-CoV-2) has already affected a large population of the world. SARS-CoV-2 belongs to the same family of severe acute respiratory syndrome coronavirus(SARS-CoV) and Middle East respiratory syndrome coronavirus(MERSCoV). COVID-19 has a complex pathology involving severe acute respiratory infection, hyper-immune response, and coagulopathy. At present, there is no therapeutic drug or vaccine approved for the disease. There is an urgent need for an ideal animal model that can reflect clinical symptoms and underlying etiopathogenesis similar to COVID-19 patients which can be further used for evaluation of underlying mechanisms, potential vaccines, and therapeutic strategies. The current review provides a paramount insight into the available animal models of SARS-CoV-2, SARS-CoV, and MERS-CoV for the management of the diseases.     

Potential Sources and Transmission of Salmonella and Antimicrobial Resistance in Kampala,Uganda

In sub‒Saharan Africa, non‒typhoidal Salmonellae (NTS) cause invasive disease particularly in children and HIV infected adults, but the disease epidemiology is poorly understood. Between 2012 and 2013, we investigated NTS sources and transmission in Kampala. We detected Salmonella in 60% of the influent and 60% of the effluent samples from a wastewater treatment plant and 53.3% of the influent and 10% of the effluent samples from waste stabilization ponds that serve the human population; 40.9% of flush‒water samples from ruminant slaughterhouses, 6.6% of the poultry fecal samples from live bird markets and 4% of the fecal samples from swine at slaughter; and in 54.2% of the water samples from a channel that drains storm–water and effluents from the city. We obtained 775 Salmonella isolates, identified 32 serovars, and determined resistance to 15 antimicrobials. We genotyped common serovars using multiple‒locus variable number tandem repeats analysis or pulsed‒field gel electrophoresis. In addition, we analyzed 49 archived NTS isolates from asymptomatic livestock and human clinical cases. Salmonella from ruminant and swine sources were mostly pan‒susceptible (95%) while poultry isolates were generally more resistant. Salmonella Kentucky isolated from poultry exhibited extensive drug resistance characterized by resistance to 10 antimicrobials. Interestingly, similar genotypes of S. Kentucky but with less antimicrobial resistance (AMR) were found in poultry, human and environmental sources. The observed AMR patterns could be attributed to host or management factors associated with production. Alternatively, S. Kentucky may be prone to acquiring AMR. The factors driving AMR remain poorly understood and should be elucidated. Overall, shared genotypes and AMR phenotypes were found in NTS from human, livestock and environmental sources, suggesting zoonotic and environmental transmissions most likely occur. Information from this study could be used to control NTS transmission.     

Rapid Salinity Mapping by Electromagnetic Induction for Determining Riparian Restoration Potential

The feasibility of measuring soil salinity with electromagnetic induction (EM) for determining riparian restoration potential was investigated on a 28-hectare plot at the Bosque del Apache National Wildlife Refuge in central New Mexico. The plot was cleared of exotic Tamarix chinensis (saltcedar), surveyed and gridded into 1370.2 hectare sections. Soil samples and EM measurements were taken at each section. We compared laboratory-determined EC_e values from the soil samples with EC_a values calculated from the EM measurements using a model developed by Rhoades et al. (1990). Direct comparison of EC_e values determined from the two methods yields a low correlation due to sample-size differences but the calculated EC_a was able to accurately predict whether the measured EC_e would lie above or below some threshold value. An assessment of general site suitability for riparian restoration with electromagnetic induction has proven to be a rapid, accurate, and cost-effective alternative to intensive soil sampling.     

Submicroscopic Gametocytes and the Transmission of Antifolate-Resistant Plasmodium falciparum in Western Kenya

Background

Single nucleotide polymorphisms (SNPs) in the dhfr and dhps genes are associated with sulphadoxine-pyrimethamine (SP) treatment failure and gametocyte carriage. This may result in enhanced transmission of mutant malaria parasites, as previously shown for chloroquine resistant parasites. In the present study, we determine the association between parasite mutations, submicroscopic P. falciparum gametocytemia and malaria transmission to mosquitoes.

Methodology/Principal Findings

Samples from children treated with SP alone or in combination with artesunate (AS) or amodiaquine were genotyped for SNPs in the dhfr and dhps genes. Gametocytemia was determined by microscopy and Pfs25 RNA–based quantitative nucleic acid sequence–based amplification (Pfs25 QT-NASBA). Transmission was determined by membrane-feeding assays. We observed no wild type infections, 66.5% (127/191) of the infections expressed mutations at all three dhfr codons prior to treatment. The presence of all three mutations was not related to higher Pfs25 QT-NASBA gametocyte prevalence or density during follow-up, compared to double mutant infections. The proportion of infected mosquitoes or oocyst burden was also not related to the number of mutations. Addition of AS to SP reduced gametocytemia and malaria transmission during follow-up.

Conclusions/Significance

In our study population where all infections had at least a double mutation in the dhfr gene, additional mutations were not related to increased submicroscopic gametocytemia or enhanced malaria transmission. The absence of wild-type infections is likely to have reduced our power to detect differences. Our data further support the use of ACT to reduce the transmission of drug-resistant malaria parasites.     

Transmission Potential and Design of Adequate Control Measures for Marburg Hemorrhagic Fever

Marburg hemorrhagic fever is rare yet among the most severe diseases affecting humans, with case fatality ratio even higher than 80%. By analyzing the largest documented Marburg hemorrhagic fever epidemic, which occurred in Angola in 2005 and caused 329 deaths, and data on viral load over time in non-human primates, we make an assessment of transmissibility and severity of the disease. We also give insight into the control of new Marburg hemorrhagic fever epidemics to inform appropriate health responses. We estimated the distribution of the generation time to have mean 9 days (95%CI: 8.2–10 days) and standard deviation 5.4 days (95%CI: 3.9–8.6 days), and the basic reproduction number to be  = 1.59 (95%CI: 1.53–1.66). Model simulations suggest that a timely isolation of cases, starting no later than 2–3 days after symptoms onset, is sufficient to contain an outbreak. Our analysis reveals that Marburg hemorrhagic fever is characterized by a relatively small reproduction number and by a relatively long generation time. Such factors, along with the extremely high severity and fatality, support the rare occurrence of large epidemics in human populations. Our results also support the effectiveness of social distancing measures - case isolation in particular - to contain or at least to mitigate an emerging outbreak. This work represents an advance in the knowledge required to manage a potential Marburg hemorrhagic fever epidemic.     

Bovine Norovirus: Carbohydrate Ligand,Environmental Contamination,and Potential Cross-Species Transmission via Oysters

Noroviruses (NoV) are major agents of acute gastroenteritis in humans and the primary pathogens of shellfish-related outbreaks. Previous studies showed that some human strains bind to oyster tissues through carbohydrate ligands that are similar to their human receptors. Thus, based on presentation of shared norovirus carbohydrate ligands, oysters could selectively concentrate animal strains with increased ability to overcome species barriers. In comparison with human GI and GII strains, bovine GIII NoV strains, although frequently detected in bovine feces and waters of two estuaries of Brittany, were seldom detected in oysters grown in these estuaries. Characterization of the carbohydrate ligand from a new GIII strain indicated recognition of the alpha-galactosidase (α-Gal) epitope not expressed by humans, similar to the GIII.2 Newbury2 strain. This ligand was not detectable on oyster tissues, suggesting that oysters may not be able to accumulate substantial amounts of GIII strains due to the lack of shared carbohydrate ligand and that they should be unable to contribute to select GIII strains with an increased ability to recognize humans.Environmental sources of animal pathogens and, most specifically, of RNA viruses may constitute substantial risk factors for cross-species transmission to humans (14). In this context, noroviruses (NoVs) infecting cattle could be of importance owing to the high densities of cows bred in areas of human activities. The ability of shellfish to concentrate pathogens released in seawater raises questions about the transmission of animal NoVs to humans through oyster consumption, but so far very few studies have compared water and shellfish contamination. One of the first such studies, conducted more than 30 years ago, comparing the presence of enterovirus by cell culture in water and oysters yielded about the same frequency of positive water (59%) and shellfish samples (35%) (12). More recently, phages of Bacteroides fragilis and Salmonella detected in sewage effluents were also detected in receiving waters and oysters (6). Human NoVs were detected in 75% of river water samples and in 60% of oyster beds (38). Only one study reported the detection of porcine norovirus in 15% of shellfish collected from the U.S. market but no information from the surrounding water was available (8).NoVs are small nonenveloped viruses approximately 30 nm in diameter with a positive-sense, single-stranded RNA genome. They belong to the Caliciviridae family, and in humans they are the most frequent cause of diarrhea outbreaks in all age groups (11, 28). They are classified in five genogroups, with human strains belonging to genogroups I, II, and IV, GIII strains infecting cattle, and murine strains classified in GV (45). Recently, two new genogroups (VI and VII) infecting animals have been proposed (29). Based on analysis of the open reading frame 2 (ORF2) sequence encoding the capsid protein, high diversity has been observed, with the result that genogroups have been subdivided into clusters, including up to 19 for GII strains. Porcine NoVs have been classified into three clusters of GII (GII.11, GII.18, and GII.19) while all bovine strains of NoV described so far belong to GIII (25, 29, 41, 45). The first bovine strain, Bo/Newbury2/1976/UK (NB2), was isolated in the United Kingdom from calves with diarrhea (43). Later, another distinct genotype of bovine NoV, Bo/Jena/1978/GER, was identified in Germany (21). These two strains represent the prototypes of the GIII.2 and GIII.1 genotypes, respectively.Although many gaps persist in our understanding of human NoV infections and pathogenesis, recent advances demonstrated a genetically determined host susceptibility based on histo-blood group antigen diversity. Various human NoV strains attach to distinct carbohydrates of the ABH and Lewis histo-blood group family, and evidence accumulated from volunteer studies and outbreaks indicates that binding to these carbohydrates is required for infection (19, 35). In addition, it was recently shown that the prototype bovine GIII.2 strain binds to a related carbohydrate structure which is absent from human tissues (44). Similarly, it was also demonstrated that some strains of either GI or GII specifically attach to oysters tissues through recognition of histo-blood group antigens (HBGAs) (17, 22, 36). This finding could help explain other observations, such as the rapid contamination of oysters, long persistence of viral particles, and, consequently, shellfish-borne outbreaks (3, 16). It additionally suggests that oysters may not merely act as passive filters randomly accumulating virus particles but, instead, may also act as selective filters specifically concentrating strains by recognition of carbohydrate epitopes shared with humans. As shellfish are grown in coastal waters frequently exposed to contamination from bovine in neighboring fields, they may be contaminated by these animal strains. This raises the issue of the potential role of oysters in the emergence of bovine NoVs into the human population.The aim of our study is to provide quantitative data on the presence of GIII NoV strains in comparison with GI and GII strains in bovine feces, rivers, or estuarine waters as well as shellfish from an area of both high cattle density and high-density oyster breeding. The possibility of GIII strain-specific binding to carbohydrate ligands of oyster tissues that may be shared with cows and humans is additionally examined. The results are discussed in the context of the environmental data in order to provide a first appreciation of the risk of GIII NoV transmission to humans through oyster consumption.