Density-Dependent Mortality of the Human Host in Onchocerciasis: Relationships between Microfilarial Load and Excess Mortality

Human onchocerciasis (River Blindness) is a parasitic disease leading to visual impairment including blindness. Blindness may lead to premature death, but infection with the parasite itself (Onchocerca volvulus) may also cause excess mortality in sighted individuals. The excess risk of mortality may not be directly (linearly) proportional to the intensity of infection (a measure of how many parasites an individual harbours). We analyze cohort data from the Onchocerciasis Control Programme in West Africa, collected between 1974 and 2001, by fitting a suite of quantitative models (including a ‘null’ model of no relationship between infection intensity and mortality, a (log-) linear function, and two plateauing curves), and choosing the one that is the most statistically adequate. The risk of human mortality initially increases with parasite density but saturates at high densities (following an S-shape curve), and such risk is greater in younger individuals for a given infection intensity. Our results have important repercussions for programmes aiming to control onchocerciasis (in terms of how the benefits of the programme are calculated), for measuring the burden of disease and mortality caused by the infection, and for a better understanding of the processes that govern the density of parasite populations among human hosts

Eliminating Onchocerciasis after 14 Years of Vector Control: A Proved Strategy

From 1976 through 1989, weekly aerial spraying operations against blackflies were carried out along the rivers of a wide savanna area of West Africa (~700,000 km2) where onchocerciasis was hyperendemic. The level of endemicity began to decrease significantly after 4 years of vector control and became very low in 1989. This situation has been maintained without any vector control activity or chemotherapy, and no incidence of any new cases has been detected. An ophthalmological study carried out in 2000 has confirmed these good results, showing only cicatricial ocular lesions in the examined population. These results led to the conclusion that 14 years of vector control may achieve long-term elimination of onchocerciasis, even in the absence of chemotherapy, provided that the treated areas are not subjected to any contamination by exogenous parasites carried in infected humans or flies

Adjusted point parameter estimates, maximum log-likelihoods, and risk of mortality attributable to <i>Onchocerca volvulus</i> infection.

a<p>Dose-response models were fitted assuming microfilarial loads were measured with error. MLL: Maximum Log Likelihood; AR: Attributable Risk.</p>b<p>The degree of measurement error is summarized by parameter <i>k</i> of the negative binomial distribution, which is an inverse measure of extra-Poisson variation in the distribution of microfilarial counts measured per individual.</p>c<p>Evaluated at the posterior means of the estimated parameters; analogous to the maximum log-likelihood of the model.</p>d<p>Naïve: Point parameter estimates assuming no measurement error in microfilarial loads (see <a href="http://www.plosntds.org/article/info:doi/10.1371/journal.pntd.0001578#pntd-0001578-t003" target="_blank">Table 3</a>);</p>e<p>Poisson measurement errors;</p>f<p>Measurement error estimated from published data <a href="http://www.plosntds.org/article/info:doi/10.1371/journal.pntd.0001578#pntd.0001578-Picq1" target="_blank">[43]</a>;</p>g<p>Arbitrarily large measurement error.</p>h<p>Parameter value fixed, not estimated.</p

Relative mortality risk with increasing <i>Onchocerca volvulus</i> microfilarial load in the Onchocerciasis Control Programme cohort.

<p>Observed (open squares) and fitted (solid line) relative risk of mortality, with fitted (log-)sigmoid dose-response model adjusted to the average age of individuals within the cohort. Shaded (grey) area represents the 95% Bayesian credible interval around the fitted line; vertical error bars are 95% confidence intervals around observations. Inset permits visual inspection of the mortality relative risk at parasite loads ≤40 microfilariae per skin snip.</p

Definitions of parameters and variables.

<p>Definitions of parameters and variables.</p

Measurement error-adjusted and fitted relative mortality risk in the Onchocerciasis Control Programme cohort.

<p>Panels from top to bottom correspond to adjustments for increasing assumed magnitudes of measurement error as defined by parameter <i>k</i> of the negative binomial measurement error model (see <i>Measurement Error</i> section in the main text). In panel A, <i>k</i>→∞, corresponding to Poisson measurement error. In panel B, <i>k</i> = 15, as estimated from published data <a href="http://www.plosntds.org/article/info:doi/10.1371/journal.pntd.0001578#pntd.0001578-Picq1" target="_blank">[43]</a> (<a href="http://www.plosntds.org/article/info:doi/10.1371/journal.pntd.0001578#pntd.0001578.s003" target="_blank">Protocol S3</a>). In panel C, <i>k</i> = 1. In all panels the solid and dashed lines represent, respectively, the fitted (log-)sigmoid and (log-)linear dose-response models. Note the absence of error bars around the model-derived point estimates of relative risk (<a href="http://www.plosntds.org/article/info:doi/10.1371/journal.pntd.0001578#pntd.0001578.s001" target="_blank">Protocol S1</a>) and around the fitted dose-response. This is because regression calibration cannot account fully for the uncertainty introduced by adjusting the observed data for measurement error (see <a href="http://www.plosntds.org/article/info:doi/10.1371/journal.pntd.0001578#s4" target="_blank">Discussion</a>).</p

Summary of mortality data collected by the onchocerciasis control programme in West Africa From 1974 through 2001.

a<p>Inclusion criteria comprise all the consistency checks described in the text plus participation in at least two surveys.</p

Measurement error-adjusted microfilarial loads plotted against their observed values.

<p>Each panel corresponds to an adjustment for a different assumed magnitude of measurement error as defined by parameter <i>k</i> of the negative binomial measurement error model (see <i>Measurement Error</i> section in the main text). In panel A, <i>k</i>→∞ which corresponds to Poisson measurement error. In panel B, <i>k</i> = 15 as estimated from published data <a href="http://www.plosntds.org/article/info:doi/10.1371/journal.pntd.0001578#pntd.0001578-Picq1" target="_blank">[43]</a> (see <a href="http://www.plosntds.org/article/info:doi/10.1371/journal.pntd.0001578#pntd.0001578.s003" target="_blank">Protocol S3</a>). In panel C, <i>k</i> = 1, which corresponds to an arbitrarily large degree of measurement error. In each panel the solid red line is the diagonal representing perfect agreement between observed and adjusted microfilarial loads.</p

Trente ans de lutte contre l’onchocercose en Afrique de l’Ouest. Traitements larvicides et protection de l’environnement

La lutte contre l'onchocercose, ou cécité des rivières, une maladie parasitaire endémique, fut entreprise en Afrique de l'Ouest dans une perspective do développement durable. Tous les moyens technologiques disponibles ont de ce fait été mobilisés pour le contrôle du vecteur, une simulie, puis du parasite responsables de cette maladie, par le Programme de Lutte contre l’Onchocercose en Afrique de l'Ouest (OCP). La lutte antivectorielle consistant en épandages d’insecticides chimiques sur les sites de développement de la simulie dans les rivières, il est apparu indispensable d’assurer la sauvegarde de l’environnement aquatique qui fournit aux communautés riveraines eau et ressources biologiques. Les technologies les plus modernes ont été mises en œuvre dès leur mise au point, pour combattre la maladie, contribuant ainsi à la protection de ce milieu. Le programme de surveillance écologique des rivières traitées par des larvicides anti-simulies a été mis en place dès le lancement d’OCP. et assuré par des spécialistes de I' hydrobiologie des pays africains participants du Programme, sous la supervision d’un groupe international d’experts indépendants, le Groupe Écologique. OCP est incontestablement un succès aussi bien pour ce qui est du contrôle de la maladie que de la protection de l'environnement. Il est l'exemple unique au monde d’un programme de santé publique de longue durée qui depuis son origine a mis en œuvre tout ce qui était possible pour harmoniser les enjeux de l’amélioration de la santé et ceux de la protection de l’environnement. Il s'est achevé avec la satisfaction de laisser aux générations montantes un environnement non dégradé et des vallées libérées de l’onchocercose, qui permettront d’accroître la productivité agricole des pays africains.The control of onchocerciasis, or river blindness, an endemic parasitic disease, was implemented in West Africa in the perspective of sustainable development AH the available technological means to fight this disease, by way of the control of its blackfly vector, then its parasite, were therefore implemented by the Onchocerciasis Control Programme in West Africa (OCP). Vector control being achieved through applications of chemicals on its river breeding sites, it was necessary, at the same time, to fight for the preservation of the aquatic environment, which supplies the communities that live along the rivers with water and biological resources. This was the spirit in which the OCP was set up and implemented, and the most modem technologies were used as they become available to fight the disease, thus facilitating the preservation of the aquatic environment. This Programme has indisputably been a success as regards the control of the disease as also from the point of view of the preservation of the environment The aquatic monitoring programme of the rivers under treatment with anti-simulid larvicides was set up right from the very beginning, and performed by national experts of the Participating Countries of the Programme, under the aegis of a group of international independent experts, the Ecological Croup The Onchocerciasis Control Programme in West Africa is an unique example in the world of a long-term public health programme which has made every effort possible from its inception to adequately combine health and environment issues. It ended with the satisfaction of bequeathing to the coming generations a non degraded environment and valleys freed from onchocerciasis which would increase the agricultural productivity of the countries