Changing demographics of visceral leishmaniasis in northeast Brazil: Lessons for the future

<div><p>Background</p><p>Visceral leishmaniasis (VL) caused by <i>Leishmania infantum</i> became a disease of urban areas in Brazil in the last 30 years and there has been an increase in asymptomatic <i>L</i>. <i>infantum</i> infection with these areas.</p><p>Methodology/Principal findings</p><p>A retrospective study of human VL was performed in the state of Rio Grande do Norte, Brazil, for the period of 1990–2014. The data were divided into five-time periods. For all VL cases, data on sex, age, nutritional status and childhood vaccination were collected. Geographic information system tools and statistical models were used to analyze the dispersion of human VL. The mean annual incidence of VL was 4.6 cases/100,000 inhabitants, with total 3,252 cases reported. The lethality rate was 6.4%. Over time the annual incidence of VL decreased in the 0–4 years (<i>p</i><0.0001) and 5–9 (p <0.0001) age groups, but increased in ages 20–39 (p<0.001) and >40 years (p<0.0001). VL occurred more often in males (β₂ = 2.5; p<0.0001). The decreased incidence of VL in children was associated with improved nutritional status and childhood immunizations including measles, poliomyelitis, BCG, and hepatitis B. Human VL correlated temporally and geographically with canine <i>L</i>. <i>infantum</i> infection (p = 0.002, R² = 0.438), with rainfall and with <i>Lutzomyia longipalpis</i> density (r = 0.762). Overall, the incidence of VL decreased, while VL-AIDS increased, especially between 2010–2014. VL was more frequently found in areas that lacked urban infrastructure, detected by lack of garbage collection and sewers, whereas HIV infection was associated with higher levels of schooling and evidence of higher socioeconomic status.</p><p>Conclusion/Significance</p><p>The demographics of VL in northeastern Brazil have changed. Disease incidence has decreased in children and increased in adults. They were associated with improvements in nutrition, socioeconomic status and immunization rates. Concurrent VL-AIDS poses a serious challenge for the future.</p></div

Mean temporal variation of VL cases / 100,000 inhabitants according to the age group⁽^*⁾ (<i>model 2</i>).

<p>Mean temporal variation of VL cases / 100,000 inhabitants according to the age group⁽<a href="http://www.plosntds.org/article/info:doi/10.1371/journal.pntd.0006164#t002fn001" target="_blank">^*</a>⁾ (<i>model 2</i>).</p

Analysis of a 25-year time series of visceral leishmaniasis, VL/AIDS and HIV in the state of Rio Grande do Norte, Brazil.

<p><b>A.</b> Incidence of VL, AIDS, and VL-AIDS co-infections in Rio Grande do Norte 1990 to 2014. <b>B.</b> VL incidence by 100,000 inhabitants and the percent of VL lethality by five-year period.</p

Risk factors for visceral leishmaniasis.

<p><b>A.</b> Association of Vaccination coverage with decreased the incidence of visceral leishmaniasis in children. Association between VL incidence(y) and vaccine coverage (x). <i>y</i> = 6.574 + 11.481<i>x</i>² − 10.13<i>x</i>³, <i>R</i>² = 0.82. <b>B.</b> Correlation between human VL and <i>L</i>. <i>infantum</i> infected dogs. <b>C.</b> Variation in rainfall index and its relation to the incidence of VL.</p

The spread of visceral leishmaniasis by micro region in a 25-year period.

<p>A. Map of Brazil showing in yellow the state of Rio Grande do Norte. Temporal and spatial distributions of human VL in the state of Rio Grande do Norte, 1990 to 2014, (cases/100,000 inhabitants).</p

Enrichment for stratified genetic variants at genetic loci associated with respective phenotype in genome-wide association studies.

<p>Inset the correlation between the enrichment for stratified SNPs at known genetic loci, and enrichment of stratified variants for SNPs associated with respective phenotype in genome-wide association studies. Further details are provided in <b>Table S10 in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0102645#pone.0102645.s021" target="_blank">File S1</a></b>.</p

Enrichment for coding variants amongst autosomal SNPs stratified between South Asians and the 1000 Genome populations (3A) and for specific functional classes of SNPs amongst South Asians compared to Europeans (3B).

<p>Enrichment is calculated compared to null hypothesis; P values are provided in <b>Table S6 and Table S7 in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0102645#pone.0102645.s021" target="_blank">File S1</a></b>.</p

Correlation between imputed and observed genotypes amongst South Asians, using phased or unphased genotypes from low coverage WGS, or using 1000 Genomes Project data.

<p>Results are shown as mean r² with genotypes observed from microarray data (<b>2A</b>) or high-coverage WGS (<b>2B</b>, WGS-28x).</p

Location of birth (1A) and principal components analysis (PCA, 1B) of the South Asians sequenced.

<p>The PCA plots shows results for all South Asians in the LOLIPOP study (SA - All, red circles), for South Asians sequenced (SA - NGS, black dots) and for HapMap2 populations.</p