The decline of leprosy in Japan: patterns and trends 1964-2008.

OBJECTIVE: Our purpose was to elucidate the patterns and trends of autochthonous leprosy in Japan from 1964 to 2008, to compare them with the findings from other studies of leprosy in decline, and to determine whether M. leprae transmission persists in Japan. DESIGN: Data on registered leprosy cases in Japan in the period 1964-2008 were analysed with reference to trends in case detection, geographical distribution, age at diagnosis, sex, classification, family history and broad correlation with socioeconomic conditions. RESULTS: A consistent decline in leprosy case detection was observed in all areas of the country over the period 1964-2008. Highest incidence was consistently in Okinawa, the southernmost part of Japan. Autochthonous leprosy has not been reported in anyone born in Japan since 1980. Increasing average age and a shift towards lower latitudes were demonstrated throughout the period. There was an inverse association between regional measures of wealth and leprosy incidence. CONCLUSIONS: Leprosy has declined throughout the past century in Japan. Autochthonous transmission has probably stopped in mainland Japan, but may still occur at a low level in Okinawa, the country's southernmost region. Analyses of data on autochthonous cases revealed patterns similar to those reported in other countries with declining leprosy. Detailed comparisons between countries with very low leprosy incidence may help us to better understand the epidemiology of leprosy

The importance of recent infection with Mycobacterium tuberculosis in an area with high HIV prevalence: a long-term molecular epidemiological study in Northern Malawi.

BACKGROUND: The proportion of cases of tuberculosis due to recent infection can be estimated in long-term population-based studies using molecular techniques. Here, we present what is, to our knowledge, the first such study in an area with high human immunodeficiency virus (HIV) prevalence. METHODS: All patients with tuberculosis in Karonga District, Malawi, were interviewed. Isolates were genotyped using restriction-fragment-length polymorphism (RFLP) patterns. Strains were considered to be "clustered" if at least 1 other patient had an isolate with an identical pattern. RESULTS: RFLP results were available from 83% of culture-positive patients from late 1995 to early 2003. When strains with <5 bands were excluded, 72% (682/948) were clustered. Maximum clustering was reached using a 4-year window, with an estimated two-thirds of cases due to recent transmission. The proportion clustered decreased with age and varied by area of residence. In older adults, clustering was less common in men and more common in patients who were HIV positive (adjusted odds ratio, 5.1 [95% confidence interval, 2.1-12.6]). CONCLUSIONS: The proportion clustered found in the present study was among the highest in the world, suggesting high rates of recent transmission. The association with HIV infection in older adults may suggest that HIV has a greater impact on disease caused by recent transmission than on that caused by reactivation

Evaluation of a village-informant driven demographic surveillance system in Karonga, Northern Malawi

This paper describes and evaluates the first demographic surveillance system (DSS) in Malawi, covering a rural population of 30,000. Unlike others, the Karonga DSS relies on trained village informants using formatted registers for the primary notification of vital events and migrations. Seven project enumerators subsequently collect detailed data on events notified by the village informants, using stringent identification procedures for households and individuals. Internal movements are traced systematically to augment event registration and data quality. Continuous evaluation of data collection is built into the methods. A re-census conducted after 2 years indicated that the routine system had registered 97% of 1,588 births, 99% of 521 deaths and 92% of 13,168 movements.demographic surveillance system, evaluation, INDEPTH network, Karonga, Malawi, methods, migration, village informant, vital registration

Documenting the decline of leprosy in Europe: The example of Northern Portugal

Summary Background: There is continued uncertainty over trends of leprosy, including in areas with low incidence, where it may be possible to identify areas where M leprae is no longer transmitted or where it no longer causes disease. WHO has reported data on leprosy in the European Region only since 2015. Methods: Data reported to WHO and published in the Weekly Epidemiological Record were reviewed, Data from five districts in northern Portugal were collected from the National General Directorate of Health and Municipal Health Authorities. Results: Basic information on 133 leprosy cases has been reported to WHO by thirteen of the 54 states in the European Union since 2015. Data on place of birth of the cases were reported by ten states since 2016, implying eleven cases possibly attributable to transmission within Europe. Detailed but incomplete data on 38 leprosy cases notified in northern Portugal 1990–2018 are described and discussed. Of those cases which appear to have been autochthonous, none were born after 1966, none were notified after 2007, and the only three notifications after 2005 were for relapses. Conclusions: Data on leprosy in the European Region are obviously incomplete. The large majority of cases now detected are attributable to infections contracted abroad, but a small number of cases possibly attributable to local transmission are still being identified. Analysis of data from five districts in northern Portugal indicate that this region is no longer endemic for the disease, and that transmission in the area is likely to have ceased at least 40 years ago. The methods illustrated in this paper could be applied to data on leprosy in other regions of Europe, to better define the geographic limits of leprosy today

Large-scale candidate gene study of leprosy susceptibility in the Karonga district of northern Malawi.

We present a large case-control candidate gene study of leprosy susceptibility. Thirty-eight polymorphic sites from 13 genes were investigated for their role in susceptibility to leprosy by comparing 270 cases with 452 controls in Karonga district, northern Malawi. Homozygotes for a silent T-->C change in codon 352 of the vitamin D receptor gene appeared to be at high risk (odds ratio [OR] = 4.3, 95% confidence interval [CI] = 1.6-11.4, P = 0.004), while homozygotes for the McCoy b blood group defining variant K1590E in exon 29 of the complement receptor 1 (formerly CD35) gene appeared to be protected (OR = 0.3, 95% CI = 0.1-0.8, P = 0.02). Borderline evidence for association with leprosy susceptibility was found for seven polymorphic sites in an additional six genes. Some of these apparent associations may be false-positive results from multiple comparisons, and several associations suggested by studies in other populations were not replicated here. These data provide evidence of inter-population heterogeneity in leprosy susceptibility

The decline of autochthonous leprosy in the Valencia Region of Spain: patterns and trends 1940-2015

Objectives: The aim of this study was to describe the patterns and trends of autochthonous leprosy in the Valencia Region (Spain). Methods: We included all new leprosy cases originating from the Valencia Region between the years 1940 and 2015. Patients originating from other countries or other Spanish regions were excluded. New cases were analysed by age, sex, clinical type, occupation, and geographic distribution. Results: A total of 442 patients with presumably autochthonous leprosy were included. Incidence rates consistently declined over the study period. Mean age at onset gradually increased from 34.2 years during the period 1940-1949 to 59.5 years during 2000-2015. There were no cases with clinical onset after 2006 and no cases born after 1973. Patients were predominantly males (57.7%) and 85.4% had multibacillary leprosy. The proportion of multibacillary cases increased gradually after 1970. The majority of male patients (67.9%) worked in agriculture. Most of the cases, especially during the later periods, were concentrated in the coastal regions. Conclusions: Our findings are consistent with trends described in other regions with declining leprosy incidence rates and suggest that the transmission of M. leprae infection in this area may well have now stopped. Autochthonous leprosy in this region has had a male predominance and a high proportion of multibacillary cases. The geographic distribution and the high incidence in agricultural workers suggest that environmental factors should be further explored

Persistence of the immune response induced by BCG vaccination.

BACKGROUND: Although BCG vaccination is recommended in most countries of the world, little is known of the persistence of BCG-induced immune responses. As novel TB vaccines may be given to boost the immunity induced by neonatal BCG vaccination, evidence concerning the persistence of the BCG vaccine-induced response would help inform decisions about when such boosting would be most effective. METHODS: A randomised control study of UK adolescents was carried out to investigate persistence of BCG immune responses. Adolescents were tested for interferon-gamma (IFN-gamma) response to Mycobacterium tuberculosis purified protein derivative (M.tb PPD) in a whole blood assay before, 3 months, 12 months (n = 148) and 3 years (n = 19) after receiving teenage BCG vaccination or 14 years after receiving infant BCG vaccination (n = 16). RESULTS: A gradual reduction in magnitude of response was evident from 3 months to 1 year and from 1 year to 3 years following teenage vaccination, but responses 3 years after vaccination were still on average 6 times higher than before vaccination among vaccinees. Some individuals (11/86; 13%) failed to make a detectable antigen-specific response three months after vaccination, or lost the response after 1 (11/86; 13%) or 3 (3/19; 16%) years. IFN-gamma response to Ag85 was measured in a subgroup of adolescents and appeared to be better maintained with no decline from 3 to 12 months. A smaller group of adolescents were tested 14 years after receiving infant BCG vaccination and 13/16 (81%) made a detectable IFN-gamma response to M.tb PPD 14 years after infant vaccination as compared to 6/16 (38%) matched unvaccinated controls (p = 0.012); teenagers vaccinated in infancy were 19 times more likely to make an IFN-gamma response of > 500 pg/ml than unvaccinated teenagers. CONCLUSION: BCG vaccination in infancy and adolescence induces immunological memory to mycobacterial antigens that is still present and measurable for at least 14 years in the majority of vaccinees, although the magnitude of the peripheral blood response wanes from 3 months to 12 months and from 12 months to 3 years post vaccination. The data presented here suggest that because of such waning in the response there may be scope for boosting anti-tuberculous immunity in BCG vaccinated children anytime from 3 months post-vaccination. This supports the prime boost strategies being employed for some new TB vaccines currently under development

The effect of BCG revaccination on all-cause mortality beyond infancy: 30-year follow-up of a population-based, double-blind, randomised placebo-controlled trial in Malawi.

BACKGROUND: Trials of BCG vaccination to prevent or reduce severity of COVID-19 are taking place in adults, some of whom have been previously vaccinated, but evidence of the beneficial, non-specific effects of BCG come largely from data on mortality in infants and young children, and from in-vitro and animal studies, after a first BCG vaccination. We assess all-cause mortality following a large BCG revaccination trial in Malawi. METHODS: The Karonga Prevention trial was a population-based, double-blind, randomised controlled in Karonga District, northern Malawi, that enrolled participants between January, 1986, and November, 1989. The trial compared BCG (Glaxo-strain) revaccination versus placebo to prevent tuberculosis and leprosy. 46 889 individuals aged 3 months to 75 years were randomly assigned to receive BCG revaccination (n=23 528) or placebo (n=23 361). Here we report mortality since vaccination as recorded during active follow-up in northern areas of the district in 1991-94, and in a demographic surveillance follow-up in the southern area in 2002-18. 7389 individuals who received BCG (n=3746) or placebo (n=3643) lived in the northern follow-up areas, and 5616 individuals who received BCG (n=2798) or placebo (n=2818) lived in the southern area. Year of death or leaving the area were recorded for those not found. We used survival analysis to estimate all-cause mortality. FINDINGS: Follow-up information was available for 3709 (99·0%) BCG recipients and 3612 (99·1%) placebo recipients in the northern areas, and 2449 (87·5%) BCG recipients and 2413 (85·6%) placebo recipients in the southern area. There was no difference in mortality between the BCG and placebo groups in either area, overall or by age group or sex. In the northern area, there were 129 deaths per 19 694 person-years at risk in the BCG group (6·6 deaths per 1000 person-years at risk [95% CI 5·5-7·8]) versus 133 deaths per 19 111 person-years at risk in the placebo group (7·0 deaths per 1000 person-years at risk [95% CI 5·9-8·2]; HR 0·94 [95% CI 0·74-1·20]; p=0·62). In the southern area, there were 241 deaths per 38 399 person-years at risk in the BCG group (6·3 deaths per 1000 person-years at risk [95% CI 5·5-7·1]) versus 230 deaths per 38 676 person-years at risk in the placebo group (5·9 deaths per 1000 person-years at risk [95% CI 5·2-6·8]; HR 1·06 [95% CI 0·88-1·27]; p=0·54). INTERPRETATION: We found little evidence of any beneficial effect of BCG revaccination on all-cause mortality. The high proportion of deaths attributable to non-infectious causes beyond infancy, and the long time interval since BCG for most deaths, might obscure any benefits. FUNDING: British Leprosy Relief Association (LEPRA); Wellcome Trust

Impact of foot-and-mouth disease on mastitis and culling on a large-scale dairy farm in Kenya

Foot and mouth disease (FMD) is a highly transmissible viral infection of cloven hooved animals associated with severe economic losses when introduced into FMD-free countries. Information on the impact of the disease in FMDV-endemic countries is poorly characterised yet essential for the prioritisation of scarce resources for disease control programmes. A FMD (virus serotype SAT2) outbreak on a large-scale dairy farm in Nakuru County, Kenya provided an opportunity to evaluate the impact of FMD on clinical mastitis and culling rate. A cohort approach followed animals over a 12-month period after the commencement of the outbreak. For culling, all animals were included; for mastitis, those over 18 months of age. FMD was recorded in 400/644 cattle over a 29-day period. During the follow-up period 76 animals were culled or died whilst in the over 18 month old cohort 63 developed clinical mastitis. Hazard ratios (HR) were generated using Cox regression accounting for non-proportional hazards by inclusion of time-varying effects. Univariable analysis showed FMD cases were culled sooner but there was no effect on clinical mastitis. After adjusting for possible confounders and inclusion of time-varying effects there was weak evidence to support an effect of FMD on culling (HR = 1.7, 95% confidence intervals [CI] 0.88-3.1, P = 0.12). For mastitis, there was stronger evidence of an increased rate in the first month after the onset of the outbreak (HR = 2.9, 95%CI 0.97-8.9, P = 0.057)