Buruli ulcer, tuberculosis and leprosy: Exploring the One Health dimensions of three most prevalent mycobacterial diseases: A narrative review.

ΟBJECTIVES: Although Buruli ulcer, tuberculosis, and leprosy are the three most common mycobacterial diseases, One Health dimensions of these infections remain poorly understood. This narrative review aims at exploring the scientific literature with respect to the presence of animal reservoir(s) and other environmental sources for the pathogens of these infections, their role in transmission to humans and the research on/practical implementation of One Health relevant control efforts. METHODS: The literature review was conducted using the online databases PubMed, Scopus, ProQuest and Google Scholar, reviewing articles that were written in English in the last 15 years. Grey literature, published by intergovernmental agencies, was also reviewed. RESULTS: For the pathogen of Buruli ulcer, evidence suggests possums as a possible animal reservoir and thus having an active role in disease transmission to humans. Cattle and some wildlife species are deemed as established animal reservoirs for tuberculosis pathogens, with a non-negligible proportion of infections in humans being of zoonotic origin. Armadillos constitute an established animal reservoir for leprosy pathogens with the transmission of the disease from armadillos to humans being deemed possible. Lentic environments, soil and other aquatic sources may represent further abiotic reservoirs for viable Buruli ulcer and leprosy pathogens infecting humans. Ongoing investigation and implementation of public health measures, targeting (sapro)zoonotic transmission can be found in all three diseases. CONCLUSION: Buruli ulcer, tuberculosis and leprosy exhibit important yet still poorly understood One Health aspects. Despite the microbiological affinity of the respective causative mycobacteria, considerable differences in their animal reservoirs, potential environmental sources and modes of zoonotic transmission are being observed. Whether these differences reflect actual variations between these diseases or rather knowledge gaps remains unclear. For improved disease control, further investigation of zoonotic aspects of all three diseases and formulation of One Health relevant interventions is urgently needed.

Vaccine value profile for Hookworm.

Hookworm, a parasitic infection, retains a considerable burden of disease, affecting the most underprivileged segments of the general population in endemic countries and remains one of the leading causes of mild to severe anemia in Low and Middle Income Countries (LMICs), particularly in pregnancy and children under 5. Despite repeated large scale Preventive Chemotherapy (PC) interventions since more than 3 decades, there is broad consensus among scholars that elimination targets set in the newly launched NTD roadmap will require additional tools and interventions. Development of a vaccine could constitute a promising expansion of the existing arsenal against hookworm. Therefore, we have evaluated the biological and implementation feasibility of the vaccine development as well as the added value of such a novel tool. Based on pipeline landscaping and the current knowledge on key biological aspects of the pathogen and its interactions with the host, we found biological feasibility of development of a hookworm vaccine to be moderate. Also, our analysis on manufacturing and regulatory issues as well as potential uptake yielded moderate implementation feasibility. Modelling studies suggest a that introduction of a vaccine in parallel with ongoing integrated interventions (PC, WASH, shoe campaigns), could substantially reduce burden of disease in a cost - saving mode. Finally a set of actions are recommended that might impact positively the likelihood of timely development and introduction of a hookworm vaccine.

Estimation of the morbidity and mortality of congenital Chagas disease: A systematic review and meta-analysis.

Chagas disease is caused by the parasite Trypanosoma cruzi which can be transmitted from mother to baby during pregnancy. There is no consensus on the proportion of infected infants with clinical signs of congenital Chagas disease (cCD). The objective of this systematic review is to determine the burden of cCD. Articles from journal inception to 2020 reporting morbidity and mortality associated with cCD were retrieved from academic search databases. Observational studies, randomized-control trials, and studies of babies diagnosed with cCD were included. Studies were excluded if they were case reports or series, without original data, case-control without cCD incidence estimates, and/or did not report number of participants. Two reviewers screened articles for inclusion. To determine pooled proportion of infants with cCD with clinical signs, individual clinical signs, and case-fatality, random effects meta-analysis was performed. We identified 4,531 records and reviewed 4,301, including 47 articles in the narrative summary and analysis. Twenty-eight percent of cCD infants showed clinical signs (95% confidence interval (CI) = 19.0%, 38.5%) and 2.2% of infants died (95% CI = 1.3%, 3.5%). The proportion of infected infants with hepatosplenomegaly was 12.5%, preterm birth 6.0%, low birth weight 5.8%, anemia 4.9%, and jaundice 4.7%. Although most studies did not include a comparison group of non-infected infants, the proportion of infants with cCD with clinical signs at birth are comparable to those with congenital toxoplasmosis (10.0%-30.0%) and congenital cytomegalovirus (10.0%-15.0%). We conclude that cCD burden appears significant, but more studies comparing infected mother-infant dyads to non-infected ones are needed to determine an association of this burden to cCD.

Knowledge, attitudes, behaviors, and serological status related to Chagas disease among Latin American migrants in Germany: A cross-sectional study in six German cities.

Background: Little is known about knowledge, attitudes and behaviors concerning Chagas disease (CD) among Latin American migrants in Germany to inform public health decision making. Methods: A cross-sectional, questionnaire-based study was conducted between March 2014 and October 2019 among Latin American migrants in six cities in Germany to obtain information on migration history, socioeconomic and insurance status, knowledge about CD, potential risk factors for Trypanosoma cruzi infection, and willingness to donate blood or organs. Results: 168 participants completed the questionnaire. The four countries with the highest proportion of participants contributing to the study population were Colombia, Mexico, Peru and Ecuador. Before migrating to Europe, the majority of the study population resided in an urban setting in houses made of stone or concrete, had higher academic education and was integrated into the German healthcare and healthcare insurance system. The majority of all study participants were also willing to donate blood and organs and a quarter of them had donated blood previously. However, many participants lacked basic knowledge about symptoms and modes of transmission of Chagas disease. One out of 56 serologic tests (1.8%) performed was positive. The seropositive female participant born in Argentina had a negative PCR test and no signs of cardiac or other organ involvement. Conclusions: The study population does not reflect the population structure at risk for T. cruzi infection in endemic countries. Most participants had a low risk profile for infection with T. cruzi. Although the sample size was small and sampling was not representative of all persons at risk in Germany, the seroprevalence found was similar to studies previously conducted in Europe. As no systematic screening for T. cruzi in Latin American blood and organ donors as well as in women of child-bearing age of Latin American origin is implemented in Germany, a risk of occasional transmission of T. cruzi remains.

Measuring endemicity and burden of leprosy across countries and regions: A systematic review and Delphi survey.

BACKGROUND: Leprosy is a chronic infectious disease caused by Mycobacterium leprae, the annual new case detection in 2019 was 202,189 globally. Measuring endemicity levels and burden in leprosy lacks a uniform approach. As a result, the assessment of leprosy endemicity or burden are not comparable over time and across countries and regions. This can make program planning and evaluation difficult. This study aims to identify relevant metrics and methods for measuring and classifying leprosy endemicity and burden at (sub)national level. METHODS: We used a mixed-method approach combining findings from a systematic literature review and a Delphi survey. The literature search was conducted in seven databases, searching for endemicity, burden and leprosy. We reviewed the available evidence on the usage of indicators, classification levels, and scoring methods to measure and classify endemicity and burden. A two round Delphi survey was conducted to ask experts to rank and weigh indicators, classification levels, and scoring methods. RESULTS: The literature review showed variation of indicators, levels, and cut-off values to measure leprosy endemicity and/or burden. The most used indicators for endemicity include new case detection rate (NCDR), new cases among children and new cases with grade 2 disability. For burden these include NCDR, MB cases, and prevalence. The classification levels 'high' and 'low' were most important. It was considered most relevant to use separate scoring methods for endemicity and burden. The scores would be derived by use of multiple indicators. CONCLUSION: There is great variation in the existing method for measuring endemicity and burden across countries and regions. Our findings contribute to establishing a standardized uniform approach to measure and classify leprosy endemicity and burden at (sub)national level, which would allow effective communication and planning of intervention strategies.

Appraisal of a Contact Tracing Training Program for COVID-19 in Greece Focusing on Vulnerable Populations.

BACKGROUND: Contact tracing as an epidemiological strategy has repeatedly contributed to the containment of various past epidemics and succeeded in controlling the spread of disease in the community. Systematic training of contact tracers is crucial in ensuring the effectiveness of epidemic containment. METHODS: An intensive training course was offered to 216 health and other professionals who work with vulnerable population groups, such as Roma, refugees, and migrants in Greece, by the scientific team of the postgraduate programme "Global Health-Disaster Medicine" of the Medical School, National and Kapodistrian University of Athens, with the support of the Swiss embassy in Greece. The course was delivered online due to the pandemic restriction measures and was comprised of 16 h over 2 days. The course curriculum was adapted in Greek using, upon agreement, a similar training course to what was developed by the Johns Hopkins University Bloomberg School of Public Health. Evaluation of the course was conducted in order to determine the short term satisfaction from participating in this training course. RESULTS: A total of 70% of the course participants completed the evaluation questionnaires and all trainers gave feedback on the course. The training modules were ranked as extremely useful by the majority of the participants and over 50% of the participants specifically stated that the course content was directly related to their work with vulnerable groups. Content about the ethics of contact tracing and the effective communication skills presented were deemed most useful. CONCLUSION: The course was well organised and provided the required skills for effective contact tracing. Many course participants intend to use some components in their work with vulnerable populations groups. Contact tracing efforts work best in a systematic and coordinated way and the provision of systematic and organised training can greatly increase its effectiveness.

Erratum: Psychosocial burden of neglected tropical diseases in eastern Colombia: an explorative qualitative study in persons affected by leprosy, cutaneous leishmaniasis and Chagas disease - ERRATUM.

[This corrects the article DOI: 10.1017/gmh.2021.18.].

Active case finding of pulmonary TB in a European refugee camp: lessons learnt from Oinofyta hosting site in Greece.

OBJECTIVES: To report on an active case finding (ACF) intervention that took place in the migrant camp of Oinofyta, Greece, upon suspicion of active TB transmission. METHODS: Upon diagnosis of 3 TB cases among camp residents, an ACF intervention among contacts was implemented. All camp residents were offered two-step screening, that is tuberculin skin testing (TST) followed by chest X-ray in case of positive TST (defined as ≥5 mm). RESULTS: 336 of 379 (89%) camp residents underwent TST testing, of whom 110 (33%) exhibited a positive skin reaction. The rate of positive TST results was particularly high in the elderly and significantly higher in adults than in children. Differences by sex or nationality were not observed. Of the 110 cases with positive TST, only 75 underwent chest X-ray, resulting in the detection of one pulmonary TB case in an adult woman. CONCLUSIONS: In the given intervention context, two-step ACF proved to be operationally cumbersome, with many residents lost to follow-up and a high Number Needed to Screen. Simpler ACF designs should be pilot-tested in similar settings in the future, and blanket screening of all camp residents should be reconsidered. Conclusions drawn by these exercises should pave the way for adopting a comprehensive, context-specific and evidence-based national strategy on TB in migrants.

Stigma, participation restriction and mental distress in patients affected by leprosy, cutaneous leishmaniasis and Chagas disease: a pilot study in two co-endemic regions of eastern Colombia.

BACKGROUND: Leprosy, cutaneous leishmaniasis (CL) and Chagas disease (CD) are neglected tropical diseases with a high psychosocial burden (PSB). These conditions are endemic in Norte de Santander and Arauca in Colombia, but data on the related PSB are scarce. Therefore, we assessed mental distress, participation restriction and stigma among CD, CL and leprosy patients. METHODS: In 2018, 305 leprosy, CD or CL patients were interviewed using a self-report questionnaire to assess mental distress, participation scale for participation restriction and explanatory model interview catalogue (EMIC) for stigma. Descriptive statistics and the significance of median score differences were compared. RESULTS: Fifty percent of CD patients and 49% of leprosy patients exhibited mental distress, percentages which were significantly higher than that of CL (26%). Twenty-seven percent of leprosy patients experienced participation restriction, which was lower for CL (6%) and CD (12%). Median EMIC scores were significantly higher for leprosy patients than for CD (27%) and CL (17%) patients. CONCLUSIONS: We found high levels of PSB among leprosy, CD and CL patients. Mental distress was highest among CD patients. Participation restriction and stigma were more prevalent in leprosy patients. Rural residence or lower educational status may impact PSB. Further investigation is needed to formulate evidence-based, holistic interventions.

Non-communicable diseases and tuberculosis: Anticipating the impending global storm.

The epidemiological transitions that have occurred in low and middle income countries (LMIC) during the past decades have led to an increased prevalence on non-communicable diseases (NCDs) in these countries, where the burden of infectious diseases (IDs), especially tuberculosis (TB), remains high. Although the true dimensions of this comorbidity have not yet been fully understood, there is a growing amount of data, over the last 10 years, that suggest a clear association between NCDs and TB. In particular, there is a continuously increasing body of evidence that diabetes mellitus, chronic respiratory conditions, tobacco use, mental health illnesses and chronic kidney disease increase TB morbidity and mortality and vice versa. This bidirectional negative association between diseases may jeopardise the achievement of the Sustainable Development Goals (SDGs) specific TB targets, thus underlying the importance of integrated public health responses towards both epidemics. Population as well as individual based approaches are required, along with both strategic and operation integration on a global scale. This year's United Nations High Level Meetings (ΗLMs) presented a rare opportunity for the political foundations of the TB and NCD responses to be dug together, thus creating a potential breakthrough in the global response to both epidemics.

Factors associated with the delay of diagnosis of leprosy in north-eastern Colombia: a quantitative analysis.

OBJECTIVES: To determine the average time in months between the beginning of symptoms and the diagnostic confirmation of leprosy by the health system and to investigate factors associated with diagnostic delay. METHODS: A total of 249 patients older than 15 years diagnosed with leprosy between 2011 and 2015, in 20 endemic municipalities of north-eastern Colombia, provided informed consent and were interviewed face-to-face. Clinical histories from health centres or hospitals where study participants were treated for leprosy were also reviewed. RESULTS: The mean delay in diagnosis of leprosy was 33.5 months. About 14.9% of patients showed a visible deformity or damage (disability grade 2, DG2) at the time of diagnosis. In multivariable regression analysis, five or more consultancies required to confirm the diagnosis and not seeking care immediately after noticing first symptoms were associated with longer diagnostic delay. CONCLUSIONS: Our study found a significant delay in diagnosis of leprosy in north-eastern Colombia, which might explain the continuously high rate of DG2 among new cases being notified in the country. Both patient- and health system-related factors were associated with longer diagnostic delay. Interventions to increase awareness of disease among the general population and timely referral to a specialised health professional are urgently needed in our study setting.

Trends and patterns in leprosy in nine states of the Republic of the Sudan 7 years after the introduction of routine contact screening.

Background: This paper analyzes the trends of key indicators reflecting the epidemiological situation of leprosy in nine different states of the Republic of the Sudan after the introduction of a systematic contact screening in 2010. Methods: The routinely assessed data from the leprosy control program from 2010 to 2016 were analyzed. Results: Despite, intense contact screening, the overall number of new cases detected showed a decreasing trend. The female:male ratio among new cases was constantly low. The overall average number of contacts needed to screen in order to detect a new case among contacts was 64. However, this number varied significantly in the nine states under investigation, with the best yield being observed in the state with the lowest case detection rate. Conclusions: The total number of new cases of leprosy in nine states of the Republic of the Sudan has shown declining tendencies since 2010. Our data are not suggestive of a significant impact of contact screening on the trends of leprosy key indicators. Overall, contact screening proved to be efficient in most states, including those that exhibited very low annual new case detection rates (ANCDRs). Sensitization of personnel undergoing training and measures improving access of females to leprosy services are urgently needed.

Insulin-like growth factor (IGF)-I and insulin in normal and growth-restricted mother/infant pairs.

Insulin-like growth factor (IGF)-I and insulin are essential for fetal growth. We investigated perinatal changes of both factors in 40 mothers and their 20 appropriate-for-gestational-age (AGA) and 20 intrauterine-growth-restricted (IUGR) fetuses and neonates on day 1 (N1) and day 4 (N4) postpartum. Fetal and N1, but not N4, IGF-I levels were increased in AGA (P < .001 and P = .037, resp.). N1 insulin levels were lower in IUGR (P = .048). Maternal, fetal, and N1 IGF-I, and fetal insulin levels positively correlated with customized centiles (r = .374, P = .035, r = .608, P < .001, r = .485, P = .006, and r = .654, P = .021, resp.). Female infants presented elevated fetal and N4 IGF-I levels (P = .023 and P = .016, resp.). Positive correlations of maternal, fetal, and neonatal IGF-I levels, and fetal insulin levels with customized centiles underline implication of both hormones in fetal growth. IUGR infants present gradually increasing IGF-I levels. Higher IGF-I levels are documented in females.

Intrauterine growth restriction and circulating neurotrophin levels at term.

BACKGROUND: Intrauterine growth restricted (IUGR) fetuses are those with estimated weight <10th customized centile, displaying signs of chronic malnutrition and hypoxia leading to brain sparing effect. Neurotrophins, [Nerve Growth Factor (NGF), Brain Derived Neurotrophic Factor (BDNF), Neurotrophin-3 (NT-3), Neurotrophin-4 (NT-4)] are important for pre- and post-natal brain development. AIMS: To investigate circulating NGF, BDNF, NT-3 and NT-4 levels in IUGR and appropriate for gestational age (AGA) fullterm fetuses and neonates (day-1 [N1] and day-4 [N4]) and in their mothers. STUDY DESIGN: Prospective case control study. SUBJECTS: 60 mothers and their single 30 IUGR and 30 AGA fullterm fetuses and neonates. OUTCOME MEASURES: Determination, by enzyme immunoassays, of NGF, BDNF, NT-3 and NT-4 plasma levels. RESULTS: No statistically significant differences existed between IUGR and AGA maternal, fetal and neonatal levels of BDNF, NT-3 and NT-4. NGF was significantly higher in AGA than IUGR maternal (p=0.007), fetal (p=0.01), neonatal day 1 (p=0.043) and 4 (p=0.003) plasma, and positively correlated with the infants' centiles and birthweights. IUGR and AGA maternal neurotrophins were higher than the respective fetal and neonatal ones and no correlation with gender or delivery mode in both groups was observed. CONCLUSIONS: In the perinatal period, circulating levels of BDNF, NT-3 and NT-4 do not differ in IUGR and AGA pregnancies, in contrast to NGF levels, which are higher in the AGA group. NGF is the only neurotrophin correlating with customized centiles and birthweights of the infants. Neurotrophin concentrations are higher in maternal plasma and do not depend on gender.

Perinatal plasma monocyte chemotactic protein-1 concentrations in intrauterine growth restriction.

Monocyte-chemotactic-protein-1 (MCP-1) plays vital roles in immune response, angiogenesis, and pregnancy outcome. We investigated plasma MCP-1 concentrations in 40 mothers and their 20 intrauterine-growth-restricted (IUGR) and 20 appropriate-for-gestational-age (AGA) fetuses and neonates on postnatal days 1 (N1) and 4 (N4). Maternal and fetal MCP-1 concentrations were decreased (P<001 and P = .018, resp.), whereas N1 MCP-1 concentrations were elevated in IUGR group (P = .012). In both groups, fetal MCP-1 concentrations were lower compared to N1 and N4 ones (P = .045, P = .012, resp., for AGA, P< .001 in each case for IUGR). Reduced maternal and fetal MCP-1 concentrations in IUGR may reflect failure of trophoblast invasion, suggesting that down-regulation of MCP-1 may be involved in the pathogenesis of IUGR. Increased MCP-1 concentrations in IUGR neonates and higher postnatal ones in all infants may be attributed to gradual initiation of ex utero angiogenesis, which is possibly enhanced in IUGR.

Investigation of midtrimester amniotic fluid factors as potential predictors of term and preterm deliveries.

AIMS: Our aim is to investigate, in 13 cases (delivering preterm) and 21 matched (for age, parity, and gestational age) controls (delivering at term), whether midtrimester amniotic fluid concentrations of elastase, secretory leukocyte proteinase inhibitor (SLPI), soluble intercellular adhesion molecule-1, and soluble vascular cell adhesion molecule predict asymptomatic intra-amniotic inflammation/infection and preterm labor. RESULTS: Concentrations of all substances were not statistically different among mothers, delivering preterm or at term. SLPI concentrations significantly increased in women, going into labor without ruptured membranes, irrespective of pre- or term delivery (P < .007, P < .001, resp) and correlated with elastase (r = 0.508, P < .002). CONCLUSIONS: Midtrimester amniotic fluid SLPI concentrations significantly decrease when membrane rupture precedes pre- or full-term labor. However, none of the investigated substances predict preterm delivery.

Soluble vascular endothelial growth factor receptor-1 in intrauterine growth restricted fetuses and neonates.

BACKGROUND: Angiogenesis, a critical process for growth and development is altered in intrauterine growth restriction (IUGR). Vascular endothelial growth factor (VEGF) and its receptors VEGFR-1, soluble (s) VEGFR-1 and VEGFR-2 represent a regulatory system, essential for both physiological and pathological angiogenesis. AIM: To study the implication of sVEGFR-1-a VEGF antagonist-in IUGR. STUDY DESIGN: Prospective study. METHODS: Twenty-five IUGR and 15 appropriate for gestational age (AGA) full-term fetuses and neonates with their mothers were included in the study. OUTCOME MEASURES: sVEGFR-1 levels were determined by enzyme immunoassay in the serum of: mothers (MS), umbilical cords (UC)-representing fetal state - and neonates on day 1 (N1) and 4 (N4) of life. RESULTS: MS, UC, N1 and N4 sVEGFR-1 levels in IUGR were significantly higher compared to respective AGA cases (p = 0.005, p = 0.026, p = 0.005 and p = 0.017, respectively). In IUGR and AGA groups, maternal sVEGFR-1 levels were significantly higher than fetal and neonatal levels (p in all cases < 0.001). The latter presented in both IUGR and AGA groups a significant decrease from UC to N4 (p in all cases < 0.01). MS, N1 and N4 sVEGFR-1 levels negatively correlated with the infants' customized centiles [(r = -0.489, p = 0.001), (r = -0.440, p = 0.004), (r = -0.431, p = 0.006), respectively]. CONCLUSIONS: Higher sVEGFR-1 levels in the IUGR as compared to the AGA group possibly reflect the predominance of antiangiogenic mechanisms present in IUGR. The decrease of sVEGFR-1 levels from UC to N4 may represent ex utero initiation of growth and development and therefore, prevalence of angiogenic mechanisms.

Possible early prediction of preterm birth by determination of novel proinflammatory factors in midtrimester amniotic fluid.

Interferon-gamma-inducible T cell-alpha chemoattractant (ITAC) is a chemokine, directing activated T lymphocytes toward sites of inflammation. ADAM-8 (A disintegrin and metalloprotease-8) is a glycoprotein expressed in cells promoting inflammation. Elastase, a protease targeting at the degradation of intra- or extracellular proteins, is inhibited by secretory leukocyte proteinase inhibitor (SLPI), which protects against microbial invasion. Adhesion molecules (soluble intercellular adhesion molecule--sICAM-1 and soluble vascular cell adhesion molecule-sVCAM--1) serve as markers of inflammation or tissue damage. We hypothesized that elevated midtrimester amniotic fluid concentrations of above substances, and decreased levels of SLPI could possibly be useful predictors of asymptomatic intra-amniotic inflammation and/or infection, eventually resulting in preterm labor and delivery. The study involved 312 women undergoing midtrimester amniocentesis. Thirteen cases, progressing to preterm delivery (<37 weeks), were matched with 21 controls (delivering >37 weeks) for age, parity, and gestational age at amniocentesis. Amniotic fluid levels of the above substances were measured by enzyme-linked immunosorbent assay (ELISA). Only amniotic fluid ITAC and ADAM-8 levels were significantly higher (P=0.005 and P < 0.02, respectively) in women delivering at <37 weeks than at >37 weeks. SLPI concentrations significantly increased in women going into labor without ruptured membranes irrespective of pre- or term delivery (P < 0.007, P < 0.001, respectively) and correlated with elastase (r=0.508, P < 0.002). In conclusion, elevated midtrimester amniotic fluid levels of ITAC and ADAM-8 could predict occult infections/inflammations, possibly resulting in preterm birth.