Case detection delay in leprosy: Testing tool reliability and measurement consistency in Ethiopia, Mozambique, and Tanzania.

BACKGROUND: Case detection delay (CDD) in leprosy is defined as the period between the onset of the first signs and symptoms and the time of diagnosis. A tool, consisting of a questionnaire and a detailed guide for researchers, which includes photos of typical skin signs and notes on establishing the timing of events, was developed to determine this period of delay in months in recently diagnosed leprosy patients. The aims of the study were to determine the reliability and consistency of this CDD assessment tool. METHODS: This study was conducted in Ethiopia, Mozambique and Tanzania. Two types of consistency were considered: over time (test-retest reliability) and across different researchers (interrater reliability). A CDD questionnaire was administered to 167 leprosy patients who were diagnosed within 6 months prior to their inclusion. One month later, the same or another researcher re-administered the CDD questionnaire to the same patients. Both test-retest and interrater reliability were assessed using the intraclass correlation coefficient (ICC), where a value greater than or equal to 0.7 is considered acceptable. RESULTS: In this study, 10 participants (6.0%) were under 15 years of age, and 56 (33.5%) were women. In the test-retest assessment, the mean CDD from the first and second interviews was 23.7 months (95% CI 14.4-34.8) and 24.0 months (95% CI 14.8-33.2), respectively. The ICC for test-retest reliability was 0.99 (95% CI 0.994-0.997). For the interrater reliability assessment, the first and second interviews revealed a mean CDD of 24.7 months (95% CI 18.2-31.1) and 24.6 months (95% CI 18.7-30.5), respectively, with an ICC of 0.90 (95% CI 0.85-0.94). A standard error of measurement of 0.46 months was found in the test-retest and 1.03 months in the interrater measurement. Most answers given by participants during the first and second interviews were matching (≥86%). Most non-matching answers were in the 0-2 month delay category (≥46%). CONCLUSION: The tool, including a questionnaire to determine the CDD of newly diagnosed leprosy patients, was validated in three African countries. The test-retest and interrater measurements demonstrated that the instrument is reliable and measures consistently. The tool can be used in routine leprosy programmes as well as in research settings.

Establishing a standard method for analysing case detection delay in leprosy using a Bayesian modelling approach.

BACKGROUND: Leprosy is an infectious disease caused by Mycobacterium leprae and remains a source of preventable disability if left undetected. Case detection delay is an important epidemiological indicator for progress in interrupting transmission and preventing disability in a community. However, no standard method exists to effectively analyse and interpret this type of data. In this study, we aim to evaluate the characteristics of leprosy case detection delay data and select an appropriate model for the variability of detection delays based on the best fitting distribution type. METHODS: Two sets of leprosy case detection delay data were evaluated: a cohort of 181 patients from the post exposure prophylaxis for leprosy (PEP4LEP) study in high endemic districts of Ethiopia, Mozambique, and Tanzania; and self-reported delays from 87 individuals in 8 low endemic countries collected as part of a systematic literature review. Bayesian models were fit to each dataset to assess which probability distribution (log-normal, gamma or Weibull) best describes variation in observed case detection delays using leave-one-out cross-validation, and to estimate the effects of individual factors. RESULTS: For both datasets, detection delays were best described with a log-normal distribution combined with covariates age, sex and leprosy subtype [expected log predictive density (ELPD) for the joint model: -1123.9]. Patients with multibacillary (MB) leprosy experienced longer delays compared to paucibacillary (PB) leprosy, with a relative difference of 1.57 [95% Bayesian credible interval (BCI): 1.14-2.15]. Those in the PEP4LEP cohort had 1.51 (95% BCI: 1.08-2.13) times longer case detection delay compared to the self-reported patient delays in the systematic review. CONCLUSIONS: The log-normal model presented here could be used to compare leprosy case detection delay datasets, including PEP4LEP where the primary outcome measure is reduction in case detection delay. We recommend the application of this modelling approach to test different probability distributions and covariate effects in studies with similar outcomes in the field of leprosy and other skin-NTDs.

Development of a questionnaire to determine the case detection delay of leprosy: A mixed-methods cultural validation study.

BACKGROUND: Delay in case detection is a risk factor for developing leprosy-related impairments, leading to disability and stigma. The objective of this study was to develop a questionnaire to determine the leprosy case detection delay, defined as the period between the first signs of the disease and the moment of diagnosis, calculated in total number of months. The instrument was developed as part of the PEP4LEP project, a large-scale intervention study which determines the most effective way to implement integrated skin screening and leprosy post-exposure prophylaxis with a single-dose of rifampicin (SDR-PEP) administration in Ethiopia, Mozambique and Tanzania. METHODOLOGY/PRINCIPAL FINDINGS: A literature review was conducted and leprosy experts were consulted. The first draft of the questionnaire was developed in Ethiopia by exploring conceptual understanding, item relevance and operational suitability. Then, the first draft of the tool was piloted in Ethiopia, Mozambique and Tanzania. The outcome is a questionnaire comprising nine questions to determine the case detection delay and two annexes for ease of administration: a local calendar to translate the patient's indication of time to number of months and a set of pictures of the signs of leprosy. In addition, a body map was included to locate the signs. A 'Question-by-Question Guide' was added to the package, to provide support in the administration of the questionnaire. The materials will be made available in English, Oromiffa (Afaan Oromo), Portuguese and Swahili via https://www.infolep.org. CONCLUSIONS/SIGNIFICANCE: It was concluded that the developed case detection delay questionnaire can be administered quickly and easily by health workers, while not inconveniencing the patient. The instrument has promising potential for use in future leprosy research. It is recommended that the tool is further validated, also in other regions or countries, to ensure cultural validity and to examine psychometric properties like test-retest reliability and interrater reliability.

PEP4LEP study protocol: integrated skin screening and SDR-PEP administration for leprosy prevention: comparing the effectiveness and feasibility of a community-based intervention to a health centre-based intervention in Ethiopia, Mozambique and Tanzania.

INTRODUCTION: Leprosy, or Hansen's disease, remains a cause of preventable disability. Early detection, treatment and prevention are key to reducing transmission. Post-exposure prophylaxis with single-dose rifampicin (SDR-PEP) reduces the risk of developing leprosy when administered to screened contacts of patients. This has been adopted in the WHO leprosy guidelines. The PEP4LEP study aims to determine the most effective and feasible method of screening people at risk of developing leprosy and administering chemoprophylaxis to contribute to interrupting transmission. METHODS AND ANALYSIS: PEP4LEP is a cluster-randomised implementation trial comparing two interventions of integrated skin screening combined with SDR-PEP distribution to contacts of patients with leprosy in Ethiopia, Mozambique and Tanzania. One intervention is community-based, using skin camps to screen approximately 100 community contacts per leprosy patient, and to administer SDR-PEP when eligible. The other intervention is health centre-based, inviting household contacts of leprosy patients to be screened in a local health centre and subsequently receive SDR-PEP when eligible. The mobile health (mHealth) tool SkinApp will support health workers' capacity in integrated skin screening. The effectiveness of both interventions will be compared by assessing the rate of patients with leprosy detected and case detection delay in months, as well as feasibility in terms of cost-effectiveness and acceptability. ETHICS AND DISSEMINATION: Ethical approval was obtained from the national ethical committees of Ethiopia (MoSHE), Mozambique (CNBS) and Tanzania (NIMR/MoHCDEC). Study results will be published open access in peer-reviewed journals, providing evidence for the implementation of innovative leprosy screening methods and chemoprophylaxis to policymakers. TRIAL REGISTRATION NUMBER: NL7294 (NTR7503).

Mycobacterium leprae transmission characteristics during the declining stages of leprosy incidence: A systematic review.

BACKGROUND: Leprosy is an infectious disease caused by Mycobacterium leprae. As incidence begins to decline, the characteristics of new cases shifts away from those observed in highly endemic areas, revealing potentially important insights into possible ongoing sources of transmission. We aimed to investigate whether transmission is driven mainly by undiagnosed and untreated new leprosy cases in the community, or by incompletely treated or relapsing cases. METHODOLOGY/PRINCIPAL FINDINGS: A literature search of major electronic databases was conducted in January, 2020 with 134 articles retained out of a total 4318 records identified (PROSPERO ID: CRD42020178923). We presented quantitative data from leprosy case records with supporting evidence describing the decline in incidence across several contexts. BCG vaccination, active case finding, adherence to multidrug therapy and continued surveillance following treatment were the main strategies shared by countries who achieved a substantial reduction in incidence. From 3950 leprosy case records collected across 22 low endemic countries, 48.3% were suspected to be imported, originating from transmission outside of the country. Most cases were multibacillary (64.4%) and regularly confirmed through skin biopsy, with 122 cases of suspected relapse from previous leprosy treatment. Family history was reported in 18.7% of cases, while other suspected sources included travel to high endemic areas and direct contact with armadillos. None of the countries included in the analysis reported a distinct increase in leprosy incidence in recent years. CONCLUSIONS/SIGNIFICANCE: Together with socioeconomic improvement over time, several successful leprosy control programmes have been implemented in recent decades that led to a substantial decline in incidence. Most cases described in these contexts were multibacillary and numerous cases of suspected relapse were reported. Despite these observations, there was no indication that these cases led to a rise in new secondary cases, suggesting that they do not represent a large ongoing source of human-to-human transmission.

High prevalence of antibiotic resistance in commensal Escherichia coli from healthy human sources in community settings.

Antibiotic resistance is a global health crisis that requires urgent action to stop its spread. To counteract the spread of antibiotic resistance, we must improve our understanding of the origin and spread of resistant bacteria in both community and healthcare settings. Unfortunately, little attention is being given to contain the spread of antibiotic resistance in community settings (i.e., locations outside of a hospital inpatient, acute care setting, or a hospital clinic setting), despite some studies have consistently reported a high prevalence of antibiotic resistance in the community settings. This study aimed to investigate the prevalence of antibiotic resistance in commensal Escherichia coli isolates from healthy humans in community settings in LMICs. Using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, we synthesized studies conducted from 1989 to May 2020. A total of 9363 articles were obtained from the search and prevalence data were extracted from 33 articles and pooled together. This gave a pooled prevalence of antibiotic resistance (top ten antibiotics commonly prescribed in LMICs) in commensal E. coli isolates from human sources in community settings in LMICs of: ampicillin (72% of 13,531 isolates, 95% CI: 65-79), cefotaxime (27% of 6700 isolates, 95% CI: 12-44), chloramphenicol (45% of 7012 isolates, 95% CI: 35-53), ciprofloxacin (17% of 10,618 isolates, 95% CI: 11-25), co-trimoxazole (63% of 10,561 isolates, 95% CI: 52-73), nalidixic acid (30% of 9819 isolates, 95% CI: 21-40), oxytetracycline (78% of 1451 isolates, 95% CI: 65-88), streptomycin (58% of 3831 isolates, 95% CI: 44-72), tetracycline (67% of 11,847 isolates, 95% CI: 59-74), and trimethoprim (67% of 3265 isolates, 95% CI: 59-75). Here, we provided an appraisal of the evidence of the high prevalence of antibiotic resistance by commensal E. coli in community settings in LMICs. Our findings will have important ramifications for public health policy design to contain the spread of antibiotic resistance in community settings. Indeed, commensal E. coli is the main reservoir for spreading antibiotic resistance to other pathogenic enteric bacteria via mobile genetic elements.

Hepatitis B mother-to-child transmission in the Eastern Region of Ghana: a cross-sectional pilot study.

INTRODUCTION: Hepatitis B is a major health concern in Ghana, where prevalence of the virus remains high and most chronic patients are infected during childhood or at birth. This study aimed to determine the prevalence and main factors associated with mother-to-child transmission of hepatitis B in the context of Ghana. METHODS: In this cross-sectional pilot study, we tested infants born to hepatitis B positive mothers at a hospital in the Eastern Region of Ghana to determine the prevalence of mother-to-child transmission. A questionnaire was completed by hepatitis B positive mothers to investigate the association between factors surrounding the birth of the child and whether transmission had occurred. These factors were analyzed independently using Fisher's exact test. To investigate the relationship between mother's age at the time of delivery and viral transmission, a univariate logistic regression analysis was performed. RESULTS: The prevalence of mother-to-child transmission was 5.9%, with 51 hepatitis B positive mothers included in the study and three infants testing positive. A majority of infants received the standard hepatitis B vaccination schedule (96.1%) while two-thirds received the birth dose. There was no significant association observed between the clinical interventions reported in the study and mother-to-child transmission. No significant association was observed between the age of the mother at the time of delivery and viral transmission (OR: 1.077, 95% CI: 0.828 - 1.403, p = 0.58). Viral marker testing during pregnancy was absent in the population and could not be reliably assessed. CONCLUSION: There was a low prevalence of HBV mother-to-child transmission observed despite a clear absence of viral marker and viral load testing. It is recommended that viral profile analysis is performed for hepatitis B positive pregnancies to identify high risk cases.

Monogenic mutations differentially affect the quantity and quality of T follicular helper cells in patients with human primary immunodeficiencies.

BACKGROUND: Follicular helper T (TFH) cells underpin T cell-dependent humoral immunity and the success of most vaccines. TFH cells also contribute to human immune disorders, such as autoimmunity, immunodeficiency, and malignancy. Understanding the molecular requirements for the generation and function of TFH cells will provide strategies for targeting these cells to modulate their behavior in the setting of these immunologic abnormalities. OBJECTIVE: We sought to determine the signaling pathways and cellular interactions required for the development and function of TFH cells in human subjects. METHODS: Human primary immunodeficiencies (PIDs) resulting from monogenic mutations provide a unique opportunity to assess the requirement for particular molecules in regulating human lymphocyte function. Circulating follicular helper T (cTFH) cell subsets, memory B cells, and serum immunoglobulin levels were quantified and functionally assessed in healthy control subjects, as well as in patients with PIDs resulting from mutations in STAT3, STAT1, TYK2, IL21, IL21R, IL10R, IFNGR1/2, IL12RB1, CD40LG, NEMO, ICOS, or BTK. RESULTS: Loss-of-function (LOF) mutations in STAT3, IL10R, CD40LG, NEMO, ICOS, or BTK reduced cTFH cell frequencies. STAT3 and IL21/R LOF and STAT1 gain-of-function mutations skewed cTFH cell differentiation toward a phenotype characterized by overexpression of IFN-γ and programmed death 1. IFN-γ inhibited cTFH cell function in vitro and in vivo, as corroborated by hypergammaglobulinemia in patients with IFNGR1/2, STAT1, and IL12RB1 LOF mutations. CONCLUSION: Specific mutations affect the quantity and quality of cTFH cells, highlighting the need to assess TFH cells in patients by using multiple criteria, including phenotype and function. Furthermore, IFN-γ functions in vivo to restrain TFH cell-induced B-cell differentiation. These findings shed new light on TFH cell biology and the integrated signaling pathways required for their generation, maintenance, and effector function and explain the compromised humoral immunity seen in patients with some PIDs.