Efficacy of Thermotherapy to Treat Cutaneous Leishmaniasis: A Meta-Analysis of Controlled Clinical Trials

Introduction

The efficacy of thermotherapy for the treatment of cutaneous leishmaniasis presents diverse results with low statistical power.

Objective

To evaluate the efficacy of thermotherapy to treat cutaneous leishmaniasis.

Methods

A meta-analysis of controlled clinical trials in 12 databases based on the implementation of a research protocol with inclusion and exclusion criteria and an assessment of methodological quality. The reproducibility and completeness were guaranteed in the information search and extraction. Heterogeneity, sensitivity and publication bias were assessed by graphical methods (Galbraith, L''Abblé, funnel plot, Egger plot, and influence plot) and analytical methods (DerSimonian-Laird, Begg and Egger). Random-effects forest plots were constructed, and a cumulative meta-analysis was performed.

Results

Eight studies were included with 622 patients who underwent thermotherapy, with an efficacy of 73.2% (95% confidence interval (CI) = 69.6-76.7%), and with 667 patients who underwent systemic treatment, with an efficacy of 70.6% (95% CI=67.1-74.1%). Heterogeneity between studies, good sensitivity for the combined measure, and no publication bias were observed. The relative risk for comparison of the efficacy of treatment was 1.02 (95%CI=0.91, 1.15), showing that the effectiveness of thermotherapy is equal to that of pentavalent antimonial drugs.

Conclusion

Due to its efficacy, greater safety and lower cost, thermotherapy should be the first treatment option for cutaneous leishmaniasis in areas where the prevalence of the mucocutaneous form is low and in patients with contraindications to systemic treatment, such as kidney, liver and heart diseases, as well as in pregnant women, infants, and patients with human immunodeficiency virus infection/acquired immune deficiency syndrome.     

Risk Factors for Anthroponotic Cutaneous Leishmaniasis at the Household Level in Kabul,Afghanistan

Background

Kabul, Afghanistan, is the largest focus of anthroponotic cutaneous leishmaniasis (ACL) in the world. ACL is a protozoan disease transmitted to humans by the bite of phlebotomine sand flies. Although not fatal, ACL can lead to considerable stigmatization of affected populations.

Methods

Using data from a standardized survey of 872 households in 4 wards of Kabul, Afghanistan, univariate and multivariate logistic regression analyses tested associations between presence of active ACL and ACL scars with 15 household-level variables.

Findings

Univariate analyses showed that active ACL was positively associated with household member''s age, ACL prevalence, and brick wall type, but negatively associated with household number of rooms, bednet use, and proportion of windows with screens. Multivariate analysis showed a positive association between active ACL and household member''s age, ACL prevalence, and brick wall type, and a negative association with household proportion of windows with screens.

Conclusion

Household-level charateristics were shown to be risk factors for ACL. Monitoring a selected number of household characteristics could assist in rapid assessments of household-level variation in risk of ACL. ACL prevention and control programs should consider improving house construction, including smoothing of walls and screening of windows.     

Forecasting Temporal Dynamics of Cutaneous Leishmaniasis in Northeast Brazil

Introduction

Cutaneous leishmaniasis (CL) is a vector-borne disease of increasing importance in northeastern Brazil. It is known that sandflies, which spread the causative parasites, have weather-dependent population dynamics. Routinely-gathered weather data may be useful for anticipating disease risk and planning interventions.

Methodology/Principal Findings

We fit time series models using meteorological covariates to predict CL cases in a rural region of Bahía, Brazil from 1994 to 2004. We used the models to forecast CL cases for the period 2005 to 2008. Models accounting for meteorological predictors reduced mean squared error in one, two, and three month-ahead forecasts by up to 16% relative to forecasts from a null model accounting only for temporal autocorrelation.

Significance

These outcomes suggest CL risk in northeastern Brazil might be partially dependent on weather. Responses to forecasted CL epidemics may include bolstering clinical capacity and disease surveillance in at-risk areas. Ecological mechanisms by which weather influences CL risk merit future research attention as public health intervention targets.     

Assessing Reports of Therapeutic Trials

A check list is described which helps the systematic assessment of reports of therapeutic trials, particularly the aspects that need to be considered in assessing their validity. The check list was used to examine 141 reports of therapeutic trials published in four British non-specialist journals in the first six months of 1966 and of 1969. Of these reports 51% were found to be acceptable and a further 16% probably acceptable; 33% were considered unacceptable because they lacked one or more of the features required in a valid report. The check list has been found useful in assessing claims made for drugs and other therapeutic measures on the basis of published reports.     

Risk factors for antimony treatment failure in American Cutaneous Leishmaniasis in Northwestern-Argentina

Background. To date, there is no specific literature available on the determinants for therapeutic failure (TF) with meglumine antimoniate (MA) in Northwestern-Argentina. This study aimed to identify epidemiological, clinical, and treatment-related factors that could be involved in TF. Methodology/Principal Findings. We performed a case-control study. Cases were represented by patients who showed TF after administration of the first course of MA treatment, whereas, controls were determined as patients who evolved towards healing after the first MA cycle received. Crude Odds Ratios and their corresponding 90% confidence intervals (CI) were calculated, and risk factors were then tested by multivariate analysis using logistic binary regression. Three hundred and eighty-four patients with a presumptive diagnosis of ACL were recruited, and 153 with a positive diagnosis were selected. We included in the study 71 patients, who underwent specific treatment with MA, presented complete data on response to treatment, and had a minimum post-treatment follow-up of 6 months in cutaneous leishmaniasis, and 12 months in mucosal leishmaniasis. Of these, 34 (47.9%) presented TF. In the initial analysis, TF was significantly associated with the geographical area of disease acquisition (p = 0.036), the presence of mucosal lesions (p = 0.042), the presence of concomitant skin and mucosal lesions (p = 0.002), and lesion age ≥ 6 months (p = 0.018). Risk factors influencing TF in the final multivariate model included the geographical area where the disease was acquired (adjusted Odd Ratio 8.062; 95% CI 1.914–33.959; p = 0.004), and lesion age ≥ 6 months (adjusted Odd Ratio 10.037; 95% CI 1.383–72.843; p = 0.023). Conclusions/Significance. The results of the present study suggest the existence of some risk factors linked to TF in Northwestern-Argentina, which deserve further investigation. Herein we recorded a high percentage of TF and we described clinical and epidemiological characteristics associated with TF that could be taken into account improving the clinical management of patients.     

Cutaneous Leishmaniasis: An Overlooked Etiology of Midfacial Destructive Lesions

Background

Midline destructive lesions of the face (MDL) have a wide range of etiologies. Cutaneous Leishmaniasis (CL) is rarely reported as a possible cause.

Methods

Fifteen patients with solitary nasal lesions caused by CL were studied. The clinical data, biopsies/scrapings and PCR were collected/performed. Ridley’s Pattern (RP) and Parasitic Index (PI) were documented.

Results

Patients’ age ranged from 1 to 60 years including 7 males and 8 females. The duration of the observed lesions ranged from 1 to 18 months. Clinically, the lesions showed 6 patterns varying from dermal erythematous papulonodular with no epidermal changes to destructive erythematous plaque with massive central hemorrhagic crust. The clinical impression ranged from neoplastic to inflammatory processes. RP varied among the cases [RP 3 (n = 6), RP 4 (n = 3), RP 5 (n = 6)]. All cases show low PI [PI 0 (n = 7), PI 1 (n = 6), PI 2 (n = 1), and PI 3 (n = 1)]. Higher PI was noted in the pediatric group [average age 24 years for PI 0–1 vs. 6.5 years for PI 2–3]. Molecular speciation showed Leishmania tropica (n = 13) and Leishmania major (n = 2). All the patients received Meglumine Antimoniate (Glucantine) injections and had initial cure defined as complete scarring and disappearance of inflammatory signs within 3 months.

Conclusion

Leishmaniasis may cause MDL especially in endemic areas. PCR is instrumental in confirming the diagnosis. MDL caused by CL showed wide spectrum of clinical and microscopic presentation.     

An Epidemiological Study of Cutaneous Leishmaniasis in Al-Jabal Al-Gharbi,Libya

Cutaneous leishmaniasis (CL) is an endemic parasitic infection in the Mediterranean region, including Libya and its Al-jabal Al-gharbi province. We aimed at studying the occupational relevance as well as other epidemiological aspects of CL. We investigated 140 CL cases who attended at Gharyan outpatient polyclinic during a period of 6 months in 2009. CL infection was clinically diagnosed and confirmed by demonstration of Leishmania parasites on smears from lesions. Our findings showed that males were more affected than females (P=0.04), and people above 10-years were more affected than younger ones (P=0.0001). A significant percent of CL cases belonged to Al-Kawasem subprovince (P=0.0001). Farm-related activities were the most frequent occupations among CL cases (P=0.04). In addition to farm workers, housewives and students are at risk groups since they are engaged at farm activities. Moreover, those who have occupations that require staying outdoors for a part of night, e.g., policemen, are also at risk. Compared to children, adult CL patients had multiple lesions (P=0.001) that were more prevalent in their upper and lower extremities than the face (P=0.0001). We conclude that CL is a major health problem in Al-jabal Al-gharbi province of Libya. The presence of rodents and sandflies makes it a suitable environment for Leishmania to spread in an endemic epidemiological pattern. Being engaged in farming activities or outdoor occupations increases the risk of infection. Various clinical patterns of CL suggest the presence of more than 1 species of Leishmania at Al-jabal Al-gharbi province. We propose that the 2 species responsible for CL in this area are L. major and L. tropica. Further investigations to identify the leishmanial species responsible for CL at Al-jabal Al-gharbi together with adoption of preventive and control programs are needed.     

Molecular Characterization of Leishmania Species Isolated from Cutaneous Leishmaniasis in Yemen

Background

Cutaneous leishmaniasis (CL) is a neglected tropical disease endemic in the tropics and subtropics with a global yearly incidence of 1.5 million. Although CL is the most common form of leishmaniasis, which is responsible for 60% of DALYs lost due to tropical-cluster diseases prevalent in Yemen, available information is very limited.

Methodology/Principal Findings

This study was conducted to determine the molecular characterization of Leishmania species isolated from human cutaneous lesions in Yemen. Dermal scrapes were collected and examined for Leishmania amastigotes using the Giemsa staining technique. Amplification of the ribosomal internal transcribed spacer 1(ITS-1) gene was carried out using nested PCR and subsequent sequencing. The sequences from Leishmania isolates were subjected to phylogenetic analysis using the neighbor-joining and maximum parsimony methods. The trees identified Leishmania tropica from 16 isolates which were represented by two sequence types.

Conclusions/Significance

The predominance of the anthroponotic species (i.e. L. tropica) indicates the probability of anthroponotic transmission of cutaneous leishmaniasis in Yemen. These findings will help public health authorities to build an effective control strategy taking into consideration person–to-person transmission as the main dynamic of transmission of CL.     

Effectiveness of Holistic Interventions for People with Severe Chronic Obstructive Pulmonary Disease: Systematic Review of Controlled Clinical Trials

Background

Despite a well-recognised burden of disabling physical symptoms compounded by co-morbidities, psychological distress and social isolation, the needs of people with severe chronic obstructive pulmonary disease (COPD) are typically poorly addressed.

Aim

To assess the effectiveness of interventions designed to deliver holistic care for people with severe COPD.

Methods

We searched 11 biomedical databases, three trial repositories (January 1990-March 2012; no language restrictions) and contacted international experts to locate published, unpublished and in-progress randomised controlled trials (RCTs), quasi-RCTs and controlled clinical trials (CCTs) that investigated holistic interventions to support patients with severe COPD in any healthcare context. The primary outcome was health-related quality of life (HRQoL). Quality assessment and data extraction followed Cochrane Collaboration methodology. We used a piloted data extraction sheet and undertook narrative synthesis.

Results

From 2,866 potentially relevant papers, we identified three trials: two RCTs (from United States and Australia), and one CCT (from Thailand): total 216 patients. Risk of bias was assessed as moderate in two studies and high in the third. All the interventions were led by nurses acting in a co-ordinating role (e.g. facilitating community support in Thailand, providing case-management in the USA, or co-ordinating inpatient care in Australia). HRQoL improved significantly in the Thai CCT compared to the (very limited) usual care (p<0.001), in two sub-domains in the American trial, but showed no significant changes in the Australian trial. Exercise tolerance, dyspnoea, and satisfaction with care also improved in the Thai trial.

Conclusions

Some 15 years after reports first highlighted the unmet needs of people with severe COPD, we have been unable to find robust trial evidence about interventions that can address those needs. There is an urgent need to develop and evaluate holistic care interventions designed improve HRQoL for people with severe COPD.

Systematic Review Registration

PROSPERO (CRD42012002430).     

Dressings Combined with Injection of Meglumine Antimoniate in the Treatment of Cutaneous Leishmaniasis: A Randomized Controlled Clinical Trial

Background

Cutaneous leishmaniasis (CL) is a neglected infectious disease and a major health problem in several developing countries. Despite some reasonable explanation for their potential benefits, there is only trace evidence regarding the role of dressings in the treatment of CL.

Methods

This randomized, assessor-blind, controlled, clinical trial was conducted in an endemic area for CL caused by Leishmania major in Iran to assess the efficacy of administration of weekly intralesional meglumine antimoniate (i.l.MA) either alone or combined with application of a silver or a non-silver polyester dressing on their lesions for 6 weeks. After screening of 241 patients with CL lesions, 83 eligible patients with 158 lesions were randomly allocated in three arms of the study. Eligibility criteria included parasitologically confirmed CL, age of 12 to 60 years; willingness to participate, duration of lesion<3 months, number of lesions<5, largest ulcer diameter<5 cm. Pregnant or lactating women were excluded. The primary outcome was absolute risk reduction (ARR) based on the proportion of complete healing, which was defined as more than 75% reduction in the size of the lesion compared with baseline in each group at the termination of treatment and 1 month later.

Findings

ARR (95% Confidence Interval [CI]) in i.l.MA versus i.l.MA+non-silver dressing groups was 5.98% (−7.07% to 20.25%), between i.l.MA versus i.l.MA+silver dressing groups was −0.23% (−13.53% to 14.82%), and between i.l.MA+non-silver dressing versus i.l.MA+silver dressing groups was −6.21%(−18.28% to 6.52%) after 6 weeks of treatment. ARR (95% CI) in i.l.MA versus i.l.MA+non-silver dressing groups was −2.22% (−22.12% to 18.10%), between i.l.MA versus i.l.MA+silver dressing groups was 3.64% (−15.36% to 22.82%), and between i.l.MA+non-silver dressing versus i.l.MA+silver dressing groups was 5.86% (−12.86% to 24.31%) 1 month later.

Conclusion

It could not be demonstrated that the efficacy of i.l.MA was improved by either dressing.

Trial Registration

Iranian Registry of Clinical Trials (IRCT.ir) IRCT138707201166N2.     

Likelihood-Based Methods for Assessing Principal Surrogate Endpoints in Vaccine Trials

Statistics in Biosciences - When evaluating principal surrogate biomarkers in vaccine trials, missingness in potential outcomes requires prediction using auxiliary variables and/or augmented study...     

Design of Viral Dynamic Studies for Efficiently Assessing Potency of Anti‐HIV Therapies in AIDS Clinical Trials

The study of HIV dynamics is one of the most important developments in recent AIDS research. It greatly improves our understanding of the pathogenesis of HIV infection. Recently it has been proposed to use HIV dynamics to evaluate the efficacy of antiviral treatments. Currently a large number of AIDS clinical trials on HIV dynamics are in development worldwide. However, many design issues that arise from HIV dynamic studies have not been addressed. In this paper, we study these problems using intensive Monte Carlo simulations and analytic methods. We evaluate a finite number of feasible candidate designs, which are currently used and proposed in AIDS clinical trials from different perspectives. We compare the viral dynamic marker and classical viral load change markers in terms of power for identifying treatment difference, asymptotic relative efficiency, and sensitivity. Finally we propose some useful suggestions for practitioners based on our results.     

Outbreak of Cutaneous Leishmaniasis among military personnel in French Guiana, 2020: Clinical,phylogenetic, individual and environmental aspects

BackgroundCutaneous Leishmaniasis (CL) is endemic in French Guiana but cases are usually sporadic. An outbreak signal was issued on May 15^th 2020 with 15 suspected cases after a military training course in the rainforest. An outbreak investigation was carried out.Methodology/Principal findingsThirty cases were confirmed. Leishmania guyanensis was the most frequent species (90%). The most frequent presentation was ulcerative (90%). Lesions on the face and hands were frequent (40% each). Eight cases (26%) presented a poor outcome after treatment with pentamidine and required a second line with amphotericin B. Three of them required further treatments with meglumine antimoniate or miltefosine. Two spots within the training area were deemed as likely sites of contamination, due to illegal logging. The isolated Leishmania strains did not form a separate cluster. Participation in Week 13 of year 2020 was associated with infection (OR = 4.59 [1.10–19.83]; p = 0.016) while undergoing only the “Fighting” exercise was protective (OR = 0.1 [0–0.74]; p = 0.021). There was no association between infection and other risk factors at the individual level. The attack rate of Regiment B (14/105 = 13.3%) was significantly higher (OR = 4.22 [1.84–9.53], p = 0.0001) compared to Regiment A (16/507 = 3.2%). The attack rate during this training course (30/858 = 3.5%) was significantly higher (OR 2.29 [1.28–4.13]; p = 0.002) than for other missions in French Guiana during the same period (22/1427 = 1.5%).ConclusionsThis outbreak could be explained by a combination of factors: climatic conditions around week 13, at-risk activities including night trainings, absence of impregnation, a lesser experience of rainforest duties in Regiment B and illegal logging attracting sandflies on military training grounds.     

Spatial Distribution of Sand Fly Vectors and Eco-Epidemiology of Cutaneous Leishmaniasis Transmission in Colombia

Background

Leishmania is transmitted by Phlebotominae insects that maintain the enzootic cycle by circulating between sylvatic and domestic mammals; humans enter the cycles as accidental hosts due to the vector’s search for blood source. In Colombia, leishmaniasis is an endemic disease and 95% of all cases are cutaneous (CL), these cases have been reported in several regions of the country where the intervention of sylvatic areas by the introduction of agriculture seem to have an impact on the rearrangement of new transmission cycles. Our study aimed to update vector species distribution in the country and to analyze the relationship between vectors’ distribution, climate, land use and CL prevalence.

Methods

A database with geographic information was assembled, and ecological niche modeling was performed to explore the potential distribution of each of the 21 species of medical importance in Colombia, using thirteen bioclimatic variables, three topographic and three principal components derived from NDVI. Binary models for each species were obtained and related to both land use coverage, and a CL prevalence map with available epidemiological data. Finally, maps of species potential distribution were summed to define potential species richness in the country.

Results

In total, 673 single records were obtained with Lutzomyia gomezi, Lutzomyia longipalpis, Psychodopygus panamensis, Psathyromyia shannoni and Pintomyia evansi the species with the highest number of records. Eighteen species had significant models, considering the area under the curve and the jackknife results: L. gomezi and P. panamensis had the widest potential distribution. All sand fly species except for Nyssomyia antunesi are mainly distributed in regions with rates of prevalence between 0.33 to 101.35 cases per 100,000 inhabitants and 76% of collection data points fall into transformed ecosystems.

Discussion

Distribution ranges of sand flies with medical importance in Colombia correspond predominantly to disturbed areas, where the original land coverage is missing therefore increasing the domiciliation potential. We highlight the importance of the use of distribution maps as a tool for the development of strategies for prevention and control of diseases.     

A Two-stage Design for Comparing Clinical Trials

A two-stage design is proposed to choose among several experimental treatments and a standard treatment in clinical trials. The first stage employs a selection procedure to select the best treatment, provided it is better than the standard. The second stage tests the hypothesis between the best treatment selected at the first stage (if any) and the standard treatment. All the treatments are assumed to follow normal distributions and the best treatment is the one with the largest population mean. The level and the power are defined and they are used to set up equations to solve unknown first stage sample size, second stage sample size, and procedure parameters. The optimal design is the one that gives the smallest average sample size. Numerical results are presented to illustrate the improvement of one design as compared to existing one stage design.