Itraconazole and leishmaniasis: A randomised double-blind trial in cutaneous disease

Cutaneous leishmaniasis (CL) is a vector-borne parasitic disease of the skin. Previous open controlled studies with oral itraconazole suggest that it was effective for CL in India. Twenty patients with localised CL participated in this trial. Patients were allocated randomly to receive capsule itraconazole and matching placebo for 6 weeks. No topical medicines were used. Demonstration of Leishmania by slit smear was mandatory. Prior to, periodically during and 3 months after completion of therapy an overall clinical assessment, liver function tests and urinalysis were performed. On decoding, out of the 10 cases receiving drug itraconazole, 7 were declared cured by clinical and parasitological criteria. No major side-effects were noted. Spontaneous remission was observed in 1 case in the placebo group at 3 months follow up. Oral itraconazole has a promising antileishmanial potential and may thus secure CL patient from the hazards of antimonials.     

Vectors of cutaneous leishmaniasis in north-central Venezuela

Abstract. An entomological survey was undertaken from January 1991 to February 1992 in El Ingenio, Miranda State, Venezuela, an endemic area of cutaneous leishmaniasis: prevalence of 10.7 cases per 100,000 inhabitants.
A total of 4863 female sandflies (Phlebotominae) of fourteen species were collected in Shannon traps, then dissected and examined for leishmanial infections.
Lutzomyia ovallesi (85.4%) and Lu. gomezl (11.2%) were the predominant anthropophilic species of sandfly. Fifty-one (1.19%) Lu. ovallesi and two(0.47%) Lu. gomezi had natural infection with Leishmania promastigotes. Identification of the parasites was done by using the polymerase chain reaction (PCR) and DNA hybridization. Two isolates from Lu. gomezi and forty-nine from Lu. ovallesi were typed as Leishmania braziliensis and three of the latter reacted with Le. mexicana also. This is the first report of Lu. gomezi with parasites typed as Le. braziliensis.
We concluded that Lu. ovallesi is the primary vector of cutaneous leishmaniasis in the north-central area of Venezuela and Lu. gomezi should be regarded as an additional vector.     

Study of an outbreak of cutaneous leishmaniasis in Venezuela. The role of domestic animals

During an outbreak of cutaneous leishmaniasis in a locality (Las Rosas, Cojedes State, Venezuela) previously non-endemic, 12.9% of humans, 7% of dogs and 21.4% of donkeys (Equus asinus) had lesions with parasites. The agent in the three hosts was identified as Leishmania braziliensis, subspecies braziliensis at least in man and donkey. The probable vector was Lutzomyia panamensis. No infection was found in a small sample of wild mammals examined. The outbreak was apparently linked with the importation of donkeys with ulcers, from endemic areas. The authors call attention to the fact that not only in the foci of "uta", but also in areas of the other forms of American cutaneous leishmaniasis, dogs are frequently found infected. They emphasize the necessity of searching for the infection in donkeys and of performing hemocultures and xenodiagnosis with sandflies in human, canine and equine cases, to verify their possible role as sources of infection, and not merely as dead ends in the epidemiological chain of the disease.     

Zoonotic cutaneous leishmaniasis due to Leishmania (Viannia) braziliensis associated with domestic animals in Venezuela and Brazil

After outbreaks of cutaneous leishmaniasis in Solano State, Venezuela, 5% of the population had parasitized ulcers while after similar outbreaks in Mesquita, Rio de Janeiro State, Brazil, 9% had the disease. In these foci children, including some under six years of age, were affected. There was no significant difference in the occurrence of the disease according to sex or type of employment. In Solano, 3% of dogs and 28% of donkeys had parasitized lesions, while in Mesquita these indices were 19.8% and 30.8% respectively. The parasite from man, dogs and equines was identified as Leishmania (Viannia) braziliensis, by zymodeme and serodeme characterization. In these foci there is evidence suggesting that leishmaniasis is a zoonosis, possibly with equines and dogs as reservoirs, although both a wild enzootic cycle and the role of man as a source of infection can not be ruled out. Transmission is assumed to occur peridomestically by sandfly vectors such as Lutzomyia panamensis in Venezuela and Lutzomyia intermedia in Brazil. Information about the origin of these foci suggests that infected equines may be an important factor in the dissemination of the parasite in a peridomestic situation where these sandflies are abundant.     

Single gene control of resistance to cutaneous leishmaniasis in mice

A series of inbred, congenic resistant, and hybrid strains of mice were intradermally inoculated with 10⁶ promastigotes of Leishmania tropica. These mice were divided into susceptible and resistant groups using the criteria of lesion size, development of metastatic foci and skin-test reactivity. At 16 weeks of infection, resistant strains A/J, DBA/1J, AKR/J, CBA/J, C3H/HeJ, NZB/BINJ, C57BL/6J, C57BL/10Sn, B10.D2, B10.129(10M), and B10.CE(30NX) had completely resolved their lesions, while susceptible SWR/J and BALB/cJ mice demonstrated large, nonhealing cutaneous lesions. In addition, BALB/cJ developed metastatic lesions on the extremities which progressively increased in size. All BALB/cJ and SWR/J mice died by 7 1/2 months of infection. The BALB/cJ x C57BL/6JF₁ hybrid behaved in an intermediate fashion showing a slower expansion of cutaneous ulcers and a delayed development of metastatic foci, however, the infection ultimately proved fatal. The F₂ generation could be separated into three distinct groups: resistant, intermediate, and susceptible mice with a lesion size distribution pattern in conformity with a 1:2:1 ratio. Male/female susceptibility differences were not noted. These data indicated that development of acquired resistance may be under the control of a single, autosomal gene. The gene did not appear to be H-2-, Ir-2-, or H-11-linked as is seen with Leishmania donovani infections.     

Domestic and peridomestic transmission of American cutaneous leishmaniasis: changing epidemiological patterns present new control opportunities

Predictions that deforestation would reduce American cutaneous leishmaniasis incidence have proved incorrect. Presentations at a recent international workshop, instead, demonstrated frequent domestication of transmission throughout Latin America. While posing new threats, this process also increases the effectiveness of vector control in and around houses. New approaches for sand fly control and effective targeting of resources are reviewed.     

Exercises to prevent lower limb injuries in youth sports: cluster randomised controlled trial

Objective To investigate the effect of a structured warm-up programme designed to reduce the incidence of knee and ankle injuries in young people participating in sports.Design Cluster randomised controlled trial with clubs as the unit of randomisation.Setting 120 team handball clubs from central and eastern Norway (61 clubs in the intervention group, 59 in the control group) followed for one league season (eight months).Participants 1837 players aged 15-17 years; 958 players (808 female and 150 male) in the intervention group; 879 players (778 female and 101 male) in the control group.Intervention A structured warm-up programme to improve running, cutting, and landing technique as well as neuromuscular control, balance, and strength.Main outcome measure The rate of acute injuries to the knee or ankle.Results During the season, 129 acute knee or ankle injuries occurred, 81 injuries in the control group (0.9 (SE 0.09) injuries per 1000 player hours; 0.3 (SE 0.17) in training v 5.3 (SE 0.06) during matches) and 48 injuries in the intervention group (0.5 (SE 0.11) injuries per 1000 player hours; 0.2 (SE 0.18) in training v 2.5 (SE 0.06) during matches). Fewer injured players were in the intervention group than in the control group (46 (4.8%) v (76 (8.6%); relative risk intervention group v control group 0.53, 95% confidence interval 0.35 to 0.81).Conclusion A structured programme of warm-up exercises can prevent knee and ankle injuries in young people playing sports. Preventive training should therefore be introduced as an integral part of youth sports programmes.     

Preventing injuries in children: cluster randomised controlled trial in primary care

ObjectiveTo assess the effectiveness of safety advice at child health surveillance consultations, provision of low cost safety equipment to families receiving means tested state benefits, home safety checks, and first aid training on frequency and severity of unintentional injuries in children at home.DesignCluster randomised controlled trial.Setting36 general practices in Nottingham.SubjectsAll children aged 3-12 months registered with participating practices.InterventionsA package of safety advice at child health surveillance consultations at 6-9, 12-15, and 18-24 months; provision of low cost safety equipment to families on means tested state benefits; and home safety checks and first aid training by health visitors.ResultsAt baseline, both groups had similar risk factors for injury, sociodemographic characteristics, safety practices, possession and use of safety equipment, knowledge and confidence in dealing with first aid, and perceptions of risk. No significant difference was found in frequency of at least one medically attended injury (odds ratio 0.97, 95% confidence interval 0.72 to 1.30), at least one attendance at an accident and emergency department for injury (1.02, 0.76 to 1.37), at least one primary care attendance for injury (0.75, 0.48 to 1.17), or at least one hospital admission for injury (0.69, 0.42 to 1.12). No significant difference in the secondary outcome measures was found between the intervention and control groups. ConclusionsThe intervention package was not effective in reducing the frequency of minor unintentional injuries in children at home, and larger trials are required to assess the effect on more severe injuries.

Key messages

• A package of activities for preventing injuries, as suggested by the Health of the Nation, delivered to families with children aged under 3 in primary care did not reduce the frequency of minor injuries
• The findings were consistent with a reduction in the frequency of more severe injuries, and larger primary care based studies are required to test this hypothesis
• The effectiveness of each of the interventions, delivered singly, is not known

     

Surgical mask to prevent influenza transmission in households: a cluster randomized trial

Background

Facemasks and respirators have been stockpiled during pandemic preparedness. However, data on their effectiveness for limiting transmission are scarce. We evaluated the effectiveness of facemask use by index cases for limiting influenza transmission by large droplets produced during coughing in households.

Methodology and Principal Findings

A cluster randomized intervention trial was conducted in France during the 2008–2009 influenza season. Households were recruited during a medical visit of a household member with a positive rapid influenza A test and symptoms lasting less than 48 hours. Households were randomized either to the mask or control group for 7 days. In the intervention arm, the index case had to wear a surgical mask from the medical visit and for a period of 5 days. The trial was initially intended to include 372 households but was prematurely interrupted after the inclusion of 105 households (306 contacts) following the advice of an independent steering committee. We used generalized estimating equations to test the association between the intervention and the proportion of household contacts who developed an influenza-like illness during the 7 days following the inclusion. Influenza-like illness was reported in 24/148 (16.2%) of the contacts in the intervention arm and in 25/158 (15.8%) of the contacts in the control arm and the difference between arms was 0.40% (95%CI: −10% to 11%, P = 1.00). We observed a good adherence to the intervention. In various sensitivity analyses, we did not identify any trend in the results suggesting effectiveness of facemasks.

Conclusion

This study should be interpreted with caution since the lack of statistical power prevents us to draw formal conclusion regarding effectiveness of facemasks in the context of a seasonal epidemic.

Trial Registration

clinicaltrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00774774","term_id":"NCT00774774"}}NCT00774774     

Assessing the effect of zooprophylaxis on zoonotic cutaneous leishmaniasis transmission: A system dynamics approach

Capturing or diverting the disease carrying vector from humans can reduce the transmission of vector borne diseases such as leishmaniasis. The use of animals that act as dead-end hosts to relieve the vector (sandfly) bites on humans is called zooprophylaxis. However, as the number of blood meal providers especially domestic animals increases, the sandflies enhanced availability of blood meals will improve its number and survival, thereby countering the impact of diverting bites from humans. Thus, the transmission model exhibits the structure of a feedback loop characterizing complex dynamic systems. In order to rigorously assess the effect of zooprophylaxis, we propose a system dynamic model for zoonotic cutaneous leishmaniasis transmission with 3 blood-meal hosts: domestic animals, humans, and a reservoir (rodents). In this context, a simulation study of the proposed model with a follow-up period of 1000 days was performed.     

Ecology of sandflies (Diptera:Psychodidae) in a restricted focus of cutaneous leishmaniasis in northern Venezuela. IV. Sandfly monthly fluctuation and leishmaniasis incidence relationship

An attempt has been made to correlate the monthly incidence of human leishmaniasis with the temporal distribution of sandfly species at San Esteban, Northern Venezuela. Upon statistical analysis, the seasonal fluctuation of L. ovallesi population correlated strongly with the human disease, while the dynamics of L. panamensis, generally believed to be the vector in the Central area of the country, showed only a very weak correlation. These findings support the hypothesis that L. panamensis might not be the main or unique species responsible for the transmission in this area and that L. ovallesi and additionally L. olmeca bicolor might be involved in the epidemiology of the disease.     

Abundance of Lutzomyia ovallesi but not Lu. gomezi (Diptera: Psychodidae) correlated with cutaneous leishmaniasis incidence in north-central Venezuela

In north-central Venezuela Lutzomyia gomezi and Lu. ovallesi are the main endophilic/anthropophilic species of phlebotomine sandflies implicated as vectors of cutaneous leishmaniasis (CL). Lutzomyia ovallesi has been found infected with Leishmania braziliensis (1.2%) and less often with Le. mexicana (0.07%), while Le. braziliensis infections have also been found in Lu. gomezi (0.47%). We investigated population densities of these sandflies using two sampling methods with four series of collections between January 1991 and March 1995 at El Ingenio, Miranda State. All-night outdoor collections from a Shannon trap were correlated with indoor collections from CDC light–traps by linear regression, which proved to be statistically significant for both species. Estimated numbers of female sandflies per house per night were found to be proportional to monthly precipitation (i.e. rainfall), with a lag time of seven months for Lu. ovallesi and of six months for Lu. gomezi . Predominance of Lu. ovallesi over Lu. gomezi ( c. 10 :1 ) was observed throughout the year, with the number of infected females estimated as 0.043 ± 0.047 Lu. ovallesi and 0.0085 ± 0.0124 Lu. gomezi per CDC trap per house per night (ratio ∼ 5:1). The mean rate of new CL cases per house per year and sandfly abundance were correlated by linear regression, showing a statistically significant relationship for Lu. ovallesi but not for Lu. gomezi . The negative intercept indicated that, on average, the CDC trap density exceeds 800 Lu. ovallesi females/house/year before new CL cases occur at El Ingenio.     

Ecology of sandflies (Diptera:Psychodidae) in a restricted focus of cutaneous leishmaniasis in northern Venezuela. III. Seasonal fluctuation

A one year-long study (March 1979-March 1980) was carried out at San Esteban, an endemic focus of cutaneous leishmaniasis in Northern Venezuela, with the aim of observing the seasonal fluctuation of the local phlebotomine sandflies species. The influence of climatic factors (temperature, relative humidity and rainfall) on population dynamics was analyzed in three collecting sites--a house, a peridomestic area and a sylvatic region. Among anthropophilic species, L. panamensis behaved as a wetseason species, the mean minimum relative humidity being the critical factor influencing the total number of individuals. When the population density of this fly decreased, it was successfully replaced by L. ovallesi, a dry-season species. On the other hand, seasonal variations of L. gomezi were more strongly affected by the temperature.     

BCG revaccination does not protect against leprosy in the Brazilian Amazon: a cluster randomised trial

Background

Although BCG has been found to impart protection against leprosy in many populations, the utility of repeat or booster BCG vaccinations is still unclear. When a policy of giving a second BCG dose to school children in Brazil was introduced, a trial was conducted to assess its impact against tuberculosis, and a leprosy component was then undertaken in parallel. Objective: to estimate the protection against leprosy imparted by a second dose of BCG given to schoolchildren.

Methods and Findings

This is a cluster randomised community trial, with 6 years and 8 months of follow-up. Study site: City of Manaus, Amazon region, a leprosy-endemic area in Brazil. Participants: 99,770 school children with neonatal BCG (aged 7–14 years at baseline), of whom 42,662 were in the intervention arm (revaccination). Intervention: BCG given by intradermal injection. Main outcome: Leprosy (all clinical forms). Results: The incidence rate ratio of leprosy in the intervention over the control arm within the follow-up, in schoolchildren with neonatal BCG, controlled for potential confounders and adjusted for clustering, was 0.99 (95% confidence interval: 0.68 to 1.45).

Conclusions/Significance

There was no evidence of protection conferred by the second dose of BCG vaccination in school children against leprosy during the trial follow-up. These results point to a need to consider the effectiveness of the current policy of BCG vaccination of contacts of leprosy cases in Brazilian Amazon region.     

Sodium stibogluconate (SSG) & paromomycin combination compared to SSG for visceral leishmaniasis in East Africa: a randomised controlled trial

Background

Alternative treatments for visceral leishmaniasis (VL) are required in East Africa. Paromomycin sulphate (PM) has been shown to be efficacious for VL treatment in India.

Methods

A multi-centre randomized-controlled trial (RCT) to compare efficacy and safety of PM (20 mg/kg/day for 21 days) and PM plus sodium stibogluconate (SSG) combination (PM, 15 mg/kg/day and SSG, 20 mg/kg/day for 17 days) with SSG (20 mg/kg/day for 30 days) for treatment of VL in East Africa. Patients aged 4–60 years with parasitologically confirmed VL were enrolled, excluding patients with contraindications. Primary and secondary efficacy outcomes were parasite clearance at 6-months follow-up and end of treatment, respectively. Safety was assessed mainly using adverse event (AE) data.

Findings

The PM versus SSG comparison enrolled 205 patients per arm with primary efficacy data available for 198 and 200 patients respectively. The SSG & PM versus SSG comparison enrolled 381 and 386 patients per arm respectively, with primary efficacy data available for 359 patients per arm. In Intention-to-Treat complete-case analyses, the efficacy of PM was significantly lower than SSG (84.3% versus 94.1%, difference = 9.7%, 95% confidence interval, CI: 3.6 to 15.7%, p = 0.002). The efficacy of SSG & PM was comparable to SSG (91.4% versus 93.9%, difference = 2.5%, 95% CI: −1.3 to 6.3%, p = 0.198). End of treatment efficacy results were very similar. There were no apparent differences in the safety profile of the three treatment regimens.

Conclusion

The 17 day SSG & PM combination treatment had a good safety profile and was similar in efficacy to the standard 30 day SSG treatment, suggesting suitability for VL treatment in East Africa.

Clinical Trials Registration

www.clinicaltrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00255567","term_id":"NCT00255567"}}NCT00255567     

Miltefosine in the treatment of cutaneous leishmaniasis caused by Leishmania braziliensis in Brazil: a randomized and controlled trial

Background

Cutaneous leishmaniasis (CL) is treated with parenteral drugs for decades with decreasing rate cures. Miltefosine is an oral medication with anti-leishmania activity and may increase the cure rates and improve compliance.

Methodology/Principal Findings

This study is a randomized, open-label, controlled clinical trial aimed to evaluate the efficacy and safety of miltefosine versus pentavalent antimony (Sb^v) in the treatment of patients with CL caused by Leishmania braziliensis in Bahia, Brazil. A total of 90 patients were enrolled in the trial; 60 were assigned to receive miltefosine and 30 to receive Sb^v. Six months after treatment, in the intention-to-treat analyses, the definitive cure rate was 53.3% in the Sb^v group and 75% in the miltefosine group (difference of 21.7%, 95% CI 0.08% to 42.7%, p = 0.04). Miltefosine was more effective than Sb^v in the age group of 13–65 years-old compared to 2–12 years-old group (78.9% versus 45% p = 0.02; 68.2% versus 70% p = 1.0, respectively). The incidence of adverse events was similar in the Sb^v and miltefosine groups (76.7% vs. 78.3%). Vomiting (41.7%), nausea (40%), and abdominal pain (23.3%) were significantly more frequent in the miltefosine group while arthralgias (20.7%), mialgias (20.7%) and fever (23.3%) were significantly more frequent in the Sb^v group.

Conclusions

This study demonstrates that miltefosine therapy is more effective than standard Sb^v and safe for the treatment of CL caused by Leishmania braziliensis in Bahia, Brazil.

Trial Registration

Clinicaltrials.gov Identifier {"type":"clinical-trial","attrs":{"text":"NCT00600548","term_id":"NCT00600548"}}NCT00600548     

Concordance of leishmaniasis cutaneous tests in Tunisia

A cross sectional study aimed to evaluate the effect of antigenic preparation (Leishmania infantum versus Leishmania major) and dose of leishmania antigens (5 x 10(6) versus 2.5 x 10(6) parasites in the same volume) on the reproducibility of delayed type hypersensitivity leishmania skin test. Results showed that among 34 individuals involved from visceral leishmaniasis endemic area. 26 (76.5%) had a positif Leishmania infantum leishmania (L-L. infantum) test and 27 (79.4%) to Leishmania major leishmania (L-L. major). Mean size of cutaneous reaction was 5.94 +/- 2.86 mm for L-L. infantum and 5.41 +/- 3.23 mm for L-L. major, with a significant positive linear association (p < 10-3). Intra-class correlation coefficient was 0.80 (CI95% = [0.64-0.93]) and concordance Kappa (kappa) was 0.57 (CI95% = [0.40-0.74]). Among 153 individuals from zoonotic cutaneous leishmaniasis. 92.9% revealed a positive test for both types of leishmanin (L-L. major full dose versus L-L. major half dose). Mean size of cutaneous reaction was 12.61 +/- 4.65 mm for the reference test and 11.30 +/- 3.95 mm for diluted one, with a positive linear association (p < 10-3). Intra-class correlation coefficient was 0.78 (IC95% = [0.71-0.84]) and concordance Kappa (kappa) was 0.82 (IC95% = [0.73-0.91]). These results demonstrate a limited effect of leishmania antigenic variation and antigen dose on the reproducibility of delayed type hypersensitivity induced by the leishmanin test.