Clive R. Davies

Advances in leishmaniasis

Governed by parasite and host factors and immunoinflammatory responses, the clinical spectrum of leishmaniasis encompasses subclinical (inapparent), localised (skin lesions), and disseminated infection (cutaneous, mucosal, or visceral). Symptomatic disease is subacute or chronic and diverse in presentation and outcome. Clinical characteristics vary further by endemic region. Despite T-cell-dependent immune responses, which produce asymptomatic and self-healing infection, or appropriate treatment, intracellular infection is probably life-long since targeted cells (tissue macrophages) allow residual parasites to persist. There is an epidemic of cutaneous leishmaniasis in Afghanistan and Pakistan and of visceral infection in India and Sudan. Diagnosis relies on visualising parasites in tissue or serology; culture and detection of parasite DNA are useful in the laboratory. Pentavalent antimony is the conventional treatment; however, resistance of visceral infection in India has spawned new treatment approaches--amphotericin B and its lipid formulations, injectable paromomycin, and oral miltefosine. Despite tangible advances in diagnosis, treatment, and basic scientific research, leishmaniasis is embedded in poverty and neglected. Current obstacles to realistic prevention and proper management include inadequate vector (sandfly) control, no vaccine, and insufficient access to or impetus for developing affordable new drugs.

Leishmaniasis: new approaches to disease control

Leishmaniasis is one of the major infectious diseases affecting the poorest regions of the world, but new developments in diagnosis, treatment, and control offer some fresh hope

Effect of insecticide-impregnated dog collars on incidence of zoonotic visceral leishmaniasis in Iranian children: a matched- cluster randomised trial

BACKGROUND Deltamethrin-impregnated dog collars reduce sandfly bite rates on dogs, and are effective in killing sandflies that attempt to feed. Because domestic dogs are the principal reservoir hosts of zoonotic visceral leishmaniasis, we tested whether community-wide application of dog collars could protect children against infection with Leishmania infantum, the parasite that causes the disease. METHODS 18 villages were paired, matched by preintervention child prevalence of L infantum infection. Within pairs, villages were randomly assigned to either control or intervention. All domestic dogs in intervention villages were provided with collars for the transmission season. The main outcome measure was incidence of L infantum infection after 1 year measured by seroconversion. Secondary outcomes were leishmanin skin test (LST) conversion and seroconversion in dogs. FINDINGS The seroconversion rate in children was 1.49% (17/1141) in the intervention villages and 2.41% (26/1078) in control villages (odds ratio 0.57, 95% CI 0.36-0.90, p=0.017). LST conversion was also lowered, but not significantly (odds ratio 0.66, 0.41-1.08, p=0.096). The seroconversion rate in dogs in intervention villages was also significantly reduced (0.46, 0.30-0.70, p=0.0003). INTERPRETATION Community-wide application of deltamethrin-impregnated dog collars not only protects domestic dogs from L infantum infections, but might also reduce the risk of L infantum infection in children. These dog collars could have a role in control of visceral leishmaniasis and replace controversial dog culling programmes in some countries. However, the effectiveness of dog collars will depend on the importance of wild versus domestic canids as reservoir hosts of L infantum.

The epidemiology and control of leishmaniasis in Andean countries

This paper reviews the current knowledge of leishmaniasis epidemiology in Venezuela, Colombia, Ecuador, Peru, and Bolivia. In all 5 countries leishmaniasis is endemic in both the Andean highlands and the Amazon basin. The sandfly vectors belong to subgenera Helcocyrtomyia, Nyssomiya, Lutzomyia, and Psychodopygus, and the Verrucarum group. Most human infections are caused by Leishmania in the Viannia subgenus. Human Leishmania infections cause cutaneous lesions, with a minority of L. (Viannia) infections leading to mucocutaneous leishmaniasis. Visceral leishmaniasis and diffuse cutaneous leishmaniasis are both rare. In each country a significant proportion of Leishmania transmission is in or around houses, often close to coffee or cacao plantations. Reservoir hosts for domestic transmission cycles are uncertain. The paper first addresses the burden of disease caused by leishmaniasis, focusing on both incidence rates and on the variability in symptoms. Such information should provide a rational basis for prioritizing control resources, and for selecting therapy regimes. Secondly, we describe the variation in transmission ecology, outlining those variables which might affect the prevention strategies. Finally, we look at the current control strategies and review the recent studies on control.

Conflict and Kala-Azar: Determinants of Adverse Outcomes of Kala-Azar among Patients in Southern Sudan

We analyzed data obtained from 3365 patients with kala-azar (KA) or post-KA dermal leishmaniasis (PKDL) treated by Medecins Sans Frontieres-Holland in south Sudan from October 1998-May 2002. Patients were malnourished (median body mass index [BMI], 15.5; median weight for height [WFH], 75.5%) and anemic (median hemoglobin (Hb) level, 8.5 g/dL). The proportion of patients with primary KA who were children <5 years old increased from 2.5%, in 1998, to 19.8%, in 2002 (P<.0001). Therapy with sodium stibogluconate cured 91.9% of patients with primary KA, and dosages of >850 mg per day did not decrease the chances of survival. Risk factors for death among adults were age > or =45 years (odds ratio [OR], 4.6), malnutrition (BMI, <13; OR, 11.0), anemia (Hb level, <8 g/dL; OR, 4.0), and duration of illness (duration, > or =5 months; OR, 2.3). Risk factors for death among children and adolescents were age <2 years (OR, 5.4,), malnutrition (WFH, <60%; OR, 5.0), anemia (Hb level, <6 g/dL; OR, 3.7), and splenomegaly (OR, 2.9). A higher risk of death was associated with episodes of diarrhea (OR, 1.4), vomiting (OR, 2.7), and bleeding (OR, 2.9). Relapse and PKDL occurred in 3.9% and 10.0% of cases, respectively.

Rapid Detection of Leishmania infantum Infection in Dogs: Comparative Study Using an Immunochromatographic Dipstick Test, Enzyme-Linked Immunosorbent Assay, and PCR

ABSTRACT Current zoonotic visceral leishmaniasis (ZVL) control programs in Brazil include the culling of Leishmania infantum-infected reservoir dogs, a strategy that has failed to prevent a rise of canine and human ZVL cases over the past decade. One of the main reasons this strategy has failed is because of a long delay between sample collection, sample analysis, and control implementation. A rapid, sensitive, and specific diagnostic tool would be highly desirable, because it would allow control interventions to be implemented in situ. We compared an immunochromatographic dipstick test to enzyme-linked immunosorbent assay (ELISA) and PCR for detecting L. infantum infections in dogs from an area of ZVL endemicity in Brazil. The dipstick test was shown to have 61 to 75% specificity and 72 to 77% sensitivity, compared to 100% specificity for both ELISA and PCR and 71 to 88% and 51 to 64% sensitivity for ELISA and PCR, respectively. Of the field samples tested, 92 of 175 (53%), 65 of 175 (37%), and 47 of 175 (27%) were positive by dipstick, ELISA, and PCR, respectively. The positive and negative predictive values for the tested dipstick were 58 to 77% and 75%, respectively. Efforts should be made to develop a more specific dipstick test for diagnosis of leishmaniasis, because they may ultimately prove more cost-effective than currently used diagnostic tests when used in mass-screening surveys.

Efficacy of Thermotherapy to Treat Cutaneous Leishmaniasis Caused by Leishmania tropica in Kabul, Afghanistan: A Randomized, Controlled Trial

BACKGROUND Pentavalent antimony is the agent recommended for treatment of cutaneous leishmaniasis (CL). Its use is problematic, because it is expensive and because of the potential for drug-associated adverse effects during a lengthy and painful treatment course. METHODS We tested the efficacy of thermotherapy for the treatment of CL due to Leishmania tropica in a randomized, controlled trial in Kabul, Afghanistan. We enrolled 401 patients with a single CL lesion and administered thermotherapy using radio-frequency waves (1 treatment of >or=1 consecutive application at 50 degrees C for 30 s) or sodium stibogluconate (SSG), administered either intralesionally (a total of 5 injections of 2-5 mL every 5-7 days, depending on lesion size) or intramuscularly (20 mg/kg daily for 21 days). RESULTS Cure, defined as complete reepithelialization at 100 days after treatment initiation, was observed in 75 (69.4%) of 108 patients who received thermotherapy, 70 (75.3%) of 93 patients who received intralesional SSG, and 26 (44.8%) of 58 patients who received intramuscular SSG. The OR for cure with thermotherapy was 2.80 (95% confidence interval [CI], 1.45-5.41), compared with intramuscular SSG treatment (P=.002). No statistically significant difference was observed in the odds of cure in comparison of intralesional SSG and thermotherapy treatments. The OR for cure with intralesional SSG treatment was 3.75 (95% CI, 1.86-7.54), compared with intramuscular SSG treatment (P<.001). The time to cure was significantly shorter in the thermotherapy group (median, 53 days) than in the intralesional SSG or intramuscularly SSG group (median, 75 days and >100 days, respectively; P=.003). CONCLUSIONS Thermotherapy is an effective, comparatively well-tolerated, and rapid treatment for CL, and it should be considered as an alternative to antimony treatment.

Reconstructing historical changes in the force of infection of dengue fever in Singapore: implications for surveillance and control

OBJECTIVE To reconstruct the historical changes in force of dengue infection in Singapore, and to better understand the relationship between control of Aedes mosquitoes and incidence of classic dengue fever. METHODS Seroprevalence data were abstracted from surveys performed in Singapore from 1982 to 2002. These data were used to develop two mathematical models of age seroprevalence. In the first model, force of infection was allowed to vary independently each year, while in the second it was described by a polynomial function. Model-predicted temporal trends were analysed using linear regression. Time series techniques were employed to investigate periodicity in predicted forces of infection, dengue fever incidence and mosquito breeding. FINDINGS Force of infection estimates showed a significant downward trend from 1966, when vector control was instigated. Force of infection estimates from both models reproduced significant increases in the percentage and average age of the population susceptible to dengue infections. Importantly, the year-on-year model independently predicted a five to six year periodicity that was also displayed by clinical incidence but absent from the Aedes household index. CONCLUSION We propose that the rise in disease incidence was due in part to a vector-control-driven reduction in herd immunity in older age groups that are more susceptible to developing clinical dengue.

Chagas disease control in Venezuela: lessons for the Andean region and beyond

Following the success of the Southern Cone programme to control Chagas disease, Andean countries are beginning to implement a similar international initiative. Important lessons could be learnt from Venezuela, which has one of the longest running national control programmes in Latin America, but has received little attention in the scientific literature. Retrospective analysis of age-specific Trypanosoma cruzi seroprevalence data and entomological sampling indicates that while the programme successfully reduced the annual incidence of infection from approximately ten per 1000 people in the 1950s to one per 1000 in the 1980s, in the susceptible population of endemic areas, transmission has not yet been interrupted and could now be increasing. Andean governments can expect control to be highly effective, but must maintain long-term vigilance and targeted control measures to consolidate these gains.

Epidemiological surveys confirm an increasing burden of cutaneous leishmaniasis in north-east Brazil

Health service records for north-east Brazil suggest a consistent rise in numbers of cases of cutaneous leishmaniasis due to Leishmania (Viannia) braziliensis over the past decade. In a study site in Pernambuco, prospective, cross-sectional and retrospective epidemiological surveys of infection (a positive Montenegro skin test response) and/or clinical symptoms confirmed a high current force of infection (0.092/year), and an approximately 10-fold increase in transmission during the last 10 years. Cross-sectional analysis indicated that the incidence rate among children (aged < or = 15 years) was lower than that among adult immigrants exposed for similar time periods, but there was no apparent difference in transmission rate according to gender. Coupled with the known behaviour of the local sandfly vector, Lutzomyia whitmani, this suggests that most people are infected outside their houses, rather than either indoors or while visiting remnant rainforest. The estimated proportion of infections which lead to cutaneous lesions (0.81-0.87) is relatively high for L. braziliensis areas. However, an unusually low proportion of clinical infections (0.0042) apparently leads to metastasis.