Linda Oskam

Physical Distance, Genetic Relationship, Age, and Leprosy Classification Are Independent Risk Factors for Leprosy in Contacts of Patients with Leprosy

BACKGROUND Close contacts of patients with leprosy have a higher risk of developing leprosy. Several risk factors have been identified, including genetic relationship and physical distance. Their independent contributions to the risk of developing leprosy, however, have never been sufficiently quantified. METHODS Logistic-regression analysis was performed on intake data from a prospective cohort study of 1037 patients newly diagnosed as having leprosy and their 21,870 contacts. RESULTS Higher age showed an increased risk, with a bimodal distribution. Contacts of patients with paucibacillary (PB) leprosy with 2-5 lesions (PB2-5) and those with multibacillary (MB) leprosy had a higher risk than did contacts of patients with single-lesion PB leprosy. The core household group had a higher risk than other contacts living under the same roof and next-door neighbors, who again had a higher risk than neighbors of neighbors. A close genetic relationship indicated an increased risk when blood-related children, parents, and siblings were pooled together. CONCLUSIONS Age of the contact, the disease classification of the index patient, and physical and genetic distance were independently associated with the risk of a contact acquiring leprosy. Contact surveys in leprosy should be not only focused on household contacts but also extended to neighbors and consanguineous relatives, especially when the patient has PB2-5 or MB leprosy.

Congenital Transmission of Visceral Leishmaniasis (Kala Azar) From an Asymptomatic Mother to Her Child

In this article, we report the case of a 16-month-old German boy who was admitted to the Childrens Hospital of Stuttgart with a 4-week history of intermittent fever, decreased appetite, weakness, fatigue, and difficulty sleeping. He was healthy at birth and remained so for the first 15 months of his life. On admission, physical examination showed enlarged cervical, axillary, and inguinal lymph nodes, as well as hepatosplenomegaly. Laboratory data revealed pancytopenia, elevated liver function tests, and hypergammaglobulinemia. Blood, stool, and urine culture results were negative. Viral infections and rheumatologic and autoimmune disorders were ruled out, but a positive titer for Leishmaniaantibodies was noted. In a liver and bone marrow biopsy, the amastigote form of the parasite could not be seen in cells. The promastigote form of Leishmania was found and the diagnosis of visceral leishmaniasis was made by combining the cultures of both the liver and the bone marrow biopsy material in 5 mL 0.9% saline on brain heart infusion agar, supplemented with defibrinated rabbit blood and incubated at 25 to 26°C for 5 days. The parasite was identified by Southern blot analysis as Leishmania infantum. Specific therapy with the antimonial compound sodium stibogluconate with a dose of 20 mg/kg body weight was begun immediately. Within 4 days, the patient became afebrile. The side effects of treatment, including erosive gastritis, cholelithiasis, worsening hepatosplenomegaly, elevation of liver enzymes, pancreatitis, and electrocardiogram abnormalities, necessitated the discontinuation of treatment after 17 days. On discharge 4 weeks later, the patient was stabilized and afebrile with a normal spleen, normal complete blood count, normal gammaglobulins, and decreasing antibody titers toLeishmania. During the next 24 months, the patient experienced intermittent episodes of abdominal pain, decreased appetite, recurrent arthralgia, and myalgia. But at his last examination in January 1998, he was well; all symptoms mentioned above had disappeared. Because the child had never left Germany, nonvector transmission was suspected and household contacts were examined. His mother was the only one who had a positive antibody titer against Leishmania donovani complex. She had traveled several times to endemic Mediterranean areas (Portugal, Malta, and Corse) before giving birth to the boy. But she had never been symptomatic for visceral leishmaniasis. Her bone marrow, spleen, and liver biopsy results were within normal limits. Culture results and polymerase chain reaction of this material were negative. A Montenegro skin test result was positive, indicating a previous infection with Leishmania. Western blot analysis showed specific recognition by maternal antibodies of antigens of Leishmania cultured from the boys tissue. Visceral leishmaniasis is endemic to several tropical and subtropical countries, but also to the Mediterranean region. It is transmitted by the sand fly (Phlebotomus, Lutzomyia). Occasional nonvector transmissions also have been reported through blood transfusions, sexual intercourse, organ transplants, excrements of dogs, and sporadically outside endemic areas. Only 8 cases of congenital acquired disease have been described before 1995, when our case occurred. In our patient, additional evaluation showed that the asymptomatic mother must have had a subclinical infection withLeishmania that was reactivated by pregnancy, and then congenitally transmitted to the child. Visceral leishmaniasis has to be considered in children with fever, pancytopenia, and splenomegaly, even if the child has not been to an endemic area and even if there is no evidence of the disease in his environment, because leishmaniasis can be transmitted congenitally from an asymptomatic mother to her child.

IDENTIFICATION AND DETERMINATION OF THE RELATIONSHIPS OF SPECIES AND STRAINS WITHIN THE GENUS LEISHMANIA USING SINGLE PRIMERS IN THE POLYMERASE CHAIN REACTION

DNA polymorphisms were assessed in different species and strains within the genus Leishmania by amplifying genomic DNA with single non-specific primers. This polymerase chain reaction (PCR) method employed non-random primers which anneal to mini- and microsatellite DNA sequences like the M13 core sequence and the simple repeat sequences (GTG)5 and (GACA)4, and the T3B primer derived from an intergenic spacer for tRNA genes. Distinctive and reproducible sets of amplified DNA fragments were obtained for all Leishmania isolates tested. The number and size of amplification products were found to be characteristic for a given taxon. Highly similar PCR profiles were observed when genomic DNA of representatives of the L. donovani, L. mexicana or L. braziliensis complexes was amplified. By comparing PCR patterns of unidentified Leishmania isolates with those obtained from reference strains it was possible to identify these isolates at the species level. The information of the amplification patterns was used for the construction of phylogenetic trees to measure the genetic relatedness within the genus Leishmania.

Comparison of PCR with the Routine Procedure for Diagnosis of Tuberculosis in a Population with High Prevalences of Tuberculosis and Human Immunodeficiency Virus

ABSTRACT Direct smear examination with Ziehl-Neelsen (ZN) staining for the diagnosis of tuberculosis (TB) as employed in most low-income countries is cheap and easy to use, but its low sensitivity is a major drawback. The low specificity of chest X-rays, used for the diagnosis of smear-negative TB, risks high levels of overdiagnosis. Major advances in molecular techniques, which rapidly identify mycobacterial DNA in sputa, may overcome these obstacles. In this study, the AMPLICOR PCR system was used to diagnose pulmonary TB in a developing country with high prevalences of both TB and human immunodeficiency virus (HIV). The sensitivity and specificity of this technique were compared to those of the usual diagnostic techniques. Sputum specimens were collected from 1,396 TB suspects attending the Rhodes Chest Clinic, Nairobi, Kenya. The specimens were analyzed for the presence of Mycobacterium tuberculosis by PCR; culture on Löwenstein-Jensen medium was used as the “gold standard.” All culture-positive samples were genotyped to identify the mycobacterial species. The sensitivity and specificity of PCR were 93 and 84%, respectively. HIV status did not affect the sensitivity of PCR. A total of 99.7% of the true smear-positive and 82.1% of the true smear-negative TB patients were correctly identified by PCR. PCR detected M. tuberculosis in 11.7% of the culture-negative suspects, 60% of which had one or two PCR-positive sputum specimens. Of the 490 positive cultures, 486 were identified as M. tuberculosis. The high sensitivity of Amplicor PCR merits usage in a clinical setting with high TB and HIV burdens. Thus, PCR can be considered as an alternative to ZN staining in combination with chest X-ray for diagnosis of TB; however, cost-effectiveness studies and operational studies are required to support an evidence-based decision of introducing PCR for TB control in high-burden environments.

Effectiveness of single dose rifampicin in preventing leprosy in close contacts of patients with newly diagnosed leprosy: cluster randomised controlled trial

Objective To determine the effectiveness of chemoprophylaxis using a single dose of rifampicin to prevent leprosy in close contacts. Design Single centre, double blind, cluster randomised, placebo controlled trial. SettingLeprosy control programme in two districts of northwest Bangladesh with a population of more than four million. Participants28 092 close contacts of 1037 patients with newly diagnosed leprosy. 21 711 contacts fulfilled the study requirements. Interventions A single dose of rifampicin or placebo given to close contacts in the second month of starting the index patient’s treatment, with follow-up for four years. Main outcome measure Development of clinical leprosy. Results 18 869 of the 21 711 contacts (86.9%) were followed-up at four years. Ninety one of 9452 contacts in the placebo group and 59 of 9417 in the rifampicin group had developed leprosy. The overall reduction in incidence of leprosy using a single dose of rifampicin in the first two years was 57% (95% confidence interval 33% to 72%). The groups did not differ between two and four years. The overall number needed to treat (NNT) to prevent a single case of leprosy among contacts was 297 (95% confidence interval 176 to 537). Differences were found between subgroups at two years, both in reduction of incidence and in NNT. ConclusionA single dose of rifampicin given to contacts of patients with newly diagnosed leprosy is effective at preventing the development of clinical leprosy at two years. The effect was maintained, but no difference was seen between the placebo and rifampicin groups beyond two years. Trial registration Current Controlled Trials ISRCTN61223447.

Knowledge and use of prevention measures related to dengue in northern Thailand

objective  To determine the frequency and determinants of knowledge of dengue infection in three sites in northern Thailand, and to compare prevention measures of people with and without knowledge of dengue.

Polymorphism N248S in the Human Toll‐Like Receptor 1 Gene Is Related to Leprosy and Leprosy Reactions

We investigated the association between a polymorphism of a key innate immunity receptor, Toll-like receptor 1 (TLR1) N248S, and susceptibility to leprosy and its clinical presentation. TLR1 N248S has been shown elsewhere to diminish TLR1 signaling and subsequent leprosy disease. The homozygous genotype SS was more frequent (P=.012) and the heterozygous SN genotype was less frequent (P=.015) in patients with leprosy than in control subjects. Additional observed differences in allelic frequency in patients who experienced reversal reactions and/or erythema nodosum leprosum reactions indicates that altered TLR1 function, or at least a TLR1 N248S-linked trait, may affect the progression from infection to disease as well as the disease course and the risk of debilitating reactional episodes in this population.

Multi-level analyses of spatial and temporal determinants for dengue infection

BackgroundDengue is a mosquito-borne viral infection that is now endemic in most tropical countries. In Thailand, dengue fever/dengue hemorrhagic fever is a leading cause of hospitalization and death among children. A longitudinal study among 1750 people in two rural and one urban sites in northern Thailand from 2001 to 2003 studied spatial and temporal determinants for recent dengue infection at three levels (time, individual and household).MethodsDeterminants for dengue infection were measured by questionnaire, land-cover maps and GIS. IgM antibodies against dengue were detected by ELISA. Three-level multi-level analysis was used to study the risk determinants of recent dengue infection.ResultsRates of recent dengue infection varied substantially in time from 4 to 30%, peaking in 2002. Determinants for recent dengue infection differed per site. Spatial clustering was observed, demonstrating variation in local infection patterns. Most of the variation in recent dengue infection was explained at the time-period level. Location of a person and the environment around the house (including irrigated fields and orchards) were important determinants for recent dengue infection.ConclusionWe showed the focal nature of asymptomatic dengue infections. The great variation of determinants for recent dengue infection in space and time should be taken into account when designing local dengue control programs.

Impact of land-use change on dengue and malaria in northern Thailand

Land-use change, a major constituent of global environmental change, potentially has significant consequences for human health in relation to mosquito-borne diseases. Land-use change can influence mosquito habitat, and therefore the distribution and abundance of vectors, and land use mediates human–mosquito interactions, including biting rate. Based on a conceptual model linking the landscape, people, and mosquitoes, this interdisciplinary study focused on the impacts of changes in land use on dengue and malaria vectors and dengue transmission in northern Thailand. Extensive data on mosquito presence and abundance, land-use change, and infection risk determinants were collected over 3 years. The results of the different components of the study were then integrated through a set of equations linking land use to disease via mosquito abundance. The impacts of a number of plausible scenarios for future land-use changes in the region, and of concomitant behavioral change were assessed. Results indicated that land-use changes have a detectable impact on mosquito populations and on infection. This impact varies according to the local environment but can be counteracted by adoption of preventive measures.

Epidemiology, diagnosis and control of leishmaniasis in the Mediterranean region.

The leishmaniases are a widespread and medically important group of parasitic diseases, some of which pose a serious health threat in communities throughout the Mediterranean basin. In 1993, a joint, collaborative study of the Mediterranean leishmaniases was initiated by scientists from Israel, Turkey, Portugal and the Netherlands. The aim of this project was the development of a multi-component approach to the successful control of all forms of leishmaniasis, with special emphasis on the more severe, visceral leishmaniasis (VL). The need for highly sensitive and accurate new tools to facilitate diagnosis and epidemiological surveys of endemic areas and for studies on the immunology of VL in laboratory models (dogs and mice) was soon recognized. It is anticipated that the development of these tools and the associated technology will provide a better understanding of the disease and improve its control.