Cutaneous Leishmaniasis in an overseas Filipino worker who responded favorably to oral Itraconazole

Introduction@#Cutaneous leishmaniasis is non-endemic in the Philippines. Antiparasitic pentavalent antimonials are acknowledged as first-line therapy for all forms of the disease. Amphotericin B is the second drug of choice but its use is limited due to side effects.@*Case Summary@#We present a case of a 32- year-old male overseas Filipino worker who presented with “volcaniform plaques” (nodules and plaques with central crater) and surrounding satellite erythematous papules on the trunk, and extremities after returning from Iraq. A diagnosis of cutaneous leishmaniasis was confirmed by the histopathologic findings of a granulomatous inflammatory infiltrate with round to oval basophilic structures in the cytoplasm of macrophages (Leishman bodies) in the dermis, which were highlighted prominently by Giemsa stain. The patient showed poor response to treatment with 4 weeks of oral Rifampicin 1200 mg daily divided into 2 doses. He was shifted to oral Itraconazole 400 mg daily divided into 2 doses for 6 weeks with dramatic improvement.@*Conclusion@#This case report highlights the favorable therapeutic response of cutaneous leishmaniasis to oral itraconazole and hence, may be recommended as first-line medication to treat infected overseas workers from endemic areas who seek treatment in the Philippines.

The impact of malnutrition on survival and the CD4 count response in HIV-infected patients starting antiretroviral therapy.

BACKGROUND: The impact that malnutrition at the time of starting antiretroviral therapy (ART) has on survival and the CD4 count response is not known. METHODS: A retrospective cohort study of patients attending the national HIV referral centre in Singapore who had a CD4 count less than 250 cells/microL and a measurement of body weight performed at the time of starting ART was carried out. Demographic and clinical variables were extracted from an existing database. Body mass index (BMI) was calculated from the weight in kilograms divided by the square of the height in metres. Moderate to severe malnutrition was defined as BMI less than 17 kg/m(2). Intent-to-treat Cox models were used to determine the predictors of survival. RESULTS: A total of 394 patients were included in the analysis, of whom 79 died during a median study follow-up of 2.4 years. Moderate to severe malnutrition was present in 16% of patients at the time of starting ART, and was found to be a significant independent predictor of death [hazard ratio (HR) 2.19, 95% confidence interval (CI) 1.29-3.73, P=0.004 for those with BMI<17 compared with those with BMI>18.5] as were stage of disease (HR 2.47, 95% CI 1.20-5.07, P=0.014 for those who were at stage C compared with those at stage A) and the type of ART [HR 0.50, 95% CI 0.27-0.93, P=0.03 for highly active antiretroviral therapy (HAART) compared with non-HAART treatment]. Malnutrition did not impair the magnitude of the increase in CD4 count at 6 or 12 months. CONCLUSIONS: Malnutrition at the time of starting ART was significantly associated with decreased survival, but the effect appeared not to be mediated by impaired immune reconstitution. Given the increasing access to ART in developing countries and the high frequency of HIV-associated wasting, studies of nutritional therapy as an adjunct to the initiation of HAART are urgently needed.

Causes of death among patients with HIV in Singapore from 1985 to 2001: results from the Singapore HIV Observational Cohort Study (SHOCS).

OBJECTIVES: To investigate the major primary and contributory causes of death among HIV patients in Singapore. DESIGN: A retrospective observational cohort study of all adult patients seen at the national referral centre for HIV in Singapore between 1985 and 2001. METHODS: Data were extracted from the patients' records by 10 trained health care workers. AIDS-defining conditions were established using predefined criteria. For each case, a single principal cause of death and up to three contributory causes were identified. RESULTS: A total of 1504 patients aged 17 years or over were seen before the end of 2001, of whom 504 have died. The most frequent principal causes of death were Mycobacterium avium (17.5%), Mycobacterium tuberculosis (9.7%), pneumonia (cause unknown) (6.5%) and Cryptococcus neoformans (6.7%). Three hundred and eighteen patients (63.1%) died from an AIDS-defining condition. CONCLUSIONS: The causes of death were similar to those found in Western cohorts, except that disseminated M. avium was a more frequent cause of death.

Susceptibility to mycobacterial infections: the importance of host genetics.

There is substantial evidence that host genetic factors are important in determining susceptibility to mycobacteria. Several different techniques have been used to identify the genes involved. Studies of an inbred strain of mice with increased susceptibility to mycobacteria, salmonella and leishmania infections led to the identification of the natural resistance-associated macrophage protein gene (Nramp1). Case-control studies have confirmed the importance of the human equivalent of this gene, NRAMP1, and have also suggested that the major histocompatibility complex and vitamin-D receptor genes may be involved in determining human susceptibility to mycobacteria. Studies of individuals with the rare condition of increased susceptibility to disseminated bacille Calmette-Guerin and other atypical mycobacterial infections have identified several abnormalities in the genes encoding the interferon gamma receptor (IFNgammaR) ligand binding chain, IFNgammaR signal transduction chain, IFNgamma signal transduction and activation of transcription-1, interleukin 12 receptor beta1 subunit and interleukin 12 p40 subunit. A genome-wide linkage study has been performed to identify genes exerting a major effect on tuberculosis susceptibility in the general population. Linkages were found to markers on chromosomes 15 and X. Studies to identify the genes responsible are in progress.

Genetic susceptibility to tuberculosis in Africans: a genome-wide scan.

Human genetic variation is an important determinant of the outcome of infection with Mycobacterium tuberculosis. We have conducted a two-stage genome-wide linkage study to search for regions of the human genome containing tuberculosis-susceptibility genes. This approach uses sibpair families that contain two full siblings who have both been affected by clinical tuberculosis. For any chromosomal region containing a major tuberculosis-susceptibility gene, affected sibpairs inherit the same parental alleles more often than expected by chance. In the first round of the screen, 299 highly informative genetic markers, spanning the entire human genome, were typed in 92 sibpairs from The Gambia and South Africa. Seven chromosomal regions that showed provisional evidence of coinheritance with clinical tuberculosis were identified. To identify whether any of these regions contained a potential tuberculosis-susceptibility gene, 22 markers from these regions were genotyped in a second set of 81 sibpairs from the same countries. Markers on chromosomes 15q and Xq showed suggestive evidence of linkage (lod = 2.00 and 1.77, respectively) to tuberculosis. The potential identification of susceptibility loci on both chromosomes 15q and Xq was supported by an independent analysis designated common ancestry using microsatellite mapping. These results indicate that genome-wide linkage analysis can contribute to the mapping and identification of major genes for multifactorial infectious diseases of humans. An X chromosome susceptibility gene may contribute to the excess of males with tuberculosis observed in many different populations.

Why is Marine combat mortality less than that of the Army?

Data from recent wars indicate that a wounded Marine had a 20% lower risk of dying than an Army soldier. Possible reasons for this difference are (1) Navy care is superior, (2) soldiers sustained more severe wounds, and (3) the services count casualties differently. Injury severity was measured in random samples of Marines and soldiers that were selected from the Wound Data and Munitions Effectiveness Team database. There was no difference in the lethality of injury and the prevalence of lifesaving first aid. Wounded Marines were more likely to wear protective vests, and this decreased Marine mortality in Vietnam. Hospitalized Marines had lower Injury Severity Scores and were less likely to be returned to duty without first being admitted to a medical treatment facility. Lower Marine combat mortality is primarily the result of the fact that a Marine with a minor soft tissue wound was more likely to be hospitalized than was a soldier with a similar injury.

Identifying genetic susceptibility factors for tuberculosis in Africans: a combined approach using a candidate gene study and a genome-wide screen.

There is convincing evidence that host genes affect the outcome of infection in human tuberculosis. Two complementary strategies were used to identify the genes involved. A linkage-based genome-wide screen was carried out to locate the positions of genes exerting a major population-wide effect on tuberculosis susceptibility. A candidate-gene-based case-control study was used to examine the effects of genes that may exert a more moderate effect on risk of clinical tuberculosis. The genome screen was conducted in two stages. In the first stage 299 microsatellite markers, spanning all 23 chromosomes, were typed in 92 independent sib-pairs, and seven regions showed some evidence of co-segregation with the disease. These seven regions were examined in a second set of 81 sib-pairs, and markers on chromosomes 15q and Xq showed evidence of linkage to tuberculosis. An X chromosome susceptibility gene may contribute to the excess of males with tuberculosis observed in many populations. The candidate gene approach compared the frequency of polymorphisms in several genes in over 400 subjects with smear-positive pulmonary tuberculosis and 400 ethnically matched healthy controls. Polymorphisms in genes encoding natural-resistance-associated macrophage protein, vitamin D receptor and mannose-binding lectin were associated with tuberculosis. These results suggest that many genes may be involved in determining host susceptibility to tuberculosis, and highlight the importance of using several different study methods to locate them.

History of surgery for penetrating chest trauma.

The military surgery experience of the past several centuries has been an important determinant of the evolution of the clinical management of penetrating thoracic trauma. The major management problems fall into two main categories: acute, life-threatening conditions such as open pneumothorax and exsanguinating hemorrhage, and chronic conditions such as clotted hemothorax, empyema, and fibrothorax. Better treatment and prevention of the latter has greatly reduced morbidity. Although hospital mortality has fallen by a factor of ten since the middle of the nineteenth century, the total mortality caused by penetrating thoracic trauma has undergone less change.

The natural resistance-associated macrophage protein and susceptibility to intracellular pathogens.

Over 20 years ago it was recognised that murine susceptibility to several antigenically unrelated pathogens was influenced by a host genetic factor. Linkage studies suggested that Lsh, Ity, and Bcg, the leishmania-, salmonella-, and mycobacteria-susceptibility genes, may be one gene, located on mouse chromosome 1. A reverse genetics strategy identified a candidate gene, Nramp1, which was expressed only in reticuloendothelial cells. A single nonconservative amino acid substitution was found to correlate with the susceptibility genotype in 27 inbred mouse strains. The production of an Nramp1 gene-disrupted mouse and a transgenic mouse, which restored the resistance genotype, conclusively proved that Nramp1 is the Bcg/Lsh/Ity gene. The Nramp family includes genes expressed in both prokaryotic and eukaryotic species. These genes have provided clues to the possible function of Nramp1. The ubiquitously expressed gene Nramp2 is an Fe(2+) transporter and a mutation in this gene causes microcytic anaemia in mice and rats. The functions of Nramp1 and its human homologue, NRAMP1, remain unknown, though it is hypothesised that they may regulate the intraphagosomal concentration of Fe(2+) and/or other cations. The identification of polymorphisms in the human NRAMP1 gene has facilitated studies on the relevance of this gene to human mycobacterial susceptibility. NRAMP1 variant alleles are strongly associated with tuberculosis, indicating that this is an important mycobacterial-susceptibility gene in humans and confirming the usefulness of this mouse model in the study of human infectious disease susceptibility.

An empirical exploration of the (delta mu)2 genetic distance for 213 human microsatellite markers.

Microsatellites are now used ubiquitously as genetic markers. One important application is to the assessment of population subdivision and phylogenetic relatedness. Such applications require a method of estimation of genetic distance. Here we examine the most widely used measure of microsatellite genetic distance, Goldstein et al.'s delta-mu squared ([delta mu]2), with respect to a large data set of 213 markers typed across samples from four diverse human populations. We find that (delta mu)2 yields plausible interpopulation distances. For the first time, we report significant interpopulation differences in mean microsatellite length, although the effect of these differences on (delta mu)2 is negligible. However, we also show that the method is extremely sensitive to one or two loci that contribute extreme values, even when a sample size of >200 loci is used. Some of these extreme loci can be removed on the grounds that some alleles carry large indels, but for others there is no clear justification for exclusion a priori. Our data suggest a rather recent African/non-African split, with an upper limit of some 70,000-80,000 years ago.

Tuberculosis and chronic hepatitis B virus infection in Africans and variation in the vitamin D receptor gene.

The active metabolite of vitamin D, 1,25 dihydroxyvitamin D3, is an important immunoregulatory hormone [1]. Its effects are exerted by interaction with the vitamin D receptor, which is present on human monocytes and activated T and B lymphocytes. Variation in the vitamin D receptor gene was typed in 2015 subjects from large case-control studies of three major infectious diseases: tuberculosis, malaria, and hepatitis B virus. Homozygotes for a polymorphism at codon 352 (genotype tt) were significantly underrepresented among those with tuberculosis (chi2=6.22, 1 df, P=. 01) and persistent hepatitis B infection (chi2=6.25, 1 df, P=.01) but not in subjects with clinical malaria compared with the other genotypes. Therefore, this genetic variant, which predisposes to low bone mineral density in many populations, may confer resistance to certain infectious diseases.

Absence of an association between intercellular adhesion molecule 1, complement receptor 1 and interleukin 1 receptor antagonist gene polymorphisms and severe malaria in a West African population.

Many genes have been shown to be involved in host susceptibility to the severe forms of Plasmodium falciparum malaria but it is likely that a large number of malaria-susceptibility genes remain to be determined. We conducted a large case-control study of children with the severe forms of this disease-cerebral malaria and severe malarial anaemia--to attempt to identify these genes. Over 1200 children in The Gambia were typed for polymorphisms of the intercellular adhesion molecule 1 (ICAM-1), complement receptor 1 (CR-1) and interleukin 1 receptor antagonist (IL-IRA) genes. None of the polymorphisms typed was significantly associated with severe disease. These data differed significantly from the results of a previous study (Chi 2 = 8.81; P = 0.003) in which the ICAM-1 gene polymorphism was shown to be significantly associated with cerebral malaria in a case-control study of 547 subjects in Kenya. This suggests that there may be heterogeneity in genetic susceptibility to this condition between these 2 African populations.