Using (1,3)-ß-D-glucan concentrations in serum to monitor the response of azole therapy in patients with eumycetoma caused by Madurella mycetomatis.

INTRODUCTION: (1,3)-ß-D-glucan is a panfungal biomarker secreted by many fungi, including Madurella mycetomatis, the main causative agent of eumycetoma. Previously we demonstrated that (1,3)-ß-D-glucan was present in serum of patients with eumycetoma. However, the use of (1,3)-ß-D-glucan to monitor treatment responses in patients with eumycetoma has not been evaluated. MATERIALS AND METHODS: In this study, we measured (1,3)-ß-D-glucan concentrations in serum with the WAKO (1,3)-ß-D-glucan assay in 104 patients with eumycetoma treated with either 400 mg itraconazole daily, or 200 mg or 300 mg fosravuconazole weekly. Serial serum (1,3)-ß-D-glucan concentrations were measured at seven different timepoints. Any correlation between initial and final (1,3)-ß-D-glucan concentrations and clinical outcome was evaluated. RESULTS: The concentration of (1,3)-ß-D-glucan was obtained in a total of 654 serum samples. Before treatment, the average (1,3)-ß-D-glucan concentration was 22.86 pg/mL. During the first 6 months of treatment, this concentration remained stable. (1,3)-ß-D-glucan concentrations significantly dropped after surgery to 8.56 pg/mL. After treatment was stopped, there was clinical evidence of recurrence in 18 patients. Seven of these 18 patients had a (1,3)-ß-D-glucan concentration above the 5.5 pg/mL cut-off value for positivity, while in the remaining 11 patients, (1,3)-ß-D-glucan concentrations were below the cut-off value. This resulted in a sensitivity of 38.9% and specificity of 75.0%. A correlation between lesion size and (1,3)-ß-D-glucan concentration was noted. CONCLUSION: Although in general (1,3)-ß-D-glucan concentrations can be measured in the serum of patients with eumycetoma during treatment, a sharp decrease in ß-glucan concentration was only noted after surgery and not during or after antimicrobial treatment. (1,3)-ß-D-glucan concentrations were not predictive for recurrence and seem to have no value in determining treatment response to azoles in patients with eumycetoma.

Safety and efficacy of paromomycin/miltefosine/liposomal amphotericin B combinations for the treatment of post-kala-azar dermal leishmaniasis in Sudan: A phase II, open label, randomized, parallel arm study.

BACKGROUND: Treatment for post-kala-azar dermal leishmaniasis (PKDL) in Sudan is currently recommended only for patients with persistent or severe disease, mainly because of the limitations of current therapies, namely toxicity and long hospitalization. We assessed the safety and efficacy of miltefosine combined with paromomycin and liposomal amphotericin B (LAmB) for the treatment of PKDL in Sudan. METHODOLOGY/PRINCIPAL FINDINGS: An open-label, phase II, randomized, parallel-arm, non-comparative trial was conducted in patients with persistent (stable or progressive disease for ≥ 6 months) or grade 3 PKDL, aged 6 to ≤ 60 years in Sudan. The median age was 9.0 years (IQR 7.0-10.0y) and 87% of patients were ≤12 years old. Patients were randomly assigned to either daily intra-muscular paromomycin (20mg/kg, 14 days) plus oral miltefosine (allometric dose, 42 days)-PM/MF-or LAmB (total dose of 20mg/kg, administered in four injections in week one) and oral miltefosine (allometric dose, 28 days)-LAmB/MF. The primary endpoint was a definitive cure at 12 months after treatment onset, defined as clinical cure (100% lesion resolution) and no additional PKDL treatment between end of therapy and 12-month follow-up assessment. 104/110 patients completed the trial. Definitive cure at 12 months was achieved in 54/55 (98.2%, 95% CI 90.3-100) and 44/55 (80.0%, 95% CI 70.2-91.9) of patients in the PM/MF and AmB/MF arms, respectively, in the mITT set (all randomized patients receiving at least one dose of treatment; in case of error of treatment allocation, the actual treatment received was used in the analysis). No SAEs or deaths were reported, and most AEs were mild or moderate. At least one adverse drug reaction (ADR) was reported in 13/55 (23.6%) patients in PM/MF arm and 28/55 (50.9%) in LAmB/MF arm, the most frequent being miltefosine-related vomiting and nausea, and LAmB-related hypokalaemia; no ocular or auditory ADRs were reported. CONCLUSIONS/SIGNIFICANCE: The PM/MF regimen requires shorter hospitalization than the currently recommended 60-90-day treatment, and is safe and highly efficacious, even for patients with moderate and severe PKDL. It can be administered at primary health care facilities, with LAmB/MF as a good alternative. For future VL elimination, we need new, safe oral therapies for all patients with PKDL. TRIAL REGISTRATION: ClinicalTrials.gov NCT03399955, https://clinicaltrials.gov/study/NCT03399955 ClinicalTrials.gov ClinicalTrials.gov.

Comparing the performance of the common used eumycetoma diagnostic tests.

OBJECTIVES: Mycetoma is a neglected tropical implantation disease caused by 70 different infectious agents. Identifying the causative organism to the species level is essential for appropriate patient management. Ultrasound, histopathology, culture and two species-specific PCRs are most the commonly used methods for species identification in endemic regions. The aim of this study was to compare the diagnostic performance of these commonly used assays using sequencing of barcoding genes as the gold standard. METHODS: This descriptive cross-sectional study was conducted at the Mycetoma Research Centre, University of Khartoum, Sudan. It included 222 patients suspected of fungal mycetoma caused by Madurella mycetomatis. RESULTS: 154 (69.3%) were correctly identified by ultrasound, histology, culture and both species-specific PCRs. In 60 patients, at least one of the diagnostic tests failed to identify M. mycetomatis. Five patients had no evidence of eumycetoma, and for three, only the ultrasound was indicative of mycetoma. The two species-specific PCRs were the most sensitive and specific methods, followed by culture and histology. Ultrasound was the least specific as it only allowed differentiation between actinomycetoma and eumycetoma. The time to result was 9.38 minutes for ultrasound, 3.76 hours for PCR, 8.5 days for histopathology and 21 days for grain culturing. CONCLUSION: Currently, PCR directly on DNA isolated from grains is the most rapid and reliable diagnostic tool to identify M. mycetomatis eumycetoma.

Epidemiological cut-off values for itraconazole and ravuconazole for Madurella mycetomatis, the most common causative agent of mycetoma.

BACKGROUND: Eumycetoma is a neglected tropical disease. It is a chronic inflammatory subcutaneous infection characterised by painless swellings which produce grains. It is currently treated with a combination of itraconazole and surgery. In an ongoing clinical study, the efficacy of fosravuconazole, the prodrug of ravuconazole, is being investigated. For both itraconazole and ravuconazole, no clinical breakpoints or epidemiological cut-off values (ECV) to guide treatment are currently available. OBJECTIVE: To determine tentative ECVs for itraconazole and ravuconazole in Madurella mycetomatis, the main causative agent of eumycetoma. MATERIALS AND METHODS: Minimal inhibitory concentrations (MICs) for itraconazole and ravuconazole were determined in 131 genetically diverse clinical M. mycetomatis isolates with the modified CLSI M38 broth microdilution method. The MIC distributions were established and used to determine ECVs with the ECOFFinder software. CYP51A sequences were sequenced to determine whether mutations occurred in this azole target gene, and comparisons were made between the different CYP51A variants and the MIC distributions. RESULTS: The MICs ranged from 0.008 to 1 mg/L for itraconazole and from 0.002 to 0.125 mg/L for ravuconazole. The M. mycetomatis ECV for itraconazole was 1 mg/L and for ravuconazole 0.064 mg/L. In the wild-type population, two CYP51A variants were found for M. mycetomatis, which differed in one amino acid at position 499 (S499G). The MIC distributions for itraconazole and ravuconazole were similar between the two variants. No mutations linked to decreased susceptibility were found. CONCLUSION: The proposed M. mycetomatis ECV for itraconazole is 1 mg/L and for ravuconazole 0.064 mg/L.

Precision Medicine in Control of Visceral Leishmaniasis Caused by L. donovani.

Precision medicine and precision global health in visceral leishmaniasis (VL) have not yet been described and could take into account how all known determinants improve diagnostics and treatment for the individual patient. Precision public health would lead to the right intervention in each VL endemic population for control, based on relevant population-based data, vector exposures, reservoirs, socio-economic factors and other determinants. In anthroponotic VL caused by L. donovani, precision may currently be targeted to the regional level in nosogeographic entities that are defined by the interplay of the circulating parasite, the reservoir and the sand fly vector. From this 5 major priorities arise: diagnosis, treatment, PKDL, asymptomatic infection and transmission. These 5 priorities share the immune responses of infection with L. donovani as an important final common pathway, for which innovative new genomic and non-genomic tools in various disciplines have become available that provide new insights in clinical management and in control. From this, further precision may be defined for groups (e.g. children, women, pregnancy, HIV-VL co-infection), and eventually targeted to the individual level.

Report of the Fifth Post-Kala-Azar Dermal Leishmaniasis Consortium Meeting, Colombo, Sri Lanka, 14-16 May 2018.

The 5th Post-Kala-Azar Dermal Leishmaniasis (PKDL) Consortium meeting brought together PKDL experts from all endemic areas to review and discuss existing and new data on PKDL. This report summarizes the presentations and discussions and provides the overall conclusions and recommendations.

Three-Dimensional Optical Scanning in Post-kala-azar Dermal Leishmaniasis (PKDL).

Post-kala-azar dermal leishmaniasis may occur after successful treatment of visceral leishmaniasis and is characterized by macules, papules, or nodules in the skin, with varying size. The response to antileishmanial therapy remains difficult to assess because there are presently no reliable biomarkers. To date, skin lesions are clinically assessed for decrease in size or change in color, which is invariably subjective. Novel 3-dimensional optical scanning devices offer safe and field-adapted methods to objectively assess skin lesions for changes over time in size and color that can be quantified with great accuracy.

Nontraumatic Myelopathy in Malawi: A Prospective Study in an Area with High HIV Prevalence.

Nontraumatic myelopathy causes severe morbidity and is not uncommon in Africa. Clinically, patients often present with paraplegia, and extrinsic cord compression and transverse myelitis are most common causes. Data on exact pathogenesis are scanty because of limitations in diagnostic methods. In Queen Elizabeth Central Hospital, Blantyre, Malawi, we recorded consecutive patients presenting with nontraumatic paraplegia for maximally 6 months between January and July 2010 and from March to December 2011. The diagnostic workup included imaging and examining blood, stool, urine, sputum, and cerebrospinal fluid (CSF) samples for infection. After discharge, additional diagnostic tests, including screening for virus infections, borreliosis, syphilis, and schistosomiasis, were carried out in the Netherlands. The clinical diagnosis was, thus, revised in retrospect with a more accurate final differential diagnosis. Of 58 patients included, the mean age was 41 years (range, 12-83 years) and the median time between onset and presentation was 18 days (range, 0-121 days), and of 55 patients tested, 23 (42%) were HIV positive. Spinal tuberculosis (n = 24, 41%), tumors (n = 16, 28%), and transverse myelitis (n = 6, 10%) were most common; in six cases (10%), no diagnosis could be made. The additional tests yielded evidence for CSF infection with Schistosoma, Treponema pallidum, Epstein-Barr virus (EBV), HHV-6, HIV, as well as a novel cyclovirus. The diagnosis of the cause of paraplegia is complex and requires access to an magnetic resonance imaging (MRI) scan and other diagnostic (molecular) tools to demonstrate infection. The major challenge is to confirm the role of detected pathogens in the pathophysiology and to design an effective and affordable diagnostic approach.

The Diagnosis of Fungal Neglected Tropical Diseases (Fungal NTDs) and the Role of Investigation and Laboratory Tests: An Expert Consensus Report.

The diagnosis of fungal Neglected Tropical Diseases (NTD) is primarily based on initial visual recognition of a suspected case followed by confirmatory laboratory testing, which is often limited to specialized facilities. Although molecular and serodiagnostic tools have advanced, a substantial gap remains between the desirable and the practical in endemic settings. To explore this issue further, we conducted a survey of subject matter experts on the optimal diagnostic methods sufficient to initiate treatment in well-equipped versus basic healthcare settings, as well as optimal sampling methods, for three fungal NTDs: mycetoma, chromoblastomycosis, and sporotrichosis. A survey of 23 centres found consensus on the key role of semi-invasive sampling methods such as biopsy diagnosis as compared with swabs or impression smears, and on the importance of histopathology, direct microscopy, and culture for mycetoma and chromoblastomycosis confirmation in well-equipped laboratories. In basic healthcare settings, direct microscopy combined with clinical signs were reported to be the most useful diagnostic indicators to prompt referral for treatment. The survey identified that the diagnosis of sporotrichosis is the most problematic with poor sensitivity across the most widely available laboratory tests except fungal culture, highlighting the need to improve mycological diagnostic capacity and to develop innovative diagnostic solutions. Fungal microscopy and culture are now recognized as WHO essential diagnostic tests and better training in their application will help improve the situation. For mycetoma and sporotrichosis, in particular, advances in identifying specific marker antigens or genomic sequences may pave the way for new laboratory-based or point-of-care tests, although this is a formidable task given the large number of different organisms that can cause fungal NTDs.

Biomarkers in Post-kala-azar Dermal Leishmaniasis.

Post-kala-azar dermal leishmaniasis (PKDL) follows visceral leishmaniasis (VL, kala-azar) in 10-60% of cases. It is characterized by an asymptomatic skin rash, usually starting in the face and consisting of macules, papules, or nodules. Diagnosis is difficult in the field and is often made clinically. There is an extensive differential diagnosis, and parasitological confirmation is preferred particularly when drug treatment is considered. The response to treatment is difficult to assess as this may be slow and lesions take long to heal, thus possibly exposing patients unnecessarily to prolonged drug treatment. Biomarkers are needed; these may be parasitological (from microscopy, PCR), serological (from blood, or from the lesion), immunological (from blood, tissue), pathological (from cytology in a smear, histology in a biopsy), repeated clinical assessment (grading, photography), or combinations. In this paper, we will review evidence for currently used biomarkers and discuss promising developments.

Post-Kala-Azar Dermal Leishmaniasis as a Reservoir for Visceral Leishmaniasis Transmission.

Post-kala-azar dermal leishmaniasis (PKDL) is a parasitic skin infection which can occur after visceral leishmaniasis (VL). Recent xenodiagnosis studies (Mondal et al., Clin. Infect. Dis., 2018) have uncovered the infectiousness of PKDL. When including this in a transmission model, PKDL cases appear as an important reservoir of infection, likely frustrating the VL elimination efforts on the Indian subcontinent.

Long term outcomes and prognostics of visceral leishmaniasis in HIV infected patients with use of pentamidine as secondary prophylaxis based on CD4 level: a prospective cohort study in Ethiopia.

BACKGROUND: The long-term treatment outcome of visceral leishmaniasis (VL) patients with HIV co-infection is complicated by a high rate of relapse, especially when the CD4 count is low. Although use of secondary prophylaxis is recommended, it is not routinely practiced and data on its effectiveness and safety are limited. METHODS: A prospective cohort study was conducted in Northwest Ethiopia from August 2014 to August 2017 (NCT02011958). HIV-VL patients were followed for up to 12 months. Patients with CD4 cell counts below 200/µL at the end of VL treatment received pentamidine prophylaxis starting one month after parasitological cure, while those with CD4 count ≥200 cells/µL were followed without secondary prophylaxis. Compliance, safety and relapse-free survival, using Kaplan-Meier analysis methods to account for variable time at risk, were summarised. Risk factors for relapse or death were analysed. RESULTS: Fifty-four HIV patients were followed. The probability of relapse-free survival at one year was 50% (95% confidence interval [CI]: 35-63%): 53% (30-71%) in 22 patients with CD4 ≥200 cells/µL without pentamidine prophylaxis and 46% (26-63%) in 29 with CD4 <200 cells/µL who started pentamidine. Three patients with CD4 <200 cells/µL did not start pentamidine. Amongst those with CD4 ≥200 cells/µL, VL relapse was an independent risk factor for subsequent relapse or death (adjusted rate ratio: 5.42, 95% CI: 1.1-25.8). Except for one case of renal failure which was considered possibly related to pentamidine, there were no drug-related safety concerns. CONCLUSION: The relapse-free survival rate for VL patients with HIV was low. Relapse-free survival of patients with CD4 count <200cells/µL given pentamidine secondary prophylaxis appeared to be comparable to patients with a CD4 count ≥200 cells/µL not given prophylaxis. Patients with relapsed VL are at higher risk for subsequent relapse and should be considered a priority for secondary prophylaxis, irrespective of their CD4 count.

A randomized trial of AmBisome monotherapy and AmBisome and miltefosine combination to treat visceral leishmaniasis in HIV co-infected patients in Ethiopia.

BACKGROUND: Visceral leishmaniasis (VL) in human immunodeficiency virus (HIV) co-infected patients requires special case management. AmBisome monotherapy at 40 mg/kg is recommended by the World Health Organization. The objective of the study was to assess if a combination of a lower dose of AmBisome with miltefosine would show acceptable efficacy at the end of treatment. METHODOLOGY/PRINCIPAL FINDINGS: An open-label, non-comparative randomized trial of AmBisome (30 mg/kg) with miltefosine (100 mg/day for 28 days), and AmBisome monotherapy (40 mg/kg) was conducted in Ethiopian VL patients co-infected with HIV (NCT02011958). A sequential design was used with a triangular continuation region. The primary outcome was parasite clearance at day 29, after the first round of treatment. Patients with clinical improvement but without parasite clearance at day 29 received a second round of the allocated treatment. Efficacy was evaluated again at day 58, after completion of treatment. Recruitment was stopped after inclusion of 19 and 39 patients in monotherapy and combination arms respectively, as per pre-specified stopping rules. At D29, intention-to-treat efficacy in the AmBisome arm was 70% (95% CI 45-87%) in the unadjusted analysis, and 50% (95% CI 27-73%) in the adjusted analysis, while in the combination arm, it was 81% (95% CI 67-90%) and 67% (95% CI 48-82%) respectively. At D58, the adjusted efficacy was 55% (95% CI 32-78%) in the monotherapy arm, and 88% (95% CI 79-98%) in the combination arm. No major safety concerns related to the study medication were identified. Ten SAEs were observed within the treatment period, and 4 deaths unrelated to the study medication. CONCLUSIONS/SIGNIFICANCE: The extended treatment strategy with the combination regimen showed the highest documented efficacy in HIV-VL patients; these results support a recommendation of this regimen as first-line treatment strategy for HIV-VL patients in eastern Africa. TRIAL REGISTRATION NUMBER: www.clinicaltrials.gov NCT02011958.

Recent Development of Visceral Leishmaniasis Treatments: Successes, Pitfalls, and Perspectives.

Research in visceral leishmaniasis in the last decade has been focused on how better to use the existing medicines as monotherapy or in combination. Systematic research by geographical regions has shown that a universal treatment is far from today's reality. Substantial progress has been made in the elimination of kala-azar in South Asia, with a clear strategy on first- and second-line therapy options of single-dose liposomal amphotericin B and a combination of paromomycin and miltefosine, respectively, among other interventions. In Eastern Africa, sodium stibogluconate (SSG) and paromomycin in combination offer an advantage compared to the previous SSG monotherapy, although not exempted of limitations, as this therapy requires 17 days of painful double injections and bears the risk of SSG-related cardiotoxicity. In this region, attempts to improve the combination therapy have been unsuccessful. However, pharmacokinetic studies have led to a better understanding of underlying mechanisms, like the underexposure of children to miltefosine treatment, and an improved regimen using an allometric dosage. Given this global scenario of progress and pitfalls, we here review what steps need to be taken with existing medicines and highlight the urgent need for oral drugs. Furthermore, it should be noted that six candidates belonging to five new chemical classes are reaching phase I, ensuring an optimistic near future.

Safety and Effectiveness of Short-Course AmBisome in the Treatment of Post-Kala-Azar Dermal Leishmaniasis: A Prospective Cohort Study in Bangladesh.

Background: A safe and effective short-course treatment regimen for post-kala-azar dermal leishmaniasis (PKDL) is considered essential for achieving and sustaining elimination of visceral leishmaniasis (VL) in the Indian subcontinent [1, 2]. Here, single-dose liposomal amphotericin B (AmBisome) has been adopted as a first-line regimen for VL; however the effectiveness and safety of AmBisome for PKDL has not been formally evaluated. Methods: The safety and effectiveness of AmBisome 15 mg/kg, given over 15 days in 5 biweekly infusions of 3 mg/kg on an outpatient basis, was evaluated between April and November 2014 in patients with clinically diagnosed PKDL, aged ≥12 years and residing in a highly VL-endemic area in Bangladesh. This was a prospective cohort observational study, with the objective to assess final cure 12 months after treatment. Clinical response was monitored at 1, 3, 6, and 12 months, and safety during treatment and up to 1 month after treatment. Results: Of the 280 patients meeting the inclusion criteria, 273 were assessed at 12 months. A complete or major improvement of lesions was seen in 245 patients (89.7%); 213 (78.0%) were considered completely cured. Lesions did not improve in 28 (10.3%) and new lesions appeared in 13 (4.8%). All patients completed treatment without severe or serious adverse events. Conclusions: A short-course 15-mg/kg AmBisome regimen proved safe and effective in the treatment of clinically diagnosed PKDL in Bangladesh, and should be considered a treatment option for routine programmatic use in the VL elimination effort in the Indian subcontinent.

Post-kala-azar dermal leishmaniasis in the Indian subcontinent: A threat to the South-East Asia Region Kala-azar Elimination Programme.

BACKGROUND: The South-East Asia Region Kala-azar Elimination Programme (KAEP) is expected to enter the consolidation phase in 2017, which focuses on case detection, vector control, and identifying potential sources of infection. Post-kala-azar dermal leishmaniasis (PKDL) is thought to play a role in the recurrence of visceral leishmaniasis (VL)/kala-azar outbreaks, and control of PKDL is among the priorities of the KAEP. METHODOLOGY AND PRINCIPAL FINDING: We reviewed the literature with regard to PKDL in Asia and interpreted the findings in relation to current intervention methods in the KAEP in order to make recommendations. There is a considerable knowledge gap regarding the pathophysiology of VL and PKDL, especially the underlying immune responses. Risk factors (of which previous VL treatments may be most important) are poorly understood and need to be better defined. The role of PKDL patients in transmission is largely unknown, and there is insufficient information about the importance of duration, distribution and severity of the rash, time of onset, and self-healing. Current intervention methods focus on active case detection and treatment of all PKDL cases with miltefosine while there is increasing drug resistance. The prevention of PKDL by improved VL treatment currently receives insufficient attention. CONCLUSION AND SIGNIFICANCE: PKDL is a heterogeneous and dynamic condition, and patients differ with regard to time of onset after VL, chronicity, and distribution and appearance of the rash, as well as immune responses (including tendency to self-heal), all of which may vary over time. It is essential to fully describe the pathophysiology in order to make informed decisions on the most cost-effective approach. Emphasis should be on early detection of those who contribute to transmission and those who are in need of treatment, for whom short-course, effective, and safe drug regimens should be available. The prevention of PKDL should be emphasised by innovative and improved treatment for VL, which may include immunomodulation.

A trial of a 7-valent pneumococcal conjugate vaccine in HIV-infected adults.

BACKGROUND: Streptococcus pneumoniae is a leading and serious coinfection in adults with human immunodeficiency virus (HIV) infection, particularly in Africa. Prevention of this disease by vaccination with the current 23-valent polysaccharide vaccine is suboptimal. Protein conjugate vaccines offer a further option for protection, but data on their clinical efficacy in adults are needed. METHODS: In this double-blind, randomized, placebo-controlled clinical efficacy trial, we studied the efficacy of a 7-valent conjugate pneumococcal vaccine in predominantly HIV-infected Malawian adolescents and adults who had recovered from documented invasive pneumococcal disease. Two doses of vaccine were given 4 weeks apart. The primary end point was a further episode of pneumococcal infection caused by vaccine serotypes or serotype 6A. RESULTS: From February 2003 through October 2007, we followed 496 patients (of whom 44% were male and 88% were HIV-seropositive) for 798 person-years of observation. There were 67 episodes of pneumococcal disease in 52 patients, all in the HIV-infected subgroup. In 24 patients, there were 19 episodes that were caused by vaccine serotypes and 5 episodes that were caused by the 6A serotype. Of these episodes, 5 occurred in the vaccine group and 19 in the placebo group, for a vaccine efficacy of 74% (95% confidence interval [CI], 30 to 90). There were 73 deaths from any cause in the vaccine group and 63 in the placebo group (hazard ratio in the vaccine group, 1.18; 95% CI, 0.84 to 1.66). The number of serious adverse events within 14 days after vaccination was significantly lower in the vaccine group than in the placebo group (3 vs. 17, P = 0.002), and the number of minor adverse events was significantly higher in the vaccine group (41 vs. 13, P = 0.003). CONCLUSIONS: The 7-valent pneumococcal conjugate vaccine protected HIV-infected adults from recurrent pneumococcal infection caused by vaccine serotypes or serotype 6A. (Current Controlled Trials number, ISRCTN54494731.).

The immunology of post-kala-azar dermal leishmaniasis (PKDL).

Post-kala-azar dermal leishmaniasis (PKDL) is a common complication of visceral leishmaniasis (VL) caused by Leishmania donovani. Because of its possible role in transmission it is considered a public health problem in VL endemic areas. The clinical features include a skin rash consisting of macules, papules or nodules in an otherwise healthy individual; this presentation is determined by the immune response towards parasites in the skin that probably persisted from the previous VL episode. The immune response in VL, cured VL and PKDL is the result of changes in the cytokine profile that only in part can be captured under the Th1 and Th2 dichotomy. Regulatory T cells and Th 17 cells also play a role. VL is characterized by an absent immune response to Leishmania with a predominantly Th2 type of response with high levels of IL-10; after successful treatment the patient will be immune with in vitro features of a Th1 type of response and in vivo a positive leishmanin skin test. PKDL takes an intermediate position with a dissociation of the immune response between the skin and the viscera, with a Th2 and Th1 type of response, respectively. It is likely that immune responses determine the different epidemiological and clinical characteristics of PKDL in Asia and Africa; various risk factors for PKDL may influence this, such as incomplete and inadequate treatment of VL, parasite resistance and genetic factors. It should be noted that PKDL is a heterogeneous and dynamic condition and patients differ with regard to time of onset after visceral leishmaniasis (VL), chronicity, extent and appearance of the rash including related immune responses, all of which may vary over time. Better understanding of these immune responses may offer opportunities for manipulation including combined chemotherapy and immunotherapy for VL to prevent PKDL from occurring and similarly in the treatment of chronic or treatment resistant PKDL cases.

Visceral leishmaniasis: a forgotten epidemic.

Visceral leishmaniasis (VL or kala-azar) is most endemic in Asia and Africa and commonly affects young children. It is usually caused by Leishmania donovani or Leishmania infantum that are transmitted by Phlebotomine sand flies. Transmission may be anthroponotic or zoonotic or both, depending on the endemic area. Clinical features include fever, hepatosplenomegaly, weight loss and pancytopenia. Younger age, malnutrition and immunosuppression (HIV infection, use of immunosuppressive drugs) are risk factors. Many infections remain asymptomatic. Diagnosis is made by demonstration of the Leishmania parasite in aspirates of lymph node, bone marrow or spleen. Serological tests such as rK39 strip test are widely used but the sensitivity varies. qPCR is useful to detect low numbers of parasites and to monitor treatment. Treatment is with AmBisome monotherapy in most areas but with drug combinations elsewhere. HIV co-infected patients are most difficult to treat and often relapse. Control efforts focus on case finding, availability of diagnostic tools, reservoir control and protection from sand flies (insecticides, bed nets). There is no human vaccine.

Mycetoma: a unique neglected tropical disease.

Mycetoma can be caused by bacteria (actinomycetoma) or fungi (eumycetoma) and typically affects poor communities in remote areas. It is an infection of subcutaneous tissues resulting in mass and sinus formation and a discharge that contains grains. The lesion is usually on the foot but all parts of the body can be affected. The causative microorganisms probably enter the body by a thorn prick or other lesions of the skin. Mycetoma has a worldwide distribution but is restricted to specific climate zones. Microbiological diagnosis and characterisation of the exact organism causing mycetoma is difficult; no reliable serological test exists but molecular techniques to identify relevant antigens have shown promise. Actinomycetoma is treated with courses of antibiotics, which usually include co-trimoxazole and amikacin. Eumycetoma has no acceptable treatment at present; antifungals such as ketoconazole and itraconazole have been used but are unable to eradicate the fungus, need to be given for long periods, and are expensive. Amputations and recurrences in patients with eumycetoma are common.