Long Term Outcomes of Nasoseptal Perforation Repair With an Anterior Ethmoidal Artery Flap.

BACKGROUND: Nasoseptal perforation repair is a challenging condition with no standard technique for repair recognized. METHODS: A case series of consecutive patients who underwent nasoseptal perforation repair with an anterior ethmoidal artery flap was conducted. Demographic data, preoperative features of the perforation and postoperative outcomes were analyzed. Closure rate, complications and persistence of nasal symptoms were documented. RESULTS: Thirty-two patients were included in the study. The average perforation diameter was 1.48 cm (range: 0.4-3 cm). Iatrogenic trauma was the most common cause (56% of patients). Nine cases ended up being idiopathic. The overall closure rate was 81%, but 87.5% when perforation had a 2-cm diameter or less. Of the six failures, 2 were due to flap necrosis and 4 to a residual anterior perforation. Despite the persistence, 2 patients solved their symptoms. One patient underwent revision surgery. CONCLUSION: The anterior ethmoidal artery flap is a reliable and minimal invasive technique for closure of symptomatic perforations. For defects larger than 2 cm, a lower success rate and additional reconstructive measures should be considered. Objective questionnaires are needed in order to evaluate functional outcomes.

Endoscopic Endonasal Transpterygoid Approach to Sphenoid Sinus Lateral Recess Defects.

Background Lesions affecting sphenoid sinus lateral recess (SSLR) are difficult to visualize and manipulate through the transnasal routes, especially when the sinus is highly pneumatized. External approaches to this area involve extensive surgery and are associated with significant morbidity. The aims of this study are to present our experience with the endoscopic transpterygoid approach as a method for approaching lesions of the SSLR and to evaluate the outcomes of this procedure. Methods Clinical charts of patients who had lesions in the SSLR and who were treated at our institution from September 1998 to June 2018 were retrospectively reviewed. All these patients were managed by the endoscopic endonasal transpterygoid approach. Results Thirty-nine patients were identified. No cerebrospinal fluid leak recurrences were observed during follow-up (range: 1-19.7 years; median: 2.3 years). Hypoesthesia (temporary, 1; persistent, 4) in the region innervated by the maxillary branch of the trigeminal nerve was detected in five (12.8%) patients, while symptoms due to the Vidian nerve damage (dry eye, 3; dry nasal mucosa, 1) were present in four (10%) patients. Conclusions Although the endoscopic endonasal transpterygoid approach is an excellent corridor for dealing with lesions of the SSLR, limited rate of neurologic and lacrimal complications was observed. Potential morbidity of the intervention should be discussed during preoperative counselling.

Frontal Sinus Preservation During Cerebrospinal Fluid Leak Repair.

BACKGROUND: To validate the repair of frontal sinus cerebrospinal fluid (CSF) leaks with preservation of frontal sinus drainage pathway (FSDP), independently of the approach used, and to establish the indications and limits of the endoscopic approach. METHODS: A retrospective evaluation of patients undergoing surgery for frontal sinus CSF leaks was performed. Demographics, indications for both endoscopic/combined endoscopic and open approaches, complications, methods for maintaining FSDP, and perioperative outcomes were examined. RESULTS: Fifty-three patients (average age 45 years) with frontal sinus CSF leaks were treated surgically from 2000 to 2018. All CSF leak repairs were successful at the 1st attempt with a mean follow-up of 76.8 months (range 4-227 months). Etiology was spontaneous (14), traumatic (26), and iatrogenic (13). In 17 patients, a purely endoscopic approach was performed, while an endoscopic endonasal orbital transposition procedure was added in 4 out of this group. In 23 patients, a combined endoscopic and osteoplastic procedure was employed, while in 13 patients a combined craniotomy and endoscopic procedure was performed. All frontal sinuses remained patent except for 2 cranialization patients. CONCLUSION: With contemporary endoscopic instrumentation and techniques, endoscopic closure of frontal sinus CSF leaks even in the far superolateral wall is feasible in selected patients. However, the surgeon should consider the option of combining an external approach when required. Preserving the FSDP should be the main aim regardless of the approach.

Septal Flip Flap for Anterior Skull Base Reconstruction After Endoscopic Transnasal Craniectomy: Long-Term Outcomes.

BACKGROUND: Endoscopic endonasal anterior skull base malignant sinonasal tumor resection and reconstruction remains a challenge. We describe our septal flip flap (SFF) reconstruction, a new surgical technique for repairing anterior skull base defects and report our outcomes. METHODS: We retrospectively reviewed the clinical data of 24 patients who underwent skull base reconstruction using a SFF following endoscopic resection with transnasal craniectomy. We raise the SFF from the contralateral nasal septum based on the septal branches of the anterior and posterior ethmoidal arteries; the SFF is then rotated laterally for anterior skull base reconstruction after transnasal resection with craniectomy. RESULTS: The SFF was used for multiple tumor types including, most commonly, intestinal-type adenocarcinoma, followed by olfactory neuroblastoma, squamous cell carcinoma, sinonasal undifferentiated carcinoma, and other types. All of the cases had either preoperative or postoperative radiation therapy. All flaps remained viable postoperatively. Postoperatively, nasal crusting was significantly reduced with faster healing of the surgical cavity. CONCLUSIONS: The SFF adds to the clinical armamentarium the opportunity to provide vascularized mucosal coverage extending from the frontal recess back to the planum sphenoidalis. The use of SFF requires careful consideration when dealing with paranasal sinus cancers so as not to infringe oncologic principles.

Ultrasonic Scalpel-Assisted Endoscopic Endonasal Surgery of Infratemporal Fossa: Our First Impressions.

BACKGROUND: The endoscopic endonasal transpterygoid approach is emerging as a valid option for treating selected tumors in the infratemporal fossa. Compared with traditional open approaches, the endoscopic endonasal approach presents more difficulty in controlling bleeding and less choice in surgical instruments for endoscopic tumor dissection, which is often performed with bipolar forceps or steel dissectors. CASE DESCRIPTION: We describe the use of an ultrasonic scalpel device for performing endoscopic endonasal resection of 2 rare infratemporal fossa tumors (mature teratoma and hemangiopericytoma), which has not been reported in the literature so far. We also review the literature on endoscopic ultrasonic scalpel use. CONCLUSIONS: The ultrasonically activated scalpel is a safe, effective and simple to use device, which achieved excellent hemostasis and did not damage adjacent neurovascular structures.

Assessment of taste functions in allergic rhinitis patients undergoing allergen-specific immunotherapy.

BACKGROUND: We evaluated taste functions of patients with perennial allergic rhinitis (AR) before and after allergen-specific immunotherapy (AIT). METHODS: The study was designed as a prospective clinical study in our tertiary care hospital. Patients (n = 21) who were diagnosed with perennial AR on the basis of physical examination, skin prick test of at least 3* for HDM allergen and treated with AIT were enrolled in this study. A control group (n = 21) was selected from patients who were given intranasal steroids (INS) for perennial AR. Both groups had self-reported hyposmia and subjective loss of the sense of taste before treatment. Taste strips (Burghart, Wedel, Germany) were used for the taste identification scores before and after 6 months treatment. RESULTS: A total of 42 subjects were included, with a mean age of 24.1 ± 7.9 years (range 15-43 years). Overall, the AIT group showed more of an improvement of taste function, observed in the total average test scores, compared to the INS group (p < 0.05), but no change was detected between the groups before treatment. No difference was found for the bitter taste scores between the study groups (p = 0.053). CONCLUSION: Subcutaneous allergen immunotherapy resulted in more of an improvement in taste function than intranasal steroids. Further studies are needed.

Neck Muscle Mass Index as a Predictor of Post-Laryngectomy Wound Complications.

OBJECTIVE: We investigated the relationship between paravertebral muscle cross-sectional area (PVM CSA) at the third vertebra (C3) level using computerized tomography (CT) neck images and its relationship with complications after total laryngectomy. DESIGN: Retrospective analysis of 60 advanced laryngeal cancer patients who underwent total laryngectomy was performed. The cross-sectional areas of paravertebral neck muscles using neck CT at C3 level images obtained preoperatively were analyzed. RESULTS: A significant difference in PVM CSA between complication and no complication groups, F(1, 53 = 4.319, P = .043), was identified by ANCOVA. There were no significant differences in between-subject effects: T-stage ( F = 1.652, P = .204), body mass index ( F = 0.889, P = .35), albumin ( F = .359, P = .552), age ( F = 1.623 P = .208), and smoking ( F = 4.319, P = .41). CONCLUSION: The PVM CSA measured at C3 level on pretreatment CT may help identify patients at higher risk of postoperative wound complications after total laryngectomy and who may particularly benefit from preoperative optimization of nutritional status.

Safety and efficacy of single dose versus multiple doses of AmBisome for treatment of visceral leishmaniasis in eastern Africa: a randomised trial.

BACKGROUND: Anti-leishmanial drug regimens that include a single dose AmBisome could be suitable for eastern African patients with symptomatic visceral leishmaniasis (VL) but the appropriate single dose is unknown. METHODOLOGY: A multi-centre, open-label, non-inferiority, randomized controlled trial with an adaptive design, was conducted to compare the efficacy and safety of a single dose and multiple doses of AmBisome for the treatment of VL in eastern Africa. The primary efficacy endpoint was definitive cure (DC) at 6 months. Symptomatic patients with parasitologically-confirmed, non-severe VL, received a single dose of AmBisome 7.5 mg/kg body weight or multiple doses, 7 times 3 mg/kg on days 1-5, 14, and 21. If interim analyses, evaluated 30 days after the start of treatment following 40 or 80 patients, showed the single dose gave significantly poorer parasite clearance than multiple doses at the 5% significance level, the single dose was increased by 2·5 mg/kg. In a sub-set of patients, parasite clearance was measured by quantitative reverse transcriptase (qRT) PCR. PRINCIPAL FINDINGS: The trial was terminated after the third interim analysis because of low efficacy of both regimens. Based on the intention-to-treat population, DC was 85% (95%CI 73-93%), 40% (95%CI 19-64%), and 58% (95%CI 41-73%) in patients treated with multiple doses (n = 63), and single doses of 7·5 (n = 21) or 10 mg/kg (n = 40), respectively. qRT-PCR suggested superior parasite clearance with multiple doses as early as day 3. Safety data accorded with the drug label. CONCLUSIONS: The tested AmBisome regimens would not be suitable for VL treatment across eastern Africa. An optimal single dose regimen was not identified. TRIALS REGISTRATION: www.clinicaltrials.govNCT00832208.

Post-Kala-Azar Dermal Leishmaniasis: A Paradigm of Paradoxical Immune Reconstitution Syndrome in Non-HIV/AIDS Patients.

Visceral leishmaniasis (VL) is a parasitic disease characterized by immune suppression. Successful treatment is usually followed by immune reconstitution and a dermatosis called post-Kala-azar dermal leishmaniasis (PKDL). Recently, PKDL was described as one of the immune reconstitution syndromes (IRISs) in HIV/VL patients on HAART. This study aimed to present PKDL as a typical example of paradoxical IRIS in non-HIV/AIDS individuals. Published and new data on the pathogenesis and healing of PKDL was reviewed and presented. The data suggested that PKDL is a typical example of paradoxical IRIS, being a new disease entity that follows VL successful treatment and immune recovery. PKDL lesions are immune inflammatory in nature with granuloma, adequate response to immunochemotherapy, and an ensuing hypersensitivity reaction, the leishmanin skin test (LST). The data also suggested that the cytokine patterns of PKDL pathogenesis and healing are probably as follows: an active disease state dominated by IL-10 followed by spontaneous/treatment-induced IL-12 priming, IL-2 stimulation, and INF- γ production. INF- γ -activated macrophages eliminate the Leishmania parasites/antigen to be followed by LST conversion and healing. In conclusion, PKDL is a typical example of paradoxical IRIS in non-HIV/AIDS individuals with anti-inflammatory cytokine patterns that are superseded by treatment-induced proinflammatory cytokines and lesions healing.

Genotyping of human papillomavirus in paraffin embedded cervical tissue samples from women in Ethiopia and the Sudan.

Cervical cancer is the most frequent female malignancy in most developing countries. Previous studies have demonstrated a strong association of human papillomavirus (HPV) infection with dysplasia and carcinoma of the uterine cervix. The objective of this study was to identify the prevailing HPV genotypes responsible for the development of cervical cancer among women in Ethiopia and the Sudan. A molecular characterization of HPV was done on 245 paraffin embedded cervical biopsy samples collected from the two countries. Amplification of HPV and subsequent genotyping was done using SPF10 primers and Line probe assay. Of samples collected from Ethiopian patients, 93% (149/160) and 13% (21/160) had high risk and low risk HPV genotypes, respectively. Among samples collected from the Sudan, 94% (80/85) harbored high risk and 11.7% (10/85) low risk HPV genotypes. Human papillomavirus 16 was the most frequent genotype identified in samples from Ethiopia (91%, 136/149) and the Sudan (82.5%, 66/80). HPV 52, 58, and 18 were the second, third and fourth common genotypes identified in Ethiopia, whereas HPV 18, 45, and 52 were the second, third, and fourth genotypes identified in samples collected from the Sudan. Thus, individuals living in different geographical localities should receive vaccines based on the specific genotypes circulating in the area and a vaccine targeting HPV 16, 18, 45, 52, and 58 may be optimal for the control of cervical cancer in the two countries.

Immunogenicity and immune modulatory effects of in silico predicted L. donovani candidate peptide vaccines.

Visceral leishmaniasis (VL) is a serious parasitic disease for which control measures are limited and drug resistance is increasing. First and second generation vaccine candidates have not been successful. The goal of the present study was to select possibly immunogenic L. donovani donovani GP63 peptides using immunoinformatics tools and to test their immunogenicity in vitro. The amino acid sequence of L. donovani donovani GP63 [GenBank accession: ACT31401] was screened using the EpiMatrix algorithm for putative T cell epitopes that would bind to the most common HLA class II alleles (DRB1*1101 and DRB1*0804) among at-risk populations. Four T cell epitopes were selected from nine potential candidates. Stimulation of whole blood from healthy volunteers using the peptides separately produced mean IFN-γ and IL-4 levels that were not significantly different from negative controls, while the pooled peptides produced a moderate IFN-γ increase in some volunteers. However, mean IL-10 levels were significantly reduced for all individuals compared with controls. The immunogenicity of these epitopes may be harnessed most effectively in a vaccine delivered in combination with immune-modulating adjuvants.

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.govNCT00255567.

Fusobacterium nucleatum and Tannerella forsythia induce synergistic alveolar bone loss in a mouse periodontitis model.

Tannerella forsythia is strongly associated with chronic periodontitis, an inflammatory disease of the tooth-supporting tissues, leading to tooth loss. Fusobacterium nucleatum, an opportunistic pathogen, is thought to promote dental plaque formation by serving as a bridge bacterium between early- and late-colonizing species of the oral cavity. Previous studies have shown that F. nucleatum species synergize with T. forsythia during biofilm formation and pathogenesis. In the present study, we showed that coinfection of F. nucleatum and T. forsythia is more potent than infection with either species alone in inducing NF-κB activity and proinflammatory cytokine secretion in monocytic cells and primary murine macrophages. Moreover, in a murine model of periodontitis, mixed infection with the two species induces synergistic alveolar bone loss, characterized by bone loss which is greater than the additive alveolar bone losses induced by each species alone. Further, in comparison to the single-species infection, mixed infection caused significantly increased inflammatory cell infiltration in the gingivae and osteoclastic activity in the jaw bones. These data show that F. nucleatum subspecies and T. forsythia synergistically stimulate the host immune response and induce alveolar bone loss in a murine experimental periodontitis model.

Geographical variation in the response of visceral leishmaniasis to paromomycin in East Africa: a multicentre, open-label, randomized trial.

BACKGROUND: Visceral leishmaniasis (VL) is a major health problem in developing countries. The untreated disease is fatal, available treatment is expensive and often toxic, and drug resistance is increasing. Improved treatment options are needed. Paromomycin was shown to be an efficacious first-line treatment with low toxicity in India. METHODS: This was a 3-arm multicentre, open-label, randomized, controlled clinical trial to compare three treatment regimens for VL in East Africa: paromomycin sulphate (PM) at 15 mg/kg/day for 21 days versus sodium stibogluconate (SSG) at 20 mg/kg/day for 30 days; and the combination of both dose regimens for 17 days. The primary efficacy endpoint was cure based on parasite-free tissue aspirates taken 6 months after treatment. FINDINGS: Overall, 135 patients per arm were enrolled at five centres in Sudan (2 sites), Kenya (1) and Ethiopia (2), when the PM arm had to be discontinued due to poor efficacy. The trial has continued with the higher dose of PM as well as the combination of PM and SSG arms. These results will be reported later. Baseline patient characteristics were similar among treatment arms. The overall cure with PM was significantly inferior to that with SSG (63.8% versus 92.2%; difference 28.5%, 95%CI 18.8% to 38.8%, p<0.001). The efficacy of PM varied among centres and was significantly lower in Sudan (14.3% and 46.7%) than in Kenya (80.0%) and Ethiopia (75.0% and 96.6%). No major safety issues with PM were identified. CONCLUSION: The efficacy of PM at 15 mg/kg/day for 21 days was inadequate, particularly in Sudan. The efficacy of higher doses and the combination treatment warrant further studies.

Paromomycin for the treatment of visceral leishmaniasis in Sudan: a randomized, open-label, dose-finding study.

BACKGROUND: A recent study has shown that treatment of visceral leishmaniasis (VL) with the standard dose of 15 mg/kg/day of paromomycin sulphate (PM) for 21 days was not efficacious in patients in Sudan. We therefore decided to test the efficacy of paramomycin for a longer treatment duration (15 mg/kg/day for 28 days) and at the higher dose of 20 mg/kg/day for 21 days. METHODS: This randomized, open-label, dose-finding, phase II study assessed the two above high-dose PM treatment regimens. Patients with clinical features and positive bone-marrow aspirates for VL were enrolled. All patients received their assigned courses of PM intramuscularly and adverse events were monitored. Parasite clearance in bone-marrow aspirates was tested by microscopy at end of treatment (EOT, primary efficacy endpoint), 3 months (in patients who were not clinically well) and 6 months after EOT (secondary efficacy endpoint). Pharmacokinetic data were obtained from a subset of patients weighing over 30 kg. FINDINGS: 42 patients (21 per group) aged between 4 and 60 years were enrolled. At EOT, 85% of patients (95% confidence interval [CI]: 63.7% to 97.0%) in the 20 mg/kg/day group and 90% of patients (95% CI: 69.6% to 98.8%) in the 15 mg/kg/day group had parasite clearance. Six months after treatment, efficacy was 80.0% (95% CI: 56.3% to 94.3%) and 81.0% (95% CI: 58.1% to 94.6%) in the 20 mg/kg/day and 15 mg/kg/day groups, respectively. There were no serious adverse events. Pharmacokinetic profiles suggested a difference between the two doses, although numbers of patients recruited were too few to make it significant (n = 3 and n = 6 in the 20 mg/kg/day and 15 mg/kg/day groups, respectively). CONCLUSION: Data suggest that both high dose regimens were more efficacious than the standard 15 mg/kg/day PM for 21 days and could be further evaluated in phase III studies in East Africa.

Evaluation of the particle gel diffusion technique for the detection of haemoglobin S in Sudanese patients.

BACKGROUND: Sickle cell disease is a heterogenous disorder characterized by an abnormal haemoglobin and sickling phenomena of red cells. It is prevalent among certain nomadic tribes in Sudan. Painful, aplastic and haemolytic crises mark sickle cell anaemia. Haemoglobin S (HbS) is detected using haemoglobin electrophoresis, iso-electric focusing and/or high-performance liquid chromatography techniques with high sensitivity, but entails cost and expertise. This study aimed to determine the sensitivity, specificity and positive predictive values (PPV) of the ID-particle gel diffusion technique for screening, diagnosis and phenotyping of HbS in patients with a provisional diagnosis of abnormal haemoglobin. METHODS: Following informed consent, 100 sequential individuals who reported to a central referral haemoglobinopathy clinic were enrolled. ID-particle gel diffusion technique was compared with cellulose acetate electrophoresis to determine haemoglobin phenotypes. RESULTS: The ID-particle gel test detected HbAA with 100% sensitivity and 100% specificity. Sensitivity for HbS was 100%, whether as HbSS or as a mixed pattern. HbSS was identified in all cases where this is the only haemoglobin present. Other patterns were detected with <100% specificity and these would require further testing by other means to definitively identify abnormal haemoglobins. CONCLUSIONS: Although the ID-particle technique is a simple and cheap technique with high sensitivity, specificity and PPV compared with cellulose acetate electrophoresis in detecting HbSS, it could not differentiate HbAS from HbSS with high levels of HbF. High environmental temperatures could melt the test microtubes. Cellulose acetate electrophoresis remains the technique of choice for the screening of abnormal haemoglobins in the Sudan.

Addison's disease due to Histoplasma duboisii infection of the adrenal glands.

Histoplasmosis is a fungal infection caused by Histoplasma capsulatum. In the normal individual, both disseminated histoplasmosis and symptomatic adrenal histoplasmosis are rare. Herein, we describe the case of a 50-year-old gentleman residing in western Sudan who presented with a 7-month history of generalized body weakness, easy fatigue, and frequent attacks of vomiting and diarrhea. Physical examination and laboratory investigations confirmed the diagnosis of Addison's disease due to Histoplasma capsulatum var duboisii infection of the adrenal glands. He was treated with intravenous hydrocortisone, followed by oral prednisolone and itraconazole.

Immunochemotherapy of persistent post-kala-azar dermal leishmaniasis: a novel approach to treatment.

Post-kala-azar dermal leishmaniasis (PKDL) is a recognized dermatosis that follows successful treatment of visceral leishmaniasis in the Sudan. This randomized and double-blind study aimed to assess safety, immunogenicity and curative potentials of a novel immunochemotherapy regimen in patients with persistent PKDL. Following informed consent, 30 patients were randomized to receive alum-precipitated autoclaved Leishmania major (Alum/ALM) vaccine+Bacille Calmette-Guérin (BCG) and sodium stibogluconate (SSG) or vaccine diluent and SSG. The SSG+Alum/ALM+BCG proved safe with minimal local adverse events. In the SSG+vaccine group, 87% of the patients were cured by day 60 compared with 53% in the SSG alone group (SSG+vaccine efficacy=71%, 95% CI for risk ratio 0.7-1.16). On day 90 of follow-up there were two relapses in the SSG alone arm and none in the SSG+vaccine arm. Pre-treatment cytokines showed high IFN-gamma or high IFN-gamma/IL-10 levels and leishmanin skin test (LST) non-reactivity, while healing/clinical improvement were associated with LST reactivity and low IFN-gamma levels in both study groups (P=0.004). In conclusion, SSG+Alum/ALM+BCG is safe and immunogenic with significant healing potentials in persistent PKDL lesions. Immunochemotherapy probably augmented IFN-gamma production, which induced healing. Leishmanin skin reactivity is a good surrogate marker of cure in persistent PKDL lesions.

Safety and immunogenicity of a candidate vaccine for visceral leishmaniasis (Alum-precipitated autoclaved Leishmania major + BCG) in children: an extended phase II study.

BACKGROUND: Untreated visceral leishmaniasis (VL) is an inevitably fatal childhood disease. First-generation candidate vaccines for VL [autoclaved Leishmania major (ALM) + BCG] have been found to be safe and immunogenic but not superior to BCG alone. Modulation of ALM by adsorption to Alum significantly increases the immunogenicity. The Alum-adsorbed ALM vaccine was found to be safe and strongly immunogenic in healthy adult volunteers in a non-VL-endemic area. This study aimed at establishing the safety and immunogenicity of Alum-precipitated autoclaved L. major + BCG vaccine in children under field conditions. METHODS: A total of 544 healthy, leishmanin non-reactive children (<15 y) were randomly allocated to receive either a single intradermal injection of Alum/ALM + BCG or vaccine diluent (placebo). Volunteers were closely followed for 2 years at 6-month intervals for vaccine safety and immunogenicity. RESULTS: The vaccine was well tolerated with minimal side-effects. Leishmanin skin test conversion (>or=5 mm) was seen in 56%, 50%, 25% and 31% at 6, 12, 18 and 24 months post-vaccination, respectively; conversion in the placebo group was 4%, 12%, 3% and 13% at the same follow-up visits. There was no significant increase in anti-leishmanial antibodies in either study arm at any of the follow-up visits. During the study, four patients in the placebo arm developed parasitologically confirmed VL. CONCLUSION: Alum/ALM + BCG vaccine is safe and immunogenic in children under field conditions. Multiple injections might be needed to obtain results similar to those obtained in healthy volunteers.