Female genital schistosomiasis (FGS): from case reports to a call for concerted action against this neglected gynaecological disease

AbstractIn recent years, control of neglected tropical diseases has been increasingly gaining momentum and interventions against schistosomiasis are being progressively scaled-up through expansion of donated praziquantel and preventive chemotherapy campaigns. However, the public health importance of female genital schistosomiasis is not fully recognised nor its control is adequately addressed. Taking a clinical and anatomopathological perspective, we evaluated the available literature to highlight the importance of female genital schistosomiasis and its connections with two sexually transmitted infections of global importance, Human Immunodeficiency Virus (HIV) and Human Papilloma Virus. Outside the long list of clinical descriptive reports beginning in 1899, there is presently a shocking gap in epidemiological assessment and a significant underestimation of the burden of FGS remains. The scarcity of integrated approaches to address female genital schistosomiasis calls for more concerted action in its detection, treatment and prevention alongside other concomitant women’s health issues, otherwise female genital schistosomiasis will remain a neglected gynaecological disease

Drug Discovery for Kinetoplastid Diseases : Future Directions

International audienceKinetoplastid parasites have caused human disease for millennia. Significant achievements have been made toward developing new treatments for leishmaniasis (particularly on the Indian subcontinent) and for human African trypanosomiasis (HAT). Moreover, the sustained decrease in the incidence of HAT has made the prospect of elimination a tantalizing reality. Despite the gains, no new chemical or biological entities to treat kinetoplastid diseases have been registered in more than three decades, and more work is needed to discover safe and effective therapies for patients with Chagas disease and leishmaniasis. Advances in tools for drug discovery and novel insights into the biology of the host-parasite interaction may provide opportunities for accelerated progress. Here, we summarize the output from a gathering of scientists and physicians who met to discuss the current status and future directions in drug discovery for kinetoplastid diseases

Female genital schistosomiasis (FGS): from case reports to a call for concerted action against this neglected gynaecological disease

In recent years, control of neglected tropical diseases has been increasing gaining momentum and interventions against schistosomiasis are being progressively scaled-up through expansion of donated praziquantel and preventive chemotherapy campaigns. However, the public health importance of female genital schistosomiasis is not fully recognised nor its control is adequately addressed. Taking a clinical and anatomopathological perspective, we evaluated the available literature to highlight the importance female genital schistosomiasis and its connections with two sexually transmitted infections of global importance, Human Immunodeficiency Virus (HIV) and Human Papilloma Virus. Outside the long list of clinical descriptive reports beginning in 1899, there is presently a shocking gap in epidemiological assessment and a significant underestimation of the burden of FGS remains. The scarcity of integrated approaches to address female genital schistosomiasis calls for more concerted action in its detection, treatment and prevention alongside other concomitant women’s health issues, otherwise female genital schistosomiasis will remain a neglected gynaecological disease

Diagnosis of O. volvulus infection via skin exposure to diethylcarbamazine: clinical evaluation of a transdermal delivery technology-based patch

Abstract Background Elimination of onchocerciasis in Africa is now regarded as an achievable goal in many areas. This makes monitoring changes in infection prevalence a key component of control programmes. Monitoring is currently based on determining the presence of O. volvulus microfilariae in skin snips, an invasive, labour-intensive method. The Onchocerciasis Control Programme (OCP) had established procedures to detect O. volvulus infections via the localized skin reaction induced by killing of microfilariae upon skin exposure to diethylcarbamazine via a patch (OCP-patch). Large scale OCP - patch use is difficult due to labour-intensive patch preparation. At the request of TDR, a manufacturer specialized in transdermal-delivery systems developed a ready-to-use diethylcarbamazine (DEC) containing patch (LTS-2 patch). To qualify this patch for large scale studies of its sensitivity and specificity, this study evaluated its ease of application, ability to detect infection and DEC exposure related adverse reactions compared to the OCP-patch in 30 infected individuals. Methods Each participant with 0.2–36.8 O. volvulus microfilariae/mg skin received the OCP-patch and 4 days later the LTS-2 patch at the left and right iliac crest, respectively, for 24 h. Presence and characteristics of local skin reactions were assessed at patch removal and 6 h later. Skin reaction and Mazzotti reaction rates were compared with Fisher’s exact and a paired t-test, respectively. Results The LTS-2 patch could be applied within 10 s. Mild itching occured at 63.3 % of OCP-patch (duration 8.9 ± 11.8 h) and 26.7 % of LTS-2 patch sites (duration 1.0 ± 2.5 h) and was the most frequent Mazzotti reaction. At patch removal after 24 h, a diagnostic local skin reaction was present under 90 % of OCP-patches and 83 % of LTS-2 patches; 6 h later, it was present at 93 % of OCP-patch and 100 % of LTS-2 patch sites. Conclusions The data suggest that safety, tolerability and ability to detect infections of the LTS-2 patch are comparable to those of the OCP-patch. They qualify the LTS-2 patch for field studies to determine LTS-2 patch sensitivity, specificity and utility during large scale use and thus to inform use of the LTS-2 patch by onchocerciasis control programmes to determine prevalence of infection. Trial registration Current controlled Trials ISRCTN76875372

A. Skin microfilaria density pre-treatment by sex of participant and number of onchocercal nodules.

<p>B. Skin microfilaria density pre-treatment by number of live female macrofilariae and sum of live (LI) and dead, non-calcified female macrofilariae (LIDD). Only data from participants who had not more palpable nodule sites at month 18 than at pre-treatment and who had agreed to excision of all palpable nodules or who had no palpable nodules are included. For display reasons, the×axis maximum in Figure B was set to 9. The data from the man with 8 nodules in Figure A who had 13 live female macrofilariae and 3 dead, non-calcified female macrofilariae and 50.2 mf/mg skin pre-treatment are thus not displayed.</p

Percentage reduction from pre-treatment in skin microfilariae density (mean, standard deviation) 8 days, 1, 2, 3, 6, 12 and 18 months after treatment by treatment group.

<p>A Total e-mITT population, B Severely infected in the e-mITT population treated with ivermectin or 8 mg moxidectin. For the ivermectin treatment group, means and standard deviations are shown across all severely infected and without the suboptimal microfilariae responders (Ivermectin - SOMR). Tx – treatment, SD – standard deviation shown in one direction. Marker positions for different treatment groups have been placed around the measurement time point to allow, to the extent possible, differentiation between overlapping means and SD.</p

A Randomized, Single-Ascending-Dose, Ivermectin-Controlled, Double-Blind Study of Moxidectin in <i>Onchocerca volvulus</i> Infection

<div><p>Background</p><p>Control of onchocerciasis as a public health problem in Africa relies on annual mass ivermectin distribution. New tools are needed to achieve elimination of infection. This study determined in a small number of <i>Onchocerca volvulus</i> infected individuals whether moxidectin, a veterinary anthelminthic, is safe enough to administer it in a future large study to further characterize moxidectin's safety and efficacy. Effects on the parasite were also assessed.</p><p>Methodology/Principal Findings</p><p>Men and women from a forest area in South-eastern Ghana without ivermectin mass distribution received a single oral dose of 2 mg (N = 44), 4 mg (N = 45) or 8 mg (N = 38) moxidectin or 150 µg/kg ivermectin (N = 45) with 18 months follow up. All ivermectin and 97%–100% of moxidectin treated participants had Mazzotti reactions. Statistically significantly higher percentages of participants treated with 8 mg moxidectin than participants treated with ivermectin experienced pruritus (87% vs. 56%), rash (63% vs. 42%), increased pulse rate (61% vs. 36%) and decreased mean arterial pressure upon 2 minutes standing still after ≥5 minutes supine relative to pre-treatment (61% vs. 27%). These reactions resolved without treatment. In the 8 mg moxidectin and ivermectin arms, the mean±SD number of microfilariae/mg skin were 22.9±21.1 and 21.2±16.4 pre-treatment and 0.0±0.0 and 1.1±4.2 at nadir reached 1 and 3 months after treatment, respectively. At 6 months, values were 0.0±0.0 and 1.6±4.5, at 12 months 0.4±0.9 and 3.4±4.4 and at 18 months 1.8±3.3 and 4.0±4.8, respectively, in the 8 mg moxidectin and ivermectin arm. The reduction from pre-treatment values was significantly higher after 8 mg moxidectin than after ivermectin treatment throughout follow up (p<0.01).</p><p>Conclusions/Significance</p><p>The 8 mg dose of moxidectin was safe enough to initiate the large study. Provided its results confirm those from this study, availability of moxidectin to control programmes could help them achieve onchocerciasis elimination objectives.</p><p>Trial Registration</p><p>ClinicalTrails.gov <a href="http://www.clinicaltrials.gov/ct2/show/NCT00300768" target="_blank">NCT00300768</a></p></div

Number (%) of subjects with adverse events by adverse event category, with Mazzotti reactions for which Fisher's exact text between at least one moxidectin treatment group and ivermectin treatment group yielded p-value<0.05 and for SSPH (mITT population).

<p>UnAE Adverse event unrelated to study drug or study participation. ADR Adverse drug reaction, MAZ Mazzotti reaction, MAP mean arterial pressure: Diastolic pressure+1/3 (Systolic pressure - Diastolic Pressure).</p>1<p>2 mg: Anaemia from 144 days post-treatment, 4 mg: prolonged prothrombin time from 549 days post-treatment, haematuria 390 days post-treatment, 8 mg: prolonged prothrombin time 32 days after treatment.</p>2<p>After standing still for 2 minutes following at least 5 minutes supine.</p>3<p>SAPH severe asymptomatic postural hypotension, asymptomatic decrease in MAP by ≥35 mmHg relative to baseline after 2 min standing still following ≥5 minutes supine.</p>4<p>SSPH severe symptomatic postural hypotension, diagnosed when a subject cannot stand still for 2 minutes after ≥5 minutes supine due to drop in blood pressure.</p><p>* p<0.05 for pairwise comparison of moxidectin treatment group vs. ivermectin treatment group.</p

Demographics and pre-treatment characteristics of all participants treated (mITT population).

<p>* Presence of palpable nodules was not an inclusion criterion.</p><p>** Based on histological examination of all palpable nodules excised at month 18.</p><p>Percentages calculated based on number of subjects with excised nodules.</p><p>***Nodulectomies >5 years ago.</p><p>**** Based on eye with lower acuity.</p

Overview of assessment of treatment effects.

<p>D: Day, M: Month. X indicates examination at each time point indicated in the top row, numbers indicate the day or alternative days for performing the examination.</p>1<p>PE: Physical examination including neurological examination and subcutaneous nodule palpation.</p>2<p>VS: Vital signs including temperature, respiratory rate, pulse rate (PR) and blood pressure (BP) after at least 5 minutes supine.</p><p>PR and BP were repeated after 2 minutes standing following ≥5 minutes supine.</p><p>Day 1: once before and 3 times after drug administration PR and BP after ≥5 minutes supine and subsequent 2 minutes standing still, Days 2–8: 5 times, PR and BP after ≥5 minutes supine and subsequent 2 minutes standing still, Days 9–17: twice, supine only, M1–M18: once, supine only.</p>3<p>12 lead ECG on day 1 approximately 4 hours after drug administration.</p>4<p>OE: Ocular Examination included visual acuity, visual fields (calibrated Goldman perimeter), colour vision, intraocular pressure, examination of the fundus, slit lamp examination of anterior segment, counting of microfilariae in anterior chamber, living and dead microfilariae in cornea and punctate opacities.</p><p>Colour fundus photography and fluorescein angiography to month 3, thereafter as per protocol only in participants with lesions or visual defects on OE (which was not applicable).</p>5<p>LE: Laboratory evaluations included: serum biochemistry (Na⁺, K⁺, Cl⁻, bicarbonate, glucose, total protein, albumin, urea, creatinine, alkaline phosphatase, lactic dehydrogenase, total bilirubin, gamma-glutamyl transpeptidase, aspartate aminotransferase, and alanine aminotransferase), hematology (prothrombin time, a complete blood cell count, hematocrit, hemoglobin, 5-part differential white blood cell count, platelet count), dipstick semiquantitative urinalysis microscopic urine evaluation, urine and blood microfilariae quantitation after nucleopore membrane filtration and Giemsa staining.</p>6<p>Minimum of 1 mg from each iliac crest and calf with a 2 mm corneoscleral punch.</p>7<p>Aseptical excision of all palpable nodules under 2% xylocaine anaesthesia.</p>8<p>Blood sampling time points for pharmacokinetics (PK) on day 1–4: within 2 hours of drug administration, 1, 2, 4, 8, 24, and 72 hours after treatment.</p