Omalizumab prevents anaphylaxis and improves symptoms in systemic mastocytosis: Efficacy and safety observations.

BACKGROUND: Patients with systemic mastocytosis (SM) may suffer from mast cell (MC) mediator-related symptoms insufficiently controlled by conventional therapy. Omalizumab is an established treatment in other MC-driven diseases, but experiences in SM are limited. OBJECTIVE: To assess the efficacy and safety of omalizumab in SM. METHODS: In our patient cohort, we evaluated all SM patients treated with omalizumab. A physician global assessment of type and severity of symptoms was performed at baseline, at 3 and 6 months and at latest follow-up. Quality of life was assessed by visual analogue scale. S-tryptase and KIT D816V allele burden were monitored. RESULTS: A total of 14 adult SM patients (10 ISM, 2 BMM, 1 SSM, and 1 ASM-AHN) received omalizumab with a median duration of 17 months (range: 1-73 months). One patient was excluded due to concomitant cytoreductive therapy. In the remaining 13 patients, we observed a significant reduction in symptoms, with complete symptom control in five (38.5%), major response in three (23.1%), and a partial response in three (23.1%) patients, whereas two patients (15.4%) withdrew due to subjective side-effects at first dose. The treatment was most effective for recurrent anaphylaxis and skin symptoms, less for gastrointestinal, musculoskeletal, and neuropsychiatric symptoms. Patient-reported quality of life showed significant improvement. No significant changes in s-tryptase/KIT D816V allele burden were observed. No severe adverse events were recorded. CONCLUSIONS: Omalizumab appears to be a promising treatment option in SM, effectively preventing anaphylaxis and improving chronic MC mediator-related symptoms, insufficiently controlled by conventional therapy. Controlled studies are needed to substantiate findings.

KIT mutation analysis in mast cell neoplasms: recommendations of the European Competence Network on Mastocytosis.

Although acquired mutations in KIT are commonly detected in various categories of mastocytosis, the methodologies applied to detect and quantify the mutant type and allele burden in various cells and tissues are poorly defined. We here propose a consensus on methodologies used to detect KIT mutations in patients with mastocytosis at diagnosis and during follow-up with sufficient precision and sensitivity in daily practice. In addition, we provide recommendations for sampling and storage of diagnostic material as well as a robust diagnostic algorithm. Using highly sensitive assays, KIT D816V can be detected in peripheral blood leukocytes from most patients with systemic mastocytosis (SM) that is a major step forward in screening and SM diagnosis. In addition, the KIT D816V allele burden can be followed quantitatively during the natural course or during therapy. Our recommendations should greatly facilitate diagnostic and follow-up investigations in SM in daily practice as well as in clinical trials. In addition, the new tools and algorithms proposed should lead to a more effective screen, early diagnosis of SM and help to avoid unnecessary referrals.

DNA extraction from dried Schistosoma haematobium eggs isolated on nylon filters.

Genetic studies on Schistosoma haematobium are often carried out on DNA extracted from miracidia, cercariae or adult worms. This paper presents a method for extracting DNA from S. haematobium eggs collected from urine samples and stored on nylon filters at room temperature. DNA was extracted from dried S. haematobium eggs using the DNeasy Blood & Tissue Kit (QIAGEN Sample & Assay Technologies, Copenhagen, Denmark). Selected genes were amplified using PCR to verify that DNA extraction had been successful. DNA was extracted from 45 samples and 31 had a positive PCR reaction for either or both of the two selected genes.

Control of schistosomiasis in sub-Saharan Africa: progress made, new opportunities and remaining challenges.

Several other journal supplements have documented progress made in the control of schistosomiasis in Egypt, China and Brazil, however, with more than 97% of the schistosome infections now estimated to occur in Africa, the relevance of this special issue in Parasitology cannot be overemphasized. In total, 18 articles are presented, inclusive of a lead-editorial from the WHO highlighting a seminal resolution at the 54th World Health Assembly in 2001 that advocated de-worming. Facilitated by a US$ 30 million grant from the Bill and Melinda Gates Foundation in 2002, the Schistosomiasis Control Initiative subsequently fostered implementation of large-scale schistosomiasis (and soil-transmitted helminthiasis) control programmes in six selected African countries. From 2005, CONTRAST, a European union-funded consortium, was formed to conduct multi-disciplinary research pertaining to optimisation of schistosomiasis control. Progress made in schistosomiasis control across sub-Saharan Africa since the turn of the new millennium is reviewed, shedding light on the latest findings stemming from clinical, epidemiological, molecular and social sciences research, inclusive of public health interventions with monitoring and evaluation activities. New opportunities for integrating the control of schistosomiasis and other so-called neglected tropical diseases are highlighted, but more importantly, several opportune questions that arise from it frame the remaining challenges ahead for an enduring solution.

Remote sensing, geographical information system and spatial analysis for schistosomiasis epidemiology and ecology in Africa.

Beginning in 1970, the potential of remote sensing (RS) techniques, coupled with geographical information systems (GIS), to improve our understanding of the epidemiology and control of schistosomiasis in Africa, has steadily grown. In our current review, working definitions of RS, GIS and spatial analysis are given, and applications made to date with RS and GIS for the epidemiology and ecology of schistosomiasis in Africa are summarised. Progress has been made in mapping the prevalence of infection in humans and the distribution of intermediate host snails. More recently, Bayesian geostatistical modelling approaches have been utilized for predicting the prevalence and intensity of infection at different scales. However, a number of challenges remain; hence new research is needed to overcome these limitations. First, greater spatial and temporal resolution seems important to improve risk mapping and understanding of transmission dynamics at the local scale. Second, more realistic risk profiling can be achieved by taking into account information on people's socio-economic status; furthermore, future efforts should incorporate data on domestic access to clean water and adequate sanitation, as well as behavioural and educational issues. Third, high-quality data on intermediate host snail distribution should facilitate validation of infection risk maps and modelling transmission dynamics. Finally, more emphasis should be placed on risk mapping and prediction of multiple species parasitic infections in an effort to integrate disease risk mapping and to enhance the cost-effectiveness of their control.

The influence of transmission season on parasitological cure rates and intensity of infection after praziquantel treatment of Schistosoma haematobium-infected schoolchildren in Mozambique.

Schistosoma haematobium is refractory to praziquantel (PZQ) during the prepatent period of infection. A hypothesis based on this observation is that in areas where S. haematobium transmission is seasonal, the outcome of chemotherapy depends on the timing of the treatment relative to the annual transmission pattern. To examine this hypothesis, a study was carried out in southern Mozambique. Following demonstration of seasonal transmission, PZQ was administered separately to two cohorts of S. haematobium-infected schoolchildren in (1) the high and (2) the low transmission seasons and followed up after two months when levels of infection and intensities were measured. The prevalence of infection decreased from 54.2% and 51.7% in cohorts 1 and 2 to 30.3% and 1.8%, respectively. The geometric mean intensity of infection decreased from 23.3 eggs/10 ml of urine at baseline to 15.6 eggs/10 ml of urine in cohort 1 (treated during high transmission season), and from 23.5 eggs/10 ml urine to 7.3 eggs/10 ml of urine in cohort 2 (treated during low transmission season). The observed cure rates in cohorts 1 and 2 were 69.7% and 98.2%, respectively. Differences in infection between the cohorts in terms of cure rate and level of infection two months post-treatment were statistically significant and indicate that in areas with a seasonal transmission pattern, the effect of PZQ can be enhanced if treatment takes place during the low transmission season. We conclude that appropriately timed PZQ administration will increase the impact of schistosomiasis control programmes.

The epidemiology and small-scale spatial heterogeneity of urinary schistosomiasis in Lusaka province, Zambia.

In line with the aims of the "National Bilharzia Control Programme" and the "School Health and Nutrition Programme" in Zambia, a study on urinary schistosomiasis was conducted in 20 primary schools of Lusaka province to further our understanding of the epidemiology of the infection, and to enhance spatial targeting of control. We investigated risk factors associated with urinary schistosomiasis, and examined small-scale spatial heterogeneity in prevalence, using data collected from 1,912 schoolchildren, 6 to 15-year-old, recruited from 20 schools in Kafue and Luangwa districts. The risk factors identified included geographical location, altitude, normalized difference vegetation index (NDVI), maximum temperature, age, sex of the child and intermediate host snail abundance. Three logistic regression models were fitted assuming different random effects to allow for spatial structuring. The mean prevalence rate was 9.6%, with significance difference between young and older children (odds ratio (OR) = 0.71; 95% confidence interval (CI) = 0.51-0.96). The risk of infection was related to intermediate host snail abundance (OR = 1.03; 95% CI = 1.00-1.05) and vegetation cover (OR = 1.04; 95% CI = 1.00-1.07). Schools located either on the plateau and the valley also differed in prevalence and intensity of infection for moderate infection to none (OR = 1.64; 95% CI = 1.36- 1.96). The overall predictive performance of the spatial random effects model was higher than the ordinary logistic regression. In addition, evidence of heterogeneity of the infection risk was found at the micro-geographical level. A sound understanding of small-scale heterogeneity, caused by spatial aggregation of schoolchildren, is important to inform health planners for implementing control schistosomiasis interventions.

Spatio-temporal correlation between human and bovine schistosomiasis in China: insight from three national sampling surveys.

Insight into the spatial and temporal contamination of the environment by bovine faeces in China can provide important information on the significance of bovines in the transmission of human schistosomiasis. This insight will be useful for the new evidence-based strategy of the Chinese national schistosomiasis control programme. To enhance our understanding of the spatio-temporal relationship between the prevalence of human and bovine schistosomiasis, we performed correlation and regression analyses using data from three national sampling surveys on schistosomiasis, carried out in 1989, 1995 and 2004. In addition, we established a geographical information system and performed spatial analyses to identify the high-risk areas of the disease. We found that schistosomiasis is mainly concentrated in the marshlands along the Yangtze River. It was also noted that, although the human prevalence and force of transmission in highly endemic areas has been reduced since 1989, the relative importance of bovine schistosomiasis has increased. This is seen in a declining Spearman correlation coefficient between the infection prevalence in humans and in bovines over time (0.812 in 1989, 0.754 in 1995 and 0.376 in 2004). In parallel, the slope of the linear regression decreased from 0.395 in 1989 to 0.215 in 2004. Our data therefore suggest that future schistosomiasis control efforts in China should more vigorously address the important role of bovines in the transmission of human schistosomiasis, and to reduce the environmental contamination of Schistosoma japonicum eggs by bovines.

Modeling freshwater snail habitat suitability and areas of potential snail-borne disease transmission in Uganda.

Geographic information system (GIS-based modeling of an intermediate host snail species environmental requirements using known occurrence records can provide estimates of its spatial distribution. When other data are lacking, this can be used as a rough spatial prediction of potential snail-borne disease transmission areas. Furthermore, knowledge of abiotic factors affecting intra-molluscan parasitic development can be used to make "masks" based on remotely sensed climatic data, and these can in turn be used to refine these predictions. We used data from a recent freshwater snail survey from Uganda, environmental data and the genetic algorithm for rule-set prediction (GARP) to map the potential distribution of snail species known to act as intermediate hosts of several human and animal parasites. The results suggest that large areas of Uganda are suitable habitats for many of these snail species, indicating a large potential for disease transmission. The lack of parasitological data still makes it difficult to determine the magnitude of actual disease transmission, but the predicted snail distributions might be used as indicators of potential present and future risk areas. Some of the predicted snail distribution maps were furthermore combined with temperature masks delineating suitable temperature regimes of the parasites they host. This revealed the coinciding suitable areas for snail and parasite, but also areas suitable for host snails, but apparently not for the parasites. Assuming that the developed models correctly reflect areas suitable for transmission, the applied approach could prove useful for targeting control interventions.

Modeling the distribution of Schistosoma mansoni and host snails in Uganda using satellite sensor data and Geographical Information Systems.

The potential value of MODIS satellite sensor data on Normalized Difference Vegetation Index (NDVI) and land surface temperatures (LST) for describing the distribution of the Schistosoma mansoni-"Biomphalaria pfeifferi"/Biomphalaria sudanica parasite-snail system in inland Uganda, were tested by developing annual and seasonal composite models, and iteratively analysing for their relationship with parasite and snail distribution. The dry season composite model predicted an endemic area that produced the best fit with the distribution of schools with > or =5% prevalence. NDVI values of 151-174, day temperatures of 26-36 degrees C, and night temperatures of 15-20 degrees C were used as criteria for the prediction model. Using the same approach with host snail data indicated that most of Uganda is suitable "B. pfeifferi"/B. sudanica habitat, except for possibly the north-eastern region of the country. The parasite, however, appears to be restricted in its distribution in both the north-eastern and the south-western regions of Uganda. The absence of disease in the south-west can not be attributed to the absence of snail hosts. Results suggest a combination of satellite sensor data on temperature and standard climate data on precipitation, as the best ecological determinants of the S. mansoni-"B. pfeifferi"/B. sudanica system. Satellite composite models and logistic regression analysis, suggest low night time temperature as one of the significant factors inhibiting S. mansoni transmission in the south-western highland areas of Uganda. The developed models are, however, unique, representing species-specific ecologic preferences of the S. mansoni-"B. Pfeifferi"/B. sudanica system in inland Uganda. Further validation studies are needed to test the value of the model in other countries in East Africa.

A neotropical snail host of Schistosoma mansoni introduced into Africa and consequences for the schistosomiasis transmission Biomphalaria tenagophila in Kinshasa (Democratic Republic of Congo).

Malacological surveys carried out in the early 1970s in water bodies of the Kinshasa area, Lower Zaire (Democratic Republic of Congo), showed the appearance of a Biomphalaria species which was identified as Biomphalaria camerunensis. In 1976, other surveys confirmed the presence of the species in several sites and showed numerous infected snails with Schistosoma mansoni, demonstrating for the first time an active transmission of the parasite responsible of the intestinal schistosomiasis in this area. The most recent malacological sampling was carried out by one of us in 1994 in Mangungu River and revealed the presence of apparently the same snail species. However, conchological, anatomical and molecular studies showed that this snail may be considered as an introduced neotropical species, B. tenagophila. To our knowledge, this is the second example of the introduction of a neotropical snail host of schistosomes into Africa.

New insights into the transmission biology of urinary schistosomiasis in Zanzibar.

A better understanding of the transmission biology of urinary schistosomiasis in Zanzibar, Tanzania was only possible after the development of molecular DNA markers for identification of Bulinus africanus group snails, the potential intermediate hosts of Schistosoma haematobium. Hitherto, identification of natural populations of B. globosus and B. nasutus was problematic and the intermediate host status and distribution of either species remained speculative. By recourse to molecular markers, snail distribution maps could be drawn, revealing an allopatric distribution and, more importantly, leading to the discovery that B. nasutus played no role in transmission. Indeed, in Unguja the area of active transmission of S. haematobium to humans is confined within the distribution of B. globosus. This strong relationship may prove useful for predicting the distribution of urinary schistosomiasis within Zanzibar and, if snail schistosome compatibilities persist, in other areas nearby, e.g. coastal Tanzania and Kenya. The transmission biology of urinary schistosomiasis in Zanzibar is reviewed, the paper reports on ongoing malacological studies in Zanzibar and Kenya and finally closes by posing the question whether medical malacology forms an essential component associated with mass-scale chemotherapy control programmes.

Larval trematode infections in freshwater snails from the highveld and lowveld areas of Zimbabwe.

Between November 1998 and October 2000, freshwater snails were collected monthly from the highveld and lowveld areas of Zimbabwe to determine the occurrence of larval trematodes. A total of 13,789 snails, representing ten species, were collected from 21 sites and 916 (6.6%) harboured patent trematode infections. Eight morphologically distinguishable types of cercariae were identified. Bulinus tropicus had the highest overall prevalence of infection (13.1%). The echinostome was the most common type of cercaria recovered, contributing 38.2% of all infections. Schistosoma cercariae were recovered mainly from the highveld and comprised 8.0% of all infections. Amphistome cercariae contributed 37.6% of all infections and were recorded from both the highveld and lowveld areas with a peak prevalence occurring during the post-rainy period (March-May). The main intermediate host for amphistomes was B. tropicus. Infections in B. globosus, B. forskalii and Biomphalaria pfeifferi with amphistome cercariae are new records for Zimbabwe.

Identification of snails within the Bulinus africanus group from East Africa by multiplex SNaPshot trade mark analysis of single nucleotide polymorphisms within the cytochrome oxidase subunit I.

Identification of populations of Bulinus nasutus and B. globosus from East Africa is unreliable using characters of the shell. In this paper, a molecular method of identification is presented for each species based on DNA sequence variation within the mitochondrial cytochrome oxidase subunit I (COI) as detected by a novel multiplexed SNaPshotTM assay. In total, snails from 7 localities from coastal Kenya were typed using this assay and variation within shell morphology was compared to reference material from Zanzibar. Four locations were found to contain B. nasutus and 2 locations were found to contain B. globosus. A mixed population containing both B. nasutus and B. globosus was found at Kinango. Morphometric variation between samples was considerable and UPGMA cluster analysis failed to differentiate species. The multiplex SNaPshotTM assay is an important development for more precise methods of identification of B. africanus group snails. The assay could be further broadened for identification of other snail intermediate host species.

Identification of snails within the Bulinus africanus group from East Africa by multiplex SNaPshotTManalysis of single nucleotide polymorphisms within the cytochrome oxidase subunit I

Identification of populations of Bulinus nasutus and B. globosus from East Africa is unreliable using characters of the shell. In this paper, a molecular method of identification is presented for each species based on DNA sequence variation within the mitochondrial cytochrome oxidase subunit I (COI) as detected by a novel multiplexed SNaPshotTM assay. In total, snails from 7 localities from coastal Kenya were typed using this assay and variation within shell morphology was compared to reference material from Zanzibar. Four locations were found to contain B. nasutus and 2 locations were found to contain B. globosus. A mixed population containing both B. nasutus and B. globosus was found at Kinango. Morphometric variation between samples was considerable and UPGMA cluster analysis failed to differentiate species. The multiplex SNaPshotTM assay is an important development for more precise methods of identification of B. africanus group snails. The assay could be further broadened for identification of other snail intermediate host species

Bulinus nyassanus is an intermediate host for Schistosoma haematobium in Lake Malawi.

At Cape Maclear on the Nankumba Peninsula, close to the southern end of Lake Malawi, Schistosoma haematobium is highly prevalent in the local people and many tourists become infected with this parasite each year. A 'Bilharzia Control Programme' was initiated in this area in August 1998, as a development collaboration between the Government of Malawi, the Danish Agency for Development Assistance (Danida), and the Danish Bilharziasis Laboratory. Although Bulinus globosus is a known host for S. haematobium, B. nyassanus has not previously been incriminated as an intermediate host. However, schistosome-infected B. nyassanus were discovered in surveys to identify transmission sites on the peninsula. Experimental infections of wild-caught B. nyassanus with S. haematobium proved successful and S. haematobium eggs were found in hamsters experimentally exposed to cercariae retrieved from schistosome-infected, field-collected B. nyassanus. These are remarkable observations since, although there are very few reports of diploid members of this species group being experimentally infected with S. haematobium, B. nyassanus is a diploid member (2n = 36) of the truncatus/tropicus group. Bulinus nyassanus is probably responsible for transmission in Lake Malawi, along rather exposed shorelines, devoid of aquatic macrophytes, with a substrate of sand or gravel.

A global network for the control of snail-borne disease using satellite surveillance and geographic information systems.

At a team residency sponsored by the Rockefeller Foundation in Bellagio, Italy, 10-14 April 2000 an organizational plan was conceived to create a global network of collaborating health workers and earth scientists dedicated to the development of computer-based models that can be used for improved control programs for schistosomiasis and other snail-borne diseases of medical and veterinary importance. The models will be assembled using GIS methods, global climate model data, sensor data from earth observing satellites, disease prevalence data, the distribution and abundance of snail hosts, and digital maps of key environmental factors that affect development and propagation of snail-borne disease agents. A work plan was developed for research collaboration and data sharing, recruitment of new contributing researchers, and means of access of other medical scientists and national control program managers to GIS models that may be used for more effective control of snail-borne disease. Agreement was reached on the use of compatible GIS formats, software, methods and data resources, including the definition of a 'minimum medical database' to enable seamless incorporation of results from each regional GIS project into a global model. The collaboration plan calls for linking a 'central resource group' at the World Health Organization, the Food and Agriculture Organization, Louisiana State University and the Danish Bilharziasis Laboratory with regional GIS networks to be initiated in Eastern Africa, Southern Africa, West Africa, Latin America and Southern Asia. An Internet site, www.gnosisGIS.org, (GIS Network On Snail-borne Infections with special reference to Schistosomiasis), has been initiated to allow interaction of team members as a 'virtual research group'. When completed, the site will point users to a toolbox of common resources resident on computers at member organizations, provide assistance on routine use of GIS health maps in selected national disease control programs and provide a forum for development of GIS models to predict the health impacts of water development projects and climate variation.

Use of satellite remote sensing and geographic information systems to model the distribution and abundance of snail intermediate hosts in Africa: a preliminary model for Biomphalaria pfeifferi in Ethiopia.

Geographic information system (GIS) risk models for the snail-borne diseases caused by Schistosoma spp. and Fasciola spp. have recently been developed based on climate and satellite-retrieved data on temperature and vegetation coverage. By using these models, it was possible to describe a relationship between vegetation index (Normalized Differences Vegetation Index (NDVI)), land surface temperature (T(max)) and disease prevalence, but little reference was made to the distribution of the corresponding intermediate host snail. Presence of the intermediate host snail is a key factor determining distribution of the disease in sub-Saharan Africa and a good snail distribution mode would probably mirror the endemic area of schistosomiasis. In the present analysis, it was shown that snail distribution data corresponds with schistosomiasis prevalence data in relation to a forecast model based on NDVI and T(max) data derived from the Advanced Very High Resolution Radiometer (AVHRR) onboard the National Oceanic and Atmospheric Administration satellite series. The 'best fit' model included NDVI values from 125 to 145 and a T(max) data range of 10-32 degrees C. This model included 92.3, 90.4 and 94.6% of the positive snail sample sites in GIS query overlay areas extracted from annual, dry season and wet season composite maps, respectively. For other sites in Africa, other NDVI and T(max) ranges may be more appropriate, depending on the species of snail present, a topic that will be examined in further studies.

Application of geographic information systems and remote sensing to schistosomiasis control in China.

Progress in China on developing prediction models using remote sensing, geographic information systems and climate data with historical infection prevalence and malacology databases is reviewed. Special reference is made to the effects of the Yangtze river Three Gorges dam project on environmental changes that may impact changes in the spatial and temporal distribution and abundance of Schistosoma japonicum in China, and the future success of disease control programs.