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The potential user of product:

This is a kit that might be used by nurses at the emergency units as well as laboratory technicians. It is even possible in a near future to construct it for self diagnosis at home. All of the patients at any age that suffer from diarrhoea might use it but elderly with multiple diagnosis, previous antibiotic treatment who seek because of loose faeces might be in an confusing situation not to know which Clinique should take care of them. In such very common cases the test gives valuable information.

 

The problem or challenge that the product will solve for the user:

Acute gastroenteritis is a very common disease and a large number of patients seeking to the hospital are troubled by symptoms such as nausea, vomiting, diarrhoea and pain in the stomach. Diarrhoea, the most dominating symptom might be caused by infectious agents or by other reasons. In spite of the routine tests it is nearly impossible to distinguish between different causes of diarrhoea at admittance. Therefore the patients are isolated at The Department of Infectious Diseases until the culture results are available. The benefit of isolation is transmission arrest. However the patients with abdominal disorders or acute debut of chronic inflammatory bowel diseases (IBD) might not be diagnosed on time.

Test can distinguish infectious (bacterial, viral, parasite) gastroenteritis from non-infectious (IBD, functional) at admittance. There are no other tests yet available that can distinguish between infectious and non-infectious gastroenteritis at admittance. Test is not sensitive to previous antibiotic treatment or low bio-burden. The information obtained using the test might be complemented with other tests. As just 10-15% of diarrhoea are in need of isolating using the test might spare 85-90% of isolating cost (7000 SEK/day) at least 10000 days per year and hospital. If a patient has IBD and infection as the same time depending on the grade of immunodeficiency we might have false negative results but in the majority of cases the test turns to be positive in the case of infection in a patient with IBD.

 

Possible benefits for the patient from the product

A significant amount of patients seeking to the health care centres are consisted of patients suffering from bowel disturbances. Several diseases show diarrhoea as the primary symptom, such as pneumonia, septicaemia, acute bowel obstruction, abscess or perforation, cholecyctitis, transmittable gastroenteritis, antibiotic caused diarrhoea, inflammatory bowel disease, urinary tract infection in children and elderly, toxins and over consumption of laxantia. Because of risks for transmission these patients are isolated in at least three days before culture results are available. This period is much longer in county hospitals without equipment for X-ray and laboratory diagnosis. The patients might receive a proper treatment after several days. Approximately 10-15 % of this population are in need of isolation and the rest of patients might suffer from therapy delays. The test can distinguish infectious gastroenteritis at admittance.

 

The benefit for the healthcare system (cost, efficiency…)

The health centers perform so many different cultures, PCR and direct microscopy techniques that costs over 5000 SEK/patient at the University centers excluding transport, personal and material costs. The most proper method for treatment of acute infectious gastroenteritis is to give intravenous liquids and not to give antibiotics. Therefore it is enough to diagnose transmittable diarrhea (10-15%)and isolate the patients at the medical centers and send them back home as soon as situation is turned to stable. Verification of diagnosis by bacteriologic tests might be indicated in 1% of cases and the rest of costs might be inhibited using the index test. Costs such as 7000 sek/day/patient (excluding personal and material costs) to isolate the 85% of cases that are not transmittable. These cases might be placed at the ordinary ward at the hospital. To delay the treatment of a patient with acute abdominal diseases such as perforations and abscess means extreme extra costs that might be inhibited by establishing the diagnosis at admittance. The negative index test highlights the need of extra diagnostic methods to identify these cases. And why postpone diagnosis in a young man with diarrhea and debut of inflammatory bowel diseases when it is possible to diagnose them much sooner. It happens that young patients are operated by removing the whole bowel under suspicion of inflammatory bowel disease when the diagnosis is un-diagnosed infection. Such risks might be inhibited and a huge amount of money could be saved.

 

Estimation of the market size

In 2008 nearly 6400 patients searched the Emergency Department at the University Hospital in Linköping for bowel disturbances. There are nine University Hospitals in Sweden and 60,000 patients that seek per year to these large hospitals. Approximately over 100,000 cases per year in Sweden might seek for the problem. The test might be used in Europe and USA. Most appropriate is using the test in the countries that lack advanced diagnostic equipment.

 

Brief description of the product

The final product is based on a technique that identifies the growth factors produced during acute gastroenteritis in faeces using a new platform. We have previously observed that binding affinity of cytokines and growth factors to the component of cell membrane (heparan sulfat proteoglycan) is decreased during chronic inflammation and increased during acute inflammation. Metachromasy is a characteristic colour change exhibited by certain aniline dyes when bound to chromotropic substances. This phenomenon has been widely used in histology. When growth factors bind with high affinity to HSPG, it results in pH change that is observed in colour conversion to green. As we have studied the stability of test is at least one year in room temperature and at + 4 C.

 

Unique advantages of this product compared to available options

By seeking the hospital with diarrhoea a panel of different blood and faecal tests are taken. Blood tests are intended to check if the patient is dehydrated, liver and kidney function tests and WBC that are not specific and gives general information about the diseases. Serum C-reactive protein and procalcitonin are used to identify bacterial or viral nature of infection. The faecal tests available are taken at the same time.

 

1- Faeces cultures: Results not available at admittance.

2- Viral diagnosis by PCR for Calicivirus, Rota virus and Adenovirus: are expensive and performed in few centres. The results not available at admittance.

3- Toxin test for Chlostridium deficile: the results available within 24-36 h at centres (not holidays). It diagnoses presence of antibiotic diarrhoea.

4- Direct microscopy: Expensive. Needs trained technician. Diagnoses parasites and cysts. Results not available at admittance.

5- Calprotectin: New test. Both semi-quantitive and quantitive. At the equipped centres. Concentration is increased during both infection and IBD. Negative result is valuable to rule out IBD.

6- Faecal haemoglobin: Shows presence of blood in faeces. Is unspecific.

 

The Index test recognizes Infectious gastroenteritis at admittance before culture, toxin, PCR, or microscopy results available. No other test can function in this way. In spite of routine examinations not more than 50-55% of all infectious gastroenteritis might be verified by available methods. Positive index test (Dexact-f) result might indicate: If the patient is stable in parameters, send him/her home with recommendations. If signs of collapse and fever are dominant the patient should be isolated the routine tests initiated. The negative results might indicate: probably no bowel infection, proper examination of  the stomach and X-rays are recommended in order to rule-out other emergencies. Dexact-f strip might be the first test to choose with meeting a patient with diarrhoea. So the Emergency Departments and open health centres are going to have the most advantages by performing the test.

 

The current status of the project

Patent and patent applications

1- P8808 EP New method Dexact

1- PRV P9931SE00 Dexact Strip

CE-­‐marketing 2011-12-05; registration number 451:2011/91596

 

The internal validation results

Estimates. Sensitivity, specificity, positive predictive value, negative predictive value, and accuracy were calculated in groups with verified infectious gastroenteritis (n=207) and in those without infectious gastroenteritis (n=268), which in turn included patients with IBD, patients with other systemic diseases and healthy volunteers. The index test was able to distinguish acute infectious gastroenteritis with a sensitivity of 96.6%, specificity of 92.4%, positive predictive value of 90.9%, and negative predictive value of 97.2%. The accuracy of test was 94.3% (Table 1). No significant correlations were observed between the results of the index test and calprotectin level (R2=0·056). No significant correlation was observed between the results of the index test and the presence of blood in feces (R2=0·08).

 

References

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4- G Hartmann, T Prospero and V Brinkmann et al.,Engineered mutants of HGF/SF with reduced binding to heparan sulphate proteoglycans, decreased clearance and enhanced activity in vivo, Curr Biol 29 (1998), pp.125-34.

5- X Liu, Y Kato and M Kato et al., Existence of two nonlinear elimination mechanisms for hepatocyte growth factor in rats, Am J Physiol 273 (1997), pp. E891-897.

6- F Nayeri, J Xu and A Abdiu et al., Autocrine production of biologically active hepatocyte growth factor (HGF) by injured human skin, J Dermatol Sci 43 (2006), pp. 49-56.

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10- PM Linares and JP Gisbert, Role of growth factors in the development of lymphangiogenesis driven by inflammatory bowel disease: A review, Inflamm Bowel Dis 17 (2011), pp. 1814-1821.

11- F Nayeri, S Almer and L Brudin et al., High hepatocyte growth factor levels in faeces during acute infectious gastroenteritis, Scand J Infect Dis 35 (2003), pp. 858-862.

12- F Nayeri, D Aili and T Nayeri T et al., Hepatocyte growth factor (HGF) in fecal samples: rapid detection by surface plasmon resonance. BMC Gastroenteroly (2005), 5:13.

13- F Nayeri, I Nilsson and L Brudin et al., Stability of faecal hepatocyte growth factor determination. Scand J Clin Lab Invest 64 (2004), pp. 589-598.

14- NH Bean and PM Griffin, Foodborne disease outbreaks in the United States, 1973-1987: Pathogens, vehicles, and trends, J Food Prot 53 (1990), pp. 804-817.

 

15- AG Roseth, MK Fagerhol and E Aadland et al., Assessment of the neutrophil dominating protein calprotectin in feces. A methodologic study, Scand J Gastroenterol 27 (1992), pp. 793-798.