H. pylori diagnosis and treatment gets attention at European congress - United European Gastroenterology Week

Diagnosis and treatment of Helicobacter pylori infections and their relevance in other gastrointestinal areas produced in excess of 200 presentations and posters at the United European Gastroenterology Week meeting in Paris.

A rapid increase in the use of stable isotope-based tests as an alternative to gastroscopic biopsy procedures in confirmatory diagnosis of H. pylori infections was widely forecast and the launch of four new 13C-urea breath test systems indicates that alert marketing managers have reached the same conclusions.

Substantial interest also was shown in developments in the use of bile duct stenting, in endoscopic palliation of malignant dysphagia, in new techniques for endoscopic variceal ligation, and in the use of photodynamic therapy in esophageal cancer treatment.

Stable isotope testing comes of age

Gastric infection with H. pylori is acknowledged as a major cause of chronic gastritis, a promotor of peptic ulceration and a risk factor in gastric cancer. Although a wide range of ELISA and rapid desk-top assays for Helicobacter are available in Europe, these only detect antibodies to H. pylori, so that positive results still require confirmation by histological examination, culture, or urease testing of gastric biopsy specimens. These imply a gastroscopic procedure to obtain the biopsy specimen, with the risk that this is a focal probe rather than a global assessment of the presence of H. pylori.

A characteristic of H. pylori is its unusually high level of urease activity. If urea is given orally to a H. pylori positive patient, urea is hydrolized to produce C[O.sub.2], which is expelled in the breath. The use of mass spectrometry to detect stable isotopic forms of chemicals resulted in the use of 13C-labeled urea, so that the presence of 13C[O.sub.2] in the patient's breath could be detected. More than 20 years ago, isotope ratio mass spectrometry was first used experimentally to detect 13C-labeled carbon dioxide in breath tests. However, most of the mass spectrometers available until recently have been constructed for geological demands, offering a higher precision than is needed in biomedical applications. The need for sophisticated purification of breath gases before sampling, the high costs of research-oriented mass spectrometers and the relative slowness of operation have combined to discourage a wider use of 13C-urea breath tests (UBT) for clinical applications. As a result, most UBT test locations until now have been at university teaching hospital sites. There has been only limited interest in this technology from private laboratories or gastroenterology specialists in private practice because there was no general provision for reimbursement of 13C testing outside specialist hospital clinics.

13C tests reimbursed in Germany

The European market opportunity for 13C tests has changed rapidly with the inclusion in the latest German diagnosis-related group (DRGs) lists of the 13C-UBT procedure. These DRG lists am drawn up by the Federal Ministry of Health, with a fixed number of points allocated to each DRG procedure. The value of a point is determined annually at a regional level by negotiation and currently is valued at about DM1.70 ($1.11), making the combined reimbursement of sampling and testing in a 13C-UBT procedure valued at $26.14 to $32.68. Although Germany is the first European country to officially list a 13C test for payment, it is expected that several other countries will follow suit in the near future. The level of acceptance of the 13C-UBT procedure as a viable alternative to gastroscopy will also be affected by the availability of simpler stable isotope analyzers which can be installed and operated by gastroenterology specialists in their own clinics. Income potentially lost in carrying out fewer gastroscopies and biopsy assays can be replaced by 13C-UBT testing.

A further limitation on wider use of the 13C-UBT test is that the 13C-urea ingested by the patient prior to the breath test is classified both in Europe and the U.S. as a pharmaceutical product, subject to full regulatory control.

In Britain, for instance, the use of 13C-urea on an unlicensed basis has only been allowed on a "named-patient basis," with individual applications necessary. First full approvals for 13C-urea from the European Agency for the Evaluation of Medicinal Products (EMEA) for Europe and by the Food and Drug Administration (FDA) for the U.S. are expected this year, and will help to develop the commercial market both for urea breath test analyzers and for the associated 13C-urea substrates.

Urea breath test analyzers launched

At the Paris gastroenterology congress, four clinical analyzers for breath tests were shown (see Table 2 on page 7), with two of U.S. origin from Alimenterics (Morris Plains, New Jersey) and Finnegan MAT (San Jose, California). Alimenterics uses patented technology licensed from Rutgers University (New Brunswick, New Jersey) in its LARA (Laser-Assisted Ratio Analyzer) system. This is a fully automated system for the measurement of stable isotopes in breath using two carbon dioxide lasers, one interacting only with 12C[O.sub.2] and the other only with 13C[O.sub.2]. Using optical stimulation in a low electrical discharge and measuring electrical responses, the istopes can be differentiated. Alimenterics has completed multicenter trials for use of the analyzer and its reagents in H. pylori testing, with regulatory approval by the EMEA for the European Union (CE Mark) and by the FDA already applied for. Since [TABULAR DATA FOR TABLE 2 OMITTED] 13C-urea is classified as a pharmaceutical by both organizations, full medical product licenses are necessary, but Alimenterics expects to have EMEA clearance and FDA approval early this year. The Finnegan MAT Breath Mat analyzer is a fully automated, magnetic sector isotope ratio mass spectrometer which incorporates Finnegan MAT's acknowledged expertise in mass spectrometry to provide high performance standards. The Breath MAT is said to provide a sensitivity level of 93.9% and specificity of 97.4% in a typical application for the detection of H. pylori infection.

The two European analyzers shown in Paris were the ABCA mass spectrometer from Europa Scientific (Crewe, United Kingdom) and the IRIS infrared isotope ratio spectrometer from Wagner Analysen Technik (Worpswede, Germany). The IRIS system uses two infrared measurement cells to compare simultaneously 13C[O.sub.2] and 12C[O.sub.2] concentrations in breath samples from the patient. The IRIS system requires relatively large volume (1.2 liter) breath samples taken in sample bags. This compares with 10 ml tube samples used in mass spectrometry systems and makes the IRIS system more useful in gastroenterologic clinics, where several patients can be investigated simultaneously. Priced at about $40,000, the IRIS analyzer is intended for routine diagnostic or epidemiological use in gastroenterologic centers where cost effectiveness and time saving (90 seconds per sample) are important. Dr. Gunter Wagner, president of Wagner Analysen Technik, said the first four IRIS systems already had been installed for private gastroenterology consultants.

Other applications for 13C tests

Although H. pylori seems to be the frontrunner in stable isotope clinical tests at this stage, a wide range of other gastroenterology and nutrition tests using 13C[O.sub.2] breath tests is being considered. Such tests can be used to detect bacterial colonization and overgrowth, to measure organ function, to evaluate digestion and absorption of carbohydrates, lipids and proteins, and to assess hepatological oxidative capacity. More recently, palmitate breath tests have been proposed to investigate fatty acid metabolism and phenylalanine breath tests as confirmation of phenylketonuria (PKU) after neonatal PKU screening procedures (see Table 3).

Antibiotics: UBT and Helicobacter therapy

A collaborative study involving Baylor College of Medicine and the University of Texas Medical Center (both of Houston, Texas), and the University of Bonn and University of Magdeburg (both in Germany) reviewed differing therapy approaches used in the U.S. and Germany (Table 4 on page 8). It is significant that the "standard triple therapy" employed in the U.S. is seldom found in Germany, while the most common German therapy - PPI/AMO (proton pump inhibitor/amoxicillin) - is seldom used in the U.S. More worrisome is the discovery that close to 25% of practicing physicians in both countries still are prescribing ineffective treatments that do not include antibiotics. This suggests that the dissemination of information on currently recommended therapies is not yet optimal.

Table 3

Potential Applications for 13C Breath Tests

Breath Test          Application

13C-urea             Detection of H. pylori infection and therapy
                     control

13C-mixed            Detection of exocrine pancreatic insufficiency
triglycerides        and control of enzyme replacement therapy

13C-starch           Detection of exocrine pancreatic insufficiency

13C-octanoic acid    Measurement of gastric emptying rate of solids,
                     e.g., in diabetes therapy calibration

13C-lactose          To identify lactase or sucrase deficiencies,
(sucrose)            e.g., in bacterial overgrowth, celiac disease
                     or gastrectomy

13C-methacetin/      To monitor demethylating and oxidative activity
aminopyrine          hepatocytes of in liver disease follow-up

13C-triolein/        To measure pancreatic lypolytic activity and to
hiolein              detect fat malabsorption; replacement for stool
                     analysis

13C-glycoholic       To study enterohepatic circulation of bile
acid                 acids; to identify bacterial overgrowth or bile
                     acid loss

13C-leucine          To investigate amino acid metabolism kinetics

13C-palmitate        To investigate fatty acid metabolism

13C-phenylalanine    To confirm phenylketonuria (PKU) diagnosis

Source: Wagner Analysen Technik

Limitations in using the 13C-UBT test

While the 13C-UBT is accepted as the only currently available non-invasive technique which can accurately measure H. pylori status after eradication therapy, suppression of activity by medication can produce false negative results if tests are carried out too soon after treatment. As a result, all producers of breath test analyzers recommend that if the test is to be used for confirmation of H. pylori eradication, a delay of at least 28 days from last medication must be applied before sampling.

Similarly, protein pump inhibitors, antibiotics or bismuth, used in monotherapy, also are known to suppress the urease activity of H. pylori and may also produce negative results if they have been used less than 14 days before a UBT screening test. There also have been reports that changes in Pa[O.sub.2] of the gastric milieu following endoscopy may affect breath tests and even that gastric surgery may also produce false negative results.

Stents in biliary, esophageal applications

In endoscopic approaches to restore patency of obstructed biliary ducts where both plastic and mesh stents have been used, a restriction to the use of metallic mesh stents has been tumor ingrowth through the mesh in cases of malignant obstructions. On the other hand, plastic stents, as reported by Dr. Prat and his group at the Hopital Bicetre (Paris), require replacement every three months. Schneider (Bullach, Switzerland) has developed a partially covered version of its self-expandable Wallstent, which has been the subject of trials at the Klinikum Rechts der Isar of the Technical University of Munich (Munich, Germany). Dr. P. Born, reporting on results, disclosed that although covered biliary metal stents offer a potential solution, use of this initial prototype produced 40% dysfunctions over a nine-month period after insertion, mostly from stent occlusions which could be successfully treated by inserting additional plastic stents. Although metal stents are more expensive, both authors said they are cost-effective due to a reduced need for stent exchanges compared with plastic biliary stents such as the Soehendra Tannenbaum stent or Cotton-Leung and Cotton-Huibregtse biliary stents from Wilson-Cook Medical (Winston-Salem, North Carolina).

Malignant stenosis of the esophagus increasingly is [TABULAR DATA FOR TABLE 4 OMITTED] being treated with expandable metal stents as a palliative procedure with malignant strictures. A number of coated stents are available in Europe, including the Ultraflex Microvasive stent from Boston Scientific (Natick, Massachusetts), the Endocoil Instent from Medtronic Instent (San Diego, California), Wallstent from Schneider, and the Wilson-Cook Z Stent from Wilson-Cook Medical. Self-expanding mesh stents, delivered endoscopically, show improved stability, patency and patient comfort as compared to traditional plastic esophageal stents.

Eight different groups from various European countries reported favorably at the Paris meeting on the use of expandable metal stents with improved patient survival. Dr. Dumonceau and his group at Erasme University Hospital (Brussels, Belgium) successfully used self-expandable covered Ultraflex, Wallstent, and Wilson-Cook Z stents to control esophageal fistulas, even in the absence of stricture, although better fistula sealing was obtained with the Microvasive Ultraflex stent, attributed by Dumonceau to the inherent flexibility of the knitted design.

Variceal ligation developments

Endoscopic elastic band ligation of esophageal varices is an established technique, but a major drawback has been the necessity for multiple introductions of the endoscope, requiring an overtube. Use of the Six Shooter Saeed Multi-band ligator from Wilson-Cook Medical and the Speed-Band multi-shot ligator from Microvasive were reported by Ulrike Seitz, of the University Hospital Eppendorf (Hamburg, Germany), and Garcia Duran, of the Gregorio Maranon University Hospital (Madrid, Spain), as permitting better management, with the elimination of a requirement for reintroduction of the endoscope, along with the need to use an overtube. In the Hamburg trial, 94% of varices in previously untreated patients and 70% in patients with prior treatment were eliminated. The Madrid group concluded that there was little difference in variceal eradication or in overall cost between single-shot and multiple-shot techniques, but that fewer endoscopic sessions resulted in reduced patient trauma and discomfort.

Photodynamic therapy in esophageal cancer

Endoscopic treatment of squamous cell cancer of the esophagus using photodynamic therapy (PDT) has been investigated by Philippe Jacob and his team in the Department of Digestive Diseases at Hospital E. Herriot (Lyon, France). The group used either Photofrin from QLT (Vancouver, Canada) or Hematoporphyrin Derivative from Quentron (Ballarat, Australia), injected 72 hours prior to endoscopic laser irradiation with a 630nm dye laser at a level of 200-300 J/[cm.sup.2] of tumor surface. Complete response rates at six months were an excellent 79.4%, with a disease-specific five-year survival rate of 70%[+ or -]9%.

Dr. Jacob concluded that endoscopic PDT treatment of superficial esophageal squamous cell cancer is at least as effective as surgery and may be more satisfactory.

Table 5

Esophageal Ligation Devices

Supplier                   Product                 Type

C.R. Bard                  One-shot ligator        Single-band
(Murray Hill,                                      application
New Jersey)

Create Medic               MP-guidetube            Used with
(Tokyo)                                            overtube and
                                                   H.F. mucosectomy

Hemolastic                 Standard                Used with a
(Pieterien,                O-bands                 conventional
Switzerland)                                       hemorrhoidal set
                                                   and overtube

Microvasive                Speed-Band              Up to 5 bands per
(Watertown,                Multi-shot              intubation
Massachusetts)             ligator

Pauldrach                  OVL Set                 Single-band
Medical                                            application
(Garbsen,
Germany)

Wilson-Cook                Six Shooter             Up to 6 bands per
Medical                    Multi-band              intubation
(Winston-Salem,            ligator
North Carolina)

Source: Biomedical Business International

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