Maastricht iv/ Florence Consensus Report
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lymphoma Statement 12: H pylori eradication is the first-line treatment for low-grade gastric marginal zone (MALT) lymphoma. Evidence level: 1a Grade of recommendation: A 648
Gut 2012;61:646e664. doi:10.1136/gutjnl-2012-302084 Guidelines Low-grade MALT lymphoma accounts for approximately 50% of cases of gastrointestinal non-Hodgkin ’s lymphoma. Most are linked to H pylori infection and in the early (lugano I/II) stage low-grade MALT lymphoma can be cured by H pylori eradication in 60e80% of cases. 47e49 When the t(11,18) translocation is present, however, H pylori eradication is usually ineffective and these patients need adjunctive and alternative treatments. 50 All
patients should be followed up intensively after H pylori treat- ment and given alternative treatments (chemotherapy or radiotherapy) if the lymphoma fails to respond or progresses. 51 H pylori and extragastric diseases Statement 13: There is evidence linking H pylori to the aetiology of otherwise unexplained iron-deficiency anaemia, idiopathic thrombocytopenic purpura (ITP) and vitamin B12 deficiency. In these disorders, H pylori should be sought and eradicated. Iron-deficiency anaemia Evidence level: 1a Grade of recommendation: A ITP Evidence level: 1b Grade of recommendation: A Vitamin B12 deficiency Evidence level: 3b Grade of recommendation: B The evidence available shows no unequivocal causative association between H pylori and other extragastric disorders, including cardiovascular and neurological disorders. Statement 14: The evidence available shows no definite causative protective effect of H pylori against the following disorders nor that its eradication causes or worsens them. However, further research is needed. 1. Asthma and atopy 2. Obesity and related illnesses Statement 15: In H pylori-positive patients eradication treatment improves the bioavailability of thyroxine and l-dopa. Evidence level: 2b Grade of recommendation: B The association of H pylori with unexplained iron-deficiency anaemia has been conclusively proved in adult and paediatric populations. Two separate meta-analyses in recent years have supported this association with one illustrating a clear link between H pylori infection and iron- deficiency anaemia and the other showing that H pylori eradication increases haemoglobin levels in these patients. 52 53 Similarly, for adults with ITP, systematic reviews of past literature have shown an overall platelet response in more than 50% of the patients successfully treated for the infection and increased response rates in countries with a high prevalence of H pylori infection in background populations. 54e56
Interesting associations have been noted between H pylori and several neurological conditions, including stroke, Alzheimer ’s disease and idiopathic Parkinson ’s disease. However, these are insuf
ficient to make a clear causal or therapeutic link. 57e59
A similar situation pertains with respect to ischaemic heart disease, with several studies showing an association with disease.
60e62 The strongest link between these conditions and H pylori infection pertains to infection with a CagA-positive strain. One study showed that seropositivity to CagA was signi ficantly associated with the occurrence of acute coronary events. 63 Inverse associations have been observed between the declining rates of H pylori infection in some communities and the increasing prevalence of certain diseases such as asthma and obesity. Childhood infection with H pylori was negatively associated with asthma and allergy in a widely reported US cohort. 64
longitudinal community-based study which looked at serological markers of H pylori infection in Europe. 65 A large, population- based US cohort failed to show an association between H pylori status and body mass index (BMI). 66 H pylori infection has been linked with impaired absorption of certain drugs. The mechanism for this probably lies in decreased acid secretion in infected patients. 67 Clear associations have been observed between H pylori infection and poor bioavailability of both thyroxine and l-dopa, whereas H pylori treatment improves the bioavailability of both these drugs. 68 69
However, there is no evidence that this is of direct clinical bene fit to patients. H pylori virulence factors and host genetic polymorphisms Statement 16: Certain H pylori virulence factors and certain host genetic polymorphisms are known to affect the risk of any specific individual developing H. pylori-associated disease. However, there is no evidence that strategies based on testing for these factors are useful for an individual patient. Across populations, numerous studies have linked bacterial virulence factors and host genetic polymorphisms to patterns of gastritis and risk of disease, particularly peptic ulcer and gastric cancer.
70e74 When combined, these markedly affect disease riskdfor instance, one study showed an increased risk of gastric cancer with an OR of 87 when patients who were infected with strains with a particular vacuolating cytotoxin genotype (vacA s1) also happened to have a specific interleukin 1 b geno-
type (the T carrier polymorphism of IL-1B-511). 75 However, it is not yet possible to de fine a clinical role for testing for either bacterial virulence factors or host genetic polymorphisms in the management of individual patients. MANAGEMENT OF H PYLORI INFECTION (WORKSHOP 2) Diagnosis non invasive tests Statement 1: The diagnostic accuracy of the stool antigen test (SAT) is equivalent to the UBT if a validated laboratory-based monoclonal test is used. Evidence level: 1a Grade of recommendation: A Several non-invasive H pylori tests are established in clinical routine. The UBT using essentially [ 13 C]urea remains the best test to diagnose H pylori infection, has a high accuracy and is easy to perform.
76 During recent years new formats of the SAT using monoclonal antibodies instead of polyclonal antibodies, which lead to a constant quality of the reagents have been developed. The two formats available are: (1) laboratory tests (ELISAs) and (2) rapid in-of fice tests using an immunochromatographic technique. A meta-analysis of 22 studies including 2499 patients showed that laboratory SATs using monoclonal antibodies have a high accuracy both for initial and post-treatment diag- nosis of H pylori. 77 These data have been con firmed by more recent studies. 78 79 In contrast, the rapid in-of fice tests have a limited accuracy. 80 81 Therefore, when a SAT has to be used the recommendation is to use an ELISA format with a monoclonal antibody as reagent. Statement 2: The serological tests are not all equivalent. Only validated IgG serology tests should be used owing to variability in the accuracy of different commercial tests. Evidence level: 1b Grade of recommendation: B Statement 3: A validated IgG serology may be used in the setting of recent use of antimicrobial* and antisecretory drugs, or ulcer bleeding, atrophy and gastric malignancies. Evidence level: 1b Grade of recommendation: B *Expert opinion (5D). Serology is the third method commonly used as a non-inva- sive method to diagnose H pylori infection. Given that this infection is a chronic infection, IgG detection is only considered and the favoured method is ELISA. Gut 2012;61:646e664. doi:10.1136/gutjnl-2012-302084 649 Guidelines Commercial tests use different antigen extracts. It appears that those with high and low molecular weight are more speci fic. The accuracy of the various commercial tests has been compared using well-documented serum samples, 82 83 and showed marked variability. There are, however, several kits with an accuracy >90%. Only these validated commercial tests should be used. As was already stated at previous Maastricht conferences, serology is the only test which is not affected by local changes in the stomach that could lead to a low bacterial load and to false- negative results of the other tests. This is owing to the fact that antibodies against H pylori and especially against its most speci fic antigen CagA, remain elevated despite transient decreases of the bacterial load and even for long periods (months, even years) after the disappearance of H pylori from the stomach. 84 Decreases of the gastric H pylori bacterial load arise from the use of antimicrobial agents, of antisecretory drugs and ulcer bleeding (see also the ‘Treatment’ section). Also, bacterial load may be permanently low in premalignant and malignant lesions, including extensive IM or MALT lymphoma. 85 86
H pylori serology combined with serum pepsinogen I/II ratio may constitute a non-invasive method to detect premalignant conditions, although it has a limited sensitivity. 87
Test-and-treat strategy (cf. Statement 1, workshop 1) This approach proposed at the Maastricht 2 Conference 2 is
first part of this article. < Diagnosis of H pylori infection in patients treated with PPI Statement 4: In patients treated with PPIs: (1) if possible, PPI should be stopped for 2 weeks before testing by culture, histology, rapid urease test, UBT or stool test. Evidence level: 1b Grade of recommendation: A (2) if it is not possible, validated IgG serology can be performed. Evidence level: 2b Grade of recommendation: B PPIs are now widely available since some are generic drugs and even over-the-counter drugs in some countries. Because of their ef ficacy in treating pain and heartburn, they are widely used for symptomatic treatment of dyspepsia. As a consequence, when a patient consults for dyspeptic symptoms, there is a good chance that she/he is receiving a PPI treatment. Several studies have shown that by increasing the gastric pH, PPI use leads to local changes in the stomach. The bacterial load decreases, especially in the antrum, causing false-negative results of the diagnostic tests, with the exception of serology. Most of the studies have been carried out with UBT and showed a 10e40% rate of false-negative results. 88 89
Similar results were obtained with the SAT 90 91 and it has also proved to be the case with biopsy based tests (including culture, rapid urease test and histology) 92 but PCR has not been evaluated. Histology leads to more controversial results: the pathologists specialised in this field still consider this method suitable for diagnosing H pylori in the absence of detectable bacteria but in the presence of surrogate features (ie, polymorphonuclear cells), whereas other pathologists may not share the same opinion. Given that H pylori antibodies remain present for months after suppression and even eradication of H pylori, serology is the only test not to be affected. However, stopping PPIs 2 weeks before testing allows the bacteria to repopulate the stomach and the tests previously negative (UBT, SAT, rapid urease test, histology, culture) can once again become positive. Furthermore, no study has evalu- ated the washout period necessary after long-term PPI treatment. For UBTa study claimed that the use of a more acidic test meal would overcome the problem of false-negative tests. 93 Anti H
2 drugs may also lead to some false-negative results but to a much lesser extent 94 95
and the panel did not find it necessary to stop them before testing if using citric acid. Endoscopy-based strategy Statement 5: (1) It is important to perform culture and standard susceptibility testing to antimicrobial agents in a region or population of high clarithromycin resistance before prescription of the first-line treatment if the standard clarithromycin-containing triple therapy is being considered. Furthermore, culture and standard susceptibility testing should be considered in all regions before second-line treatment if endoscopy is carried out for another reason and generally when a second-line treatment has failed. Evidence level: 5 Grade of recommendation: D (2) If standard susceptibility testing is not possible, molecular tests can be used to detect H pylori and clarithromycin and/or fluoroquinolone resistance directly on gastric biopsies. Evidence level: 1b Grade of recommendation: A When an endoscopy is performed, biopsy-based tests such as a rapid urease test, histology and culture can be carried out. The interest of culture is mainly due to the possibility of performing antimicrobial susceptibility testing. The rationale relates to the fact that in the case of clarithromycin resistance the rate of success of the clarithromycin-containing triple therapy is very low, in the range of 10e30%. 96 97 Several
studies using tailored treatments based on H pylori suscepti- bility to antibiotics in comparison with standard empirical triple therapy have shown a better eradication rate 98 and may be cost-effective. While the cost-effectiveness may vary according to the cost of care in a given country, it is the expert ’s opinion that this approach is economically and ecologically sound in countries of high clarithromycin resistance or in speci
fic populations in some areas. After a
first failure, if an endoscopy is carried out, culture (and standard susceptibility testing) should be considered in all regions before giving a second-line treatment because the chance of having a resistant organism is high, in the range of 60e70% for clarithromycin. After a second failure, it should be performed in all cases as already recommended at the previous Maastricht conference. 3 If culture (and standard susceptibility testing) is not possible, molecular tests (including fluorescence in situ hybridisation) can be used to detect H pylori and clarithromycin and/or fluo- roquinolone resistance in gastric biopsies. Such tests have been developed recently 99e101
and kits are commercially available, 102 103
but it must be noted that the accuracy of fluoroquinolone molecular testing is not as reliable as for clarithromycin. Attempts have been made to use stools instead of gastric biopsy specimens. 104
Owing to an improved sensitivity, molec- ular tests may detect resistant organisms when they constitute a small proportion of the total bacterial load present. Further studies will determine if molecular tests predict failure more accurately or not than phenotypic tests. 105
It must be stated that there is a cross-resistance in each family of antibiotics because the same resistance mechanism occurs: resis- tance to clarithromycin indicates resistance to all macrolides, resistance to levo floxacin indicates resistance to all fluoroquinolones including moxi floxacin, for example. There is no cross-resistance between different families of antibiotics which have different resistance mechanisms. 106
However, it is important to use the compound indicateddthat is, clarithromycin for macrolides, tetracycline HCl and not doxycycline, levo floxacin or moxifloxacin but not cipro floxacin for fluoroquinolones to get good results. 650 Gut 2012;61:646e664. doi:10.1136/gutjnl-2012-302084 Guidelines Statement 6: (1) If H pylori is cultured from gastric biopsy specimens, antibiotic susceptibility testing should include metronidazole. Evidence level: 1b Grade of recommendation: A (2) If susceptibility for clarithromycin is assessed by molecular tests, the addition of culture for the assessment of metronidazole resistance is not justified. Evidence level: 5 Grade of recommendation: D The rationale is that standard metronidazole susceptibility testing lacks reproducibility 107 and no molecular alternative exists. It was shown, however, that globally metronidazole resis- tance, as determined, is associated with a lower H pylori eradi- cation rate (from 5% to 25%) 96 also in sequential treatment 108 compared with cases where the strain is metronidazole suscep- tible and that increasing metronidazole dosage and treatment duration may partially overcome resistance. Treatment Regimens available < The triple treatment including PPI-clarithromycin and amoxicillin or metronidazole proposed at the first Maastricht conference 1 to treat H pylori infection has become universal since it was recommended by all the consensus conferences held around the world. However, the most recent data show that this combination has lost some ef ficacy and often allows the cure of only a maximum of 70% of the patients, which is less than the 80% rate aimed for at the beginning and far below what should be expected for an infectious disease. 109
< While no new drug has been developed for this indication, a number of studies have been carried out in recent years using different combinations of known antibiotics. Most data were obtained with the so-called ‘sequential treatment’ which includes a 5-day period with PPI amoxicillin, followed by a 5-day period with PPI-clarithromycin-metronidazole (or tinidazole). 110 111
< It was also proposed that the three antibiotics should be taken simultaneously together with a PPI (non-bismuth quadruple therapy). 112 113
There was also a renewal of the old recipedthat is, the bismuth-containing quadruple therapy following the devel- opment of a gallenic formulation including bismuth salts, tetracycline and metronidazole in the same pill. 114e116
A summary of treatment strategies is shown in tables 2 and 3. Statement 7: PPI-clarithromycin-containing triple therapy without prior susceptibility testing should be abandoned when the clarithromycin resistance rate in the region is more than 15e20%. Evidence level: 5 Grade of recommendation: D There are several explanations for the decrease in ef ficacy of the standard triple therapy: compliance, high gastric acidity, high bacterial load, type of strains, but by far the most important is the increase in H pylori resistance to clarithromycin. The global clarithromycin resistance rate in Europe increased from 9% in 1998
117 to 17.6% in 2008e9. 118 Resistance increased in most parts of Europe, but it has now reached a prevalence >20% in
most countries in Central, Western and Southern Europe, which is considered a high resistance rate. In Northern Euro- pean countries it is
rate.
97 Following the European Medicines Agency recommendation on evaluation of medicinal products indicated for treatment of bacterial infection, three categories of bacterial species can be de fined according to their susceptibility to a given antibiotic: usually susceptible (0e10% resistant), inconstantly susceptible (10e50% resistant) and usually resistant (>50% resistant). H pylori now falls into the second category, except for Northern Europe.
119 In order to take into account the CIs of the prevalence obtained and the regional differences in a given country, a threshold of 15e20% was recommended to separate the regions of high and low clarithromycin resistance ( figure 1). Regions of low clarithromycin resistance First-line treatment. Statement 8: In areas of low clarithromycin resistance, clarithromycin-containing treatments are recommended for first-line empirical treatment. Bismuth-containing quadruple therapy is also an alternative. Evidence level: 1a Grade of recommendation: A In these regions the standard PPI-clarithromycin-containing regimen is still recommended as the first-line treatment as well as bismuth-containing regimens. Different ways of improving the PPI-clarithromycin-amoxi- cillin/metronidazole regimens have been proposed:
Increase the dose of PPI. Table 2 Summary of treatment strategies Statement Level of
evidence Grade of
recommendation Proton pump inhibitor (PPI)-clarithromycin containing triple therapy without prior susceptibility testing should be abandoned when the clarithromycin resistance rate in the region is over 15e20% 5 D In areas of low clarithromycin resistance, clarithromycin- containing treatments are recommended for first-line empirical treatment. Bismuth-containing quadruple treatment is also an alternative 1a A
treatment. If this regimen is not available sequential treatment or a non-bismuth quadruple treatment is recommended Yüklə 0,54 Mb. Dostları ilə paylaş:
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