Hilary Suzawa, MD Updated July 2013 by Anoop Agrawal, MD Helicobacter Pylori Hilary Suzawa, MD Updated July 2013 by Anoop Agrawal, MD

Nobel Prize The 2005 Nobel Prize in Physiology or Medicine 3 October 2005 The Nobel Assembly at Karolinska Institutet has today decided to award The Nobel Prize in Physiology or Medicine for 2005 jointly to Barry J. Marshall and J. Robin Warren for their discovery of "the bacterium Helicobacter pylori and its role in gastritis and peptic ulcer disease"

Helicobacter Pylori What is it? A spiral-shaped gram-negative bacterium Found in colonized gastric mucosa or adherent to the epithelial lining of the stomach Causes continuous gastric inflammation in virtually all infected persons Urease hydrolyzes urea into CO2 and ammonia and allows H. pylori to survive in acidic environment

How do you get infection? Infection is acquired via ingestion orally Transmitted during childhood in most cases Prevalence varies geographically Risk factors—increased age, AA or LA, lower level of education, developing country May be asymptomatic (90% of infected) May have sx of dyspepsia –burning, distention/bloating, nausea, belching/ flatulence, halitosis

Prevalence What percent of U.S. population is infected with H. pylori? Estimated 30-40%

Which of the following diseases is not caused by H. pylori? A. duodenal ulcers B. gastric ulcers C. gastroesophageal reflux D. gastric MALT lymphoma E. gastric cancer

Which of the following diseases is not caused by H. pylori? A. duodenal ulcers B. gastric ulcers C. gastroesophageal reflux D. gastric MALT lymphoma E. gastric cancer

Why do we care? H. pylori is the cause of most cases of Peptic Ulcer Disease (PUD) Increases risk of both duodenal and gastric ulcers 95% of pt with duodenal ulcers and 80% of pt with gastric ulcers are infected Lifetime risk of peptic ulcer in pt with H. pylori is ~3%. H. pylori causes chronic gastritis H. pylori is a primary risk factor for gastric cancer (4th most common CA worldwide) Categorized as a group I carcinogen Increased risk if H. pylori infxn for >10 yrs. H. pylori increases risk of MALT lymphoma

Which of these patients should be tested for H Which of these patients should be tested for H. pylori, rather than have endoscopy? A. 63 yo female with anemia and early satiety. B. 46 yo male with progressive dysphagia and history of weight loss C. 56 yo with new onset dyspepsia and recurrent vomiting for the past 2-3 months D. 40 yo female with abdominal pain and dyspepsia

When to test? American College of Gastroenterology Guidelines Previously in 1998 Revised in August 2007 and published in American Journal of Gastroenterology Diagnostic testing for H. pylori should only be performed if tx is intended

2007 ACG Guidelines Established indications for eradication of H pylori include peptic ulcer disease: active PUD, a h/o documented peptic ulcer gastric MALT lymphoma, gastric cancer uninvestigated dyspepsia: “test and treat strategy”

Test and Treat Strategy Uninvestigated dyspepsia (ie, unknown if pt has PUD) <55 years age No “alarm features” Bleeding Anemia Early satiety Unexplained weight loss Progressive dysphagia Odynophagia Recurrent vomiting FMH GI CA Previous esophagogastric CA The rationale for this strategy is that in some patients with dyspepsia, underlying H. pylori–induced ulcer disease is causing their symptoms. This nonendoscopic strategy is not appropriate for patients with accompanying alarm symptoms (e.g., weight loss, persistent vomiting, or gastrointestinal bleeding) or for older patients (≥45 or ≥55 years of age, depending on the specific set of guidelines) with new-onset dyspepsia, in whom endoscopy is warranted.22,23,25 The nonendoscopic strategy is also not generally recommended for patients with NSAID-associated dyspepsia, since NSAIDs can cause ulcers in the absence of H. pylori infection. An attraction of the test-and-treat strategy is that it avoids the discomfort and costs of endoscopy. However, because only a minority of patients with dyspepsia who have a positive H. pylori test have underlying ulcer disease,26,27 most patients treated by means of the test-and-treat strategy incur the inconvenience, costs, and potential side effects of therapy without a benefit. In a placebo-controlled trial of empirical treatment involving 294 patients with uninvestigated dyspepsia and a positive H. pylori breath test, the 1-year rate of symptom resolution was 50% in those receiving H. pylori–eradication therapy, as compared with 36% of those receiving placebo (P=0.02)28; 7 patients would need to receive eradication therapy for 1 patient to have a benefit. A greater benefit would be expected if treatment were limited to patients with an increased probability of having an ulcer. However, neither the characteristics of the symptoms nor the presence of other risk factors for ulcer (e.g., male sex, smoking, and family history of ulcer disease) are particularly useful in clinical practice for identifying patients with ulcer dyspepsia and those with nonulcer dyspepsia. In randomized trials comparing a noninvasive test-and-treat strategy with early endoscopy26,27 or with proton-pump–inhibitor therapy,30,31 the three strategies resulted in a similar degree of symptom improvement, but early endoscopy was more expensive than the other two strategies.32 However, the test-and-treat strategy is unlikely to be cost-effective in populations with a prevalence of H. pylori infection below 20%.33 Information is lacking on the longer-term outcomes of these strategies.

2007 ACG Guidelines Still controversy regarding whether to test for H pylori in functional dyspepsia—a subset of patients with functional dyspepsia benefit from H pylori eradication nonsteroidal anti-inflammatory drug (NSAID) use iron-deficiency anemia—recent evidence suggests a link between H pylori infection and unexplained iron-deficiency anemia. risk factors for developing gastric cancer family members of patients with ulcer disease or gastric cancer The subset may have unrecognized ulcer disease

H. pylori and GERD Prevalence of H. pylori is lower among patients with GERD and those with esophageal adenocarcinoma H. pylori-associated atrophic gastritis reduces acid secretion and may provide protection against these diseases.

H. Pylori and non-ulcer dyspepsia Randomized trials of H. pylori eradication in nonulcer dyspesia (aka functional dyspepsia) have shown no benefit There is little evidence that chronic H. pylori infection in the absence of gastric or duodenal ulceration causes UGI symptoms.

What tests are available? Non-invasive Diagnostic Tests Serologic tests Urea breath tests Stool antigen Endoscopic Tests Urease Histology Culture PCR

Gold Standard? According to 2007 ACG Guidelines “there is no single test that can be considered the gold standard for the diagnosis of H. pylori” Most appropriate test depends on clinical situation

Serologic Tests ELISA to detect IgG or IgA antibodies IgG Ab appear 2-3 weeks following infxn and slowly decrease after eradication Inexpensive and widely available Sensitivity and specificity Sensitivity 85% and specificity ~80% (from meta-analysis) Lower than in previous reports If pretest probability is low, a negative test excludes dz. If test is positive it may be a false + so recheck with a confirmatory test

Serologic Tests False + are more common in elderly and pt w/ cirrhosis Also, may underestimate infxn in elderly b/c lack of Ab response (false -) Not reliable in young children Poor PPV in low prevalence populations Limited use for F/U of therapy Takes a long time for serology to become negative In pt cured of infection, titers are at ~50% at 3 mths

2007 ACG Guideline For populations with a low pretest probability of H pylori infection, the nonendoscopic urea breath and fecal antigen tests have a better positive predictive value than do antibody tests. Antibody testing identifies an immunologic reaction to the infection, whereas the urease tests and fecal antigen test identify the presence of active H pylori infection.

A. H. pylori IgG serology B. Fecal antigen test C. Urea breath test A 40 yo male has severe GERD for which he takes a PPI. He has developed dyspepsia and abdominal pain that is new. He has tried to stop his PPI, but severe symptoms recur within days. You are inclined to employ the test and treat strategy for H. pylori. Which study do you order? A. H. pylori IgG serology B. Fecal antigen test C. Urea breath test D. EGD

Answer Serology would be appropriate in this scenario for patients on PPI therapy who cannot stop therapy for two weeks prior to the tests of active infection, i.e. stool antigen or breath test.

Urea Breath Test Hydrolysis of urea  CO2 and NH3. Measures labeled carbon. Sensitivity and specificity typically >95% in most studies False negatives with PPI, Abx, bismuth Off Abx and bismuth for >4 weeks Off PPI for > 2 weeks Used for both initial dx and F/U Wait 4 weeks before repeat for follow-up

Stool Antigen Test Sensitivity and specificity ~90% False positive (decreased specificity) in pt with acute UGI bleed False negative tests (decreased sensitivity) if patient is on PPI in prior 2 weeks or has taken antibiotics in prior 4 weeks. (24 hours for H2 blocker) Useful for documenting if eradication has been successful Wait 4-8 weeks before repeat

Urea Breath Test Reliable in kids >6 yrs Best test in elderly population Most reliable non-endoscopic test to document eradication after treatment

Endoscopy When to choose endoscopy Alarm sx such as anemia, GI bleeding, weight loss >50 yrs age 4 methods of testing: biopsy urease test, histology, bacterial culture, PCR According to AAFP article (2002) Steiner’s stain for microscopic exam is gold standard According to ACG (1998), first choice is urease test on an antral biopsy

Biopsy Urease Test Sensitivity >90% and Specificity >95% Biopsy urease testing is less expensive than histology If biopsy urease test is negative, consider histology or serology Biopsy urease tests have decreased sensitivity in pt on PPI and in pt with recent or active bleeding False negatives: recent bleed, PPI, H2 blocker, Abx, bismuth Stop PPI and other meds that may interfere 4 wks prior to endoscopy

2007 ACG Guideline In pt who have not been on PPI within 1-2 wk OR Abx or bismuth within 4 wk of EGD, the rapid urease test provides an accurate, inexpensive means of identifying H. pylori For pt who have been taking a PPI, Abx, or bismuth, EGD testing for H. pylori should include bx from the gastric body and antrum for histology +/- rapid urease testing

Culture and PCR Primary means by which Abx sensitivities can be determined Neither is widely available for clinical use Not routinely recommended

Why should we treat? Eradication Results in ulcer healing Decreases risk of ulcer recurrence—more than a 30% reduction in the risk for recurrent ulcer at 1 year Reduces risk for serious ulcer complications (perforation or bleeding) Leads to regression of MALT lymphoma Eradication of H pylori is less robust in reducing rates of dyspepsia and gastric cancer.

Treatment H. pylori regimens should have cure rates of at least 80% (desirable) Dual therapy (PPI + one abx) regimens have eradication rates of 60-85% and are not recommended Triple therapy: combination of antibiotics and PPI or H2 blocker or bismuth

Triple Therapy Regimens Previously 3 regimens consistently eradicated H. pylori with rates >90% now may be dropping to ~75-80% b/c of clarithromycin resistance First Line (ACG and Maastricht Consensus—European) PPI (lansoprazole 30 mg po BID), amoxicillin 1 gram po BID, clarithromycin 500 mg po BID x 14 days (Prevpac) Above but change amoxicillin to metronidazole 500 mg po BID for PCN allergic Alternative: PPI or H2, bismuth 525 mg po QID, 2 antibiotics (metronidazole 500 mg po QID, tetracycline 500 mg po QID) x10-14 days

Duration of Treatment Course of 7-14 days 7-day course more common in Europe 10-14-day course recommended in US Triple therapy: 14 days Quadruple therapy: 10-14 days

New Regimens Trial of quadruple therapy for non-responsive cases (ie, salvage) Regimens with levofloxacin instead of clarithromycin Sequential therapy 5 days of one regimen (PPI + amoxicillin) followed by 5 days of a second regimen (PPI, clarithromycin, tinidazole) Lactoferrin and Probiotics

Lactoferrin and Probiotics New studies adding these agents to triple therapy De Bortoli et al in Italy 206 patients Esomeprazole 20 mg, amoxicillin 1000 mg, and clarithromycin 500 mg, all twice daily for 7 days +/- bovine lactoferrin 200 mg and probiotic Probinul (Cadigroup) tablets twice daily

Lactoferrin and Probiotics Main study outcome was negative 13C-urea breath testing at 8 wks after completion Eradication of H pylori in 88.6% of intervention group vs. 72.5% of control group. Rates of adverse events were 9.5% in the intervention group vs 40.6% in the control group. Side effects of nausea, diarrhea, glossitis, and abdominal pain were more common in the control group.

Possible Outcomes Eradication Pt is treated but H. pylori remains positive (Failure of initial treatment) Pt is treated and follow-up tests are initially negative at 4 weeks (Eradication) but then become positive later (Recurrence) Recurrence can be caused by either Recrudescence or Re-infection

2007 ACG Guideline To confirm eradication of H pylori infection, testing should be performed in patients with PUD persistent dyspeptic symptoms following the test-and-treat strategy H pylori-associated MALT lymphoma status post resection of early gastric cancer

Summary H. pylori infection increases risk of PUD, chronic gastritis, gastric CA, and MALT lymphoma Check for H. pylori in pt with PUD, MALT lymphoma, undifferentiated dyspepsia Serology less reliable test; urea breath test and fecal antigen testing preferred Consider EGD for alarm sx or age >50 yrs Triple therapy for treatment has decreasing efficacy—now ~75-80% Test for eradication if PUD, persistent sx, MALT lymphoma, s/p gastric CA resection

Bibliography Chey WD, Wong BC et al. American College of Gastroenterology Guideline on the Management of Helicobacter pylori Infection. Am J Gastroenterol 2007 Aug; 102(8):1808-25. De Bortoli N, Leonardi G, Ciancia E, et al. Helicobacter pylori Eradication: A Randomized Prospective Study of Triple Therapy Versus Triple Therapy Plus Lactoferrin and Probiotics. Am J Gastroenterol. 2007; 102: 951-956. Fisschbach L and Evans E. Meta-analysis: The Effect of Antibiotic Resistance Status on the Efficacy of Triple and Quadruple First-line Therapies for Helicobacter pylori. Aliment Pharmacol Ther 2007; 26(3): 343-357.

Bibliography Gisbert J. The Recurrence of Helicobacter pylori Infection: Incidence and Variables Influencing It. A Critical Review. Am J Gastroenterol 2005; 100: 2083-2099. Meurer L et al. Management of Helicobacter pylori Infection. American Family Physician 2002; 65 (7): 1327-1336. Salles N and Megraud F. Current Management of Helicobacter pylori Infections in the Elderly. Expert Rev Anti Infect Ther. 2007; 5(5): 845-856. Suerbaum S and Michetti P. Helicobacter Pylori Infection. NEJM 2002; 347 (15): 1175-1186. Up to Date