Journal of Gastroenterology and Hepatology (2000) 15, 13771381

HELICOBACTER PYLORI INFECTION, GASTRITIS AND GASTRIC CANCER

A short-term eradication therapy for Helicobacter pylori acute gastritis

HIDEYUKI NOMURA,* KATSUHISA MIYAKE,* SEIZABURO KASHIWAGI, TOSHIRO SUGIYAMA AND MASAHIRO ASAKA

Departments of *Internal Medicine, Shin-Kokura Hospital, Kitakushu, General Medicine, Kyushu University Hospital, Fukuoka and Third Department of Internal Medicine, Hokkaido University School of Medicine, Sapporo, Japan

Abstract Background and Aims: Acute gastritis, caused by an initial infection of Helicobacter pylori (H. pylori), may resolve spontaneously, but the infection sometimes becomes chronic. We examined the efcacy of a short-term H. pylori eradication therapy on acute gastritis. Methods: Among the 15 patients with hemorrhagic acute gastritis who were randomly allocated to group A (eradication therapy) or group B (Lansoprazole, LPZ), 10 of them started to receive treatment within 1 day after the disease onset. The other ve patients began the eradication therapy 46 days after disease onset (group C). Eradication therapy consisted of a daily oral administration of each of 30 mg lansoprazole (LPZ), once a day; 400 mg clarithromycin, twice a day; 1000 mg amoxicillin, twice a day; and 300 mg rebamipide, three times a day, for one week. If the endoscopy was normal, medication was stopped for the following 4 weeks before gastric endoscopy was performed again in order to assess H. pylori eradication. Results: All group A patients were cured after the 1-week treatment and therefore, they became H. pylori negative. Group B and C patients had erosions or ulcers after the 1-week treatment and so received an additional 3-week administration of LPZ. Four weeks later, their gastritis was cured and except for one group B patient, they became H. pylori-negative. Conclusion: In patients with acute gastritis, caused by an initial H. pylori infection, eradication therapy was efcacious in achieving early healing.This therapy should be started as soon as possible after disease onset. 2000 Blackwell Science Asia Pty Ltd Key words: acute gastritis, eradication, Helicobacter pylori.

See editorial on page 1353

INTRODUCTION
Since Marshall and Warren rst demonstrated the presence of Helicobacter pylori (H. pylori ) in the gastric mucosa,1 the relationship between chronic gastritis, gastric ulcer and H. pylori has been well understood. Routes of transmission, except endoscopic infection,

have, however, remained almost unknown, but cases of oral infection24 and induction of acute gastritis by experimental ingestion of H. pylori5,6 have been reported. Although initial H. pylori infection is usually asymptomatic, mild acute gastritis to hemorrhagic erosions or multiple ulcers may be seen at endoscopy. Acute gastritis caused by initial H. pylori infection usually resolves spontaneously when symptoms are mild.7 However, if patients with acute gastritis have more severe symptoms (e.g. severe epigastric pain and

Correspondence: Dr H Nomura, Department of Internal Medicine, Shin-Kokura Hospital, 1-3-1, Kanada, Kokurakita-ku, Kitakyushu 8038505, Japan. Email: h-nomura@shin-kokura.gr.jp Accepted for publication 22 February 2000.

1378 vomiting), treatment using a histamine H2-receptor antagonist or a proton pump inhibitor may be condsidered. These treatments can improve symptoms within 2 days, but some patients develop multiple ulcers from acute gastritis, which requires treatment of 1 month or longer, and in addition, some patients develop chronic H. pylori infection6,8,9 as observed in animal studies.1012 To date, many researchers have reported successful eradication methods for H. pylori infection that are accompanied by gastric ulcers and/or duodenal ulcers. These methods have effectively prevented the recurrence of ulcers.13,14 However, the value of eradication therapy for acute gastritis that is caused by an initial H. pylori infection, has been reported only by Rocha et al.15 In the present study, we administered short-term (7 days) H. pylori eradication therapy for patients with acute hemorrhagic gastritis caused by an initial H. pylori infection, compared this to a proton pump inhibitor and evaluated the change in acute gastritis.

H Nomura et al. laboratory work was conducted at the Shin-Kokura Hospital, Japan.

Treatments
Eradication therapy consisted of a daily oral administration of 30 mg lansoprazole (LPZ), 400 mg clarithromycin (CAM), 1000 mg amoxicillin (AMPC) and 300 mg rebamipide for one week. This treatment was started within 24 h after disease onset in group A and 46 days after disease onset and rst endoscopy in group C. Group B patients received an oral administration of 30 mg/day LPZ for 1 week. All patients underwent a gastric endoscopy after the 1-week medication, and if the results were normal, the medication was stopped for the following 4 weeks. Another endoscopy and biopsy was performed after the 4 weeks in order to assess H. pylori eradication. If ulcers or erosions were found after the 1-week treatment, 30 mg/day LPZ was administered for a further 3 weeks and another endoscopy was performed to conrm the status of the lesions. Medication was then stopped for 4 weeks and a nal endoscopy was performed to assess eradication. One week after the completion of the treatment, all patients were asked about the time when subjective symptoms (e.g. stomach pain, vomiting and distention) disappeared. They were also asked about their experience of adverse effects such as diarrhea, rashes and stomatitis.

METHODS
Patients
Between June 1996 and March 1998, 18 patients who suddenly developed severe epigastric symptoms, including epigastric pain and vomiting, were endoscopically diagnosed as having hemorrhagic acute gastritis within 24 h after disease onset.16 They were conrmed to be H. pylori-positive by the CLO test (CLO testTM, Barrard Medical Products Co., Ltd, Draber, UT, USA).17 The patients did not have a history of excessive alcohol intake, had not received non-steroidal anti-inammatory agents (NSAID) for the past month and did not have a history of gastric or duodenal ulcers. We excluded seven patients who were anti-Helicobacter IgG antibody-positive and one patient who was found to be H. pylori-negative by culture and histologic results. The remaining 10 patients were then randomly allocated to either group A for H. pylori eradication therapy (n = 5) or group B for single-agent lansoprazole (LPZ) therapy (n = 5). In the same period, a further 12 patients visited our department (Department of Internal Medicine, Shin-Kokura Hospital, Japan) 46 days after gastric symptoms occurred, and ve of them were diagnosed as having acute gastritis or gastric ulcer caused by initial H. pylori infection. These ve patients were allocated to group C and treated with eradication therapy. Hence, the total number of patients, (i.e. groups A, B and C) in the present study was 15. These 15 subjects consisted of 11 males and four females, with ages that ranged between 16 and 50 years and a mean age of 35.5 years. There were no differences between groups in terms of mean age or male : female. The present study was approved by the Ethics Committee of Shin-Kokura Hospital. All patients gave informed consent to participate in this study. All procedures were conducted in accordance with the Helsinki Declaration of 1975 (revised in 1983), and all

Endoscopy, diagnosis of initial H. pylori infection, and eradication evaluation

At entry to the present study, endoscopy was performed and tissue samples were collected from three places, each in the antrum and corpus on the greater curvature. These samples were used for rapid urease testing, culture and histology. The rapid urease test was conducted by using CLO test kits (CLO testTM).17 Histologic examinations were performed by using HE and Giemsa staining. Hemorrhagic gastritis was endoscopically diagnosed when there was mucosal edema, hyperemia and bleeding present, which are associated with hemorrhagic erosions or multiple ulcers with red and/or brown hemorrhage. At entry, 2 mL of serum was collected and serum IgG antibody against H. pylori was quantied by using ELISA kits (HM-CAP, Enteric Products, Inc., NY, USA).18 Acute gastritis with hemorrhage caused by an initial H. pylori infection was diagnosed when the presence of the above-mentioned hemorrhagic gastritis or multiple ulcers were endoscopically conrmed, when tissue samples were H. pylori-positive in the CLO test, positive in culture for H. pylori, by histology and when the patient was negative for immunoglobulin (Ig)G antibodies against H. pylori. Four weeks after the completion of the treatment, the CLO test, culture and histology were performed. The patients who were detected as being negative for H.

Eradication of H. pylori acute gastritis

Table 1 Changes in endoscopic ndings of Helicobacter pylori-associated acute gastritis After the one-week treatment After the 3-week LPZ

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Patients Group A 1 2 3 4 5 Group B 6 7 8 9 10 Group C 11 12 13 14 15

Before treatment

Four weeks after the treatment

Edema, erythema, multiple ulcers and friable mucosa Edema, erythema, multiple ulcers and friable mucosa Edema, erythema, multiple ulcers and friable mucosa Edema, erythema and multiple erosions with hemorrhage. Edema, erythema and multiple erosions with hemorrhage. Edema, erythema, multiple ulcers and friable mucosa Edema, erythema, multiple ulcers and friable mucosa Edema, erythema, multiple ulcers and friable mucosa Edema, erythema and multiple erosions with hemorrhage. Edema, erythema and multiple erosions with hemorrhage. Edema, erythema and multiple ulcers Edema, erythema and multiple ulcers Edema, erythema and multiple ulcers Edema, erythema and multiple erosions with hemorrhage. Edema and multiple erosions with hemorrhage.

Erythema Normal Normal Erythema Erythema

Normal Normal Normal Normal Normal

Multiple ulcers Erythema and mutiple ulcers Multiple ulcers Erythema and multiple ulcers Erythema and multiple ulcers Multiple ulcers Erythema and multiple ulcers Erythema and multiple ulcers Erythema and multiple ulcers Multiple erosions

Cured Cured Cured Erythema Erythema

Normal Normal Normal Erythema Normal

Cured Erythema Cured Erythema Normal

Normal Normal Normal Erythema Normal

LPZ, Lansoprazole.

pylori by these three tests were considered cured of their condition.

RESULTS
Endoscopic and histologic ndings
In all patients, subjective symptoms disappeared within 2 days of treatment. Of the 10 patients in groups A and B, six patients had hemorrhagic gastritis with multiple ulcers and four patients had hemorrhagic erosions that were surrounded by red and friable mucosa. Histologically, edema, hyperemia and dense inltration of polymorphonuclear neutrophils were observed in the lamina propria, mucus layer and inside the crypts. There were no, or only a few, sites of chronic inltration of inammatory cells such as lymphocytes and plasma cells (Table 1).

After the 1-week treatment, endoscopy revealed that there were no ulcers or erosions in group A patients who started to have the eradication therapy within 24 h after disease onset. In fact, three patients only had erythema and two patients were normal (Group A patients had no symptoms). Their acute gastritis was therefore considered to be cured. Histologically, neutrophil inltration had become milder than it was at the rst examination and only edema was found in three cases. After the 4-week period without medication, endoscopy was performed again for eradication evaluation and ndings were normal in all patients. Histology was normal and no edema or hyperemia was detected.There was also no neutrophil inltration. In group B patients, who received LPZ only, subjective symptoms disappeared within 2 days, but endoscopy after the 1-week treatment revealed that three patients with hemorrhagic gastritis still had multiple, shallow, irregular ulcers. The remaining two patients with hemorrhagic erosion still had many ero-

1380 sions, but did not have hemorrhagic lesions. Histologically, inltration of polymorphonuclear neutrophils was apparent. Edema and hyperemia were still present, but their severity was reduced compared to the ndings at disease onset. Group B patients received an additional 3-week LPZ administration. After completion of the therapy, healing of the ulcers and erosions was endoscopically conrmed and thus, medication was stopped for the following 4 weeks. At the nal evaluation for eradication, ulcers had cured and all patients had become normal with the exception of case 9, who still had erythema. Histologic results of case 9 revealed mild lymphocyte inltration, but in the other four patients, there was no inltration of inammatory cells. Before treatment in group C patients, endoscopy revealed shallow, multiple ulcers in three patients and hemorrhagic erosions in two patients. After the 1-week eradication therapy, ulcers and erosions were still found, but there were no hemorrhagic lesions and the severity of ulcers and erosions was reduced compared to the ndings at disease onset. Mild edema and hyperemia were observed by using histology. After the additional 3-week LPZ administration, healing of ulcers was endoscopically conrmed and the patients were considered to be cured. Therefore, medication was stopped for the following 4 weeks and a nal examination was performed. Endoscopically, two patients had erythema, whereas the other three were normal. Histologically, there was no edema, hyperemia or polymorphonuclearneutrophil inltration. None of the patients suffered recurrence of gastritis during the 4-week period without medication.

H Nomura et al. severe epigastric pain and/or vomiting.7 Our subjects had acute gastritis with symptoms and endoscopy showed that hemorrhagic gastritis associated with mucosal edema, hyperemia, hemorrhagic erosions, and/or multiple ulcers, were mainly found in the antrum. The major histologic nding was a marked inltration of polymorphonuclear neutrophils. These ndings are consistent with previous reports.8,9,15,19 The dense inltration of polymorphonuclear neutrophils could be related to the chemotactic activity of H. pylori towards polymorphonuclear leucocytes,20 as well as the release of a neutrophil-activation factor after gastric mucosal injury caused by H. pylori.21 In the present study, we administered eradication therapy within 24 h after disease onset to patients who were diagnosed as having acute gastritis caused by initial H. pylori infection and observed complete healing after 1-week of treatment. When LPZ alone was administered, subjective symptoms disappeared within 2 days of treatment; however, with this treatment, gastric mucosal damage could still progress, which resulted in shallow ulcers found endoscopically after 1-week of treatment. In fact, group B patients needed to have an additional three weeks of LPZ administration. In contrast, in those patients who were not treated for 46 days after disease onset, gastric mucosal damage caused by H. pylori had already progressed and multiple ulcers had formed. For these therapy-delayed patients, a shortterm (1 week) eradication therapy was insufcient to achieve complete healing. They also required an additional 3 weeks of LPZ administration. Therefore, in order to achieve early healing, acute gastritis caused by initial H. pylori infection should be treated with H. pylori eradication therapy at the earliest opportunity. All patients, except one group B patient (case 9) became H. pylori-negative, regardless of the treatment type. This suggests that most patients with initial H. pylori infection could spontaneously eradicate H. pylori even if no eradication therapy is administered. However, our case 9 patient also showed that some patients cannot spontaneously eradicate H. pylori, and therefore develop a chronic infection. Other clinical reports, as well as animal studies, have also documented the establishment of chronic H. pylori infection.6,8,9 In the present study, it remains unknown whether the eradication therapy at an early disease stage can prevent the development of chronic H. pylori infection. Further studies with larger numbers of patients is necessary to clarify this point. Optimal timing to start eradication would be immediately after disease onset, when H. pylori has not yet proliferated to a large extent. It would be important to prevent gastric mucosal damage caused by H. pylori at an early stage of disease by introducing eradication treatment promptly. A proton pump inhibitor (LPZ) and two antibiotics (clarithromycin and amoxicillin) were used in the present eradication therapy. Lansoprazole possesses both in vitro and in vivo antibacterial activity.13,22 These three drugs are commonly prescribed for H. pylori eradication and their efcacy has been demonstrated.23,24 Expecting an enhanced effect on gastric mucus repair, together with the eradication effect, we added a

Findings in the CLO test, culture and histology

Before treatment, all patients were found to be H.pylori positive by the CLO test, culture and histology, but negative for anti-Helicobacter IgG antibodies. After the 1-week treatment and at the last examination, all patients except case 9 in group B were negative in the CLO test, culture and histology. Four weeks after the completion of medication, case 9 became positive in the three tests, thus showing persistence of H. pylori infection.

Adverse effects
Diarrhea occurred in one patient from each of groups A and C who received the two antibiotics (clarithromycin and amoxicillin), but the symptoms disappeared spontaneously after the completion of the eradication therapy. None of the patients developed rashes or stomatitis. No severe side-effects that required treatment to be discontinued were observed.

DISCUSSION
Initial H. pylori infection is usually asymptomatic, but it sometimes presents as acute gastritis associated with

Eradication of H. pylori acute gastritis gastroprotective agent, rebamipide, which inhibits free radical production25 and which is commonly used in antiulcer therapies in Japan. This quadruple drug treatment was highly effective. Rocha et al.15 reported an efcacy of long-term administration of metronidazole and amoxicillin on H. pylori acute gastritis. Barhosa et al.19 administered amoxicillin for 1 month and conrmed that H. pylori was cleared. In the present study, our treatment period was short (7 days), but H. pylori was completely cleared. This 7-day period was established by referring to contemporary eradication therapies for gastric and duodenal ulcers associated with H. pylori. Because our patients were cases of acute gastritis caused by initial H. pylori infection, shorter treatment periods (e.g. 35 days), might also be efcacious in eradicating H. pylori. The optimal treatment period should be investigated further in future studies. An adverse effect of our therapy was diarrhea, which was reported in two patients and was probably caused by the antibiotics. No other side-effects were observed. In conclusion, when alcohol or NSAID are not associated with patients having acute gastritis, H. pylori infection must be suspected. Acute gastritis can be cured quickly when the eradication therapy is administered within 24 h of disease onset. Therefore, at endoscopy, rapid urease testing should be conducted. Patients who test positive should be treated with an eradication therapy at the earliest possible time point in order to achieve early healing of acute gastritis.

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temic immune response, gastritis mucosal histology, and gastric juice ascorbic acid concentrations. Gut 1991; 32: 141518. Fukuda Y, Tamura K, Yamamoto I et al. Inoculation of rhesus monkeys with human Helicobacter pylori: a longterm investigation on gastric mucosa by endoscopy. Dig. Endosc. 1992; 4: 1930. Nasu M, Fujioka T, Kodama R. Helicobacter pylori-infected Japanese monkeys. J. Infect. Chemother. 1995; 1: 907. Shuto R, Fujioka T, Kubota T, Nasu M. Experimental gastritis induced by Helicobacter pylori in Japanese monkey. Infect. Immun. 1993; 61: 9339. Nagata K, Takagi E, Tsuda M et al. Inhibitory action of lansoprazole and its analogs against H. pylori: Inhibition of growth is not related to inhibition of urease. Antimicrob. Agents Chemother. 1995; 39: 56770. van der Hulst RWM, Rauws EAJ, Koycu B et al. Prevention of ulcer recurrence after eradication of Helicobacter pylori: a prospective long-term follow-up study. Gastroenterology 1997; 113: 10826. Rocha GA, Queiroz DMM, Mendes EN, Barbosa AJA, Lima GF, Oliveira CA. Helicobacter pylori acute gastritis: Histological, endoscopical, clinical and therapeutic features. Am. J. Gastroenterol. 1991; 86: 15925. Akamatsu T, Tabata K, Hironaga M, Kawakami H, Uyeda M. Transmission of Helicobacter pylori infection via exible beroptic endoscopy. Am. J. Infect. Control 1996; 24: 396401. Marshall BJ,Warren JR, Francis GJ et al. Rapid urease test in the management of Campylobacter pylori-disassociated gastritis. Am. J. Gastroenterol. 1987; 82: 20010. Evans DJ, Evans DG, Graham DY, Klein PD. A sensitive and specic serologic test for detection of Campylobacter pylori infection. Gastroenterology 1989; 96: 10048. Barbosa AJA, Queiroz DMM, Mendes EN, Rocha GA, Carvalho AS, Roquete ML. Campylobacter pylori associated acute gastritis in a child. J. Clin. Pathol. 1989; 42: 779. Nielsen H, Anderson LP. Chemotactic activity of Helicobacter pylori sonicate for human polymorphonuclear leukocytes and monocytes. Gut 1992; 33: 73842. Moony C, Keenan J, Munster D et al. Neutrophil activation by Helicobacter pylori. Gut 1991; 32: 8537. Jhala NC, McFarland MM, Brightham SA, Morale B, Rubin W, Atkinson BF. The effects of short-term lansoprazole therapy on Helicobacter pylori infection and antral gastritis in duodenal ulcer patients. Am. J. Gastroenterol. 1995; 90: 18248. Lind T, Veldhuyzen Z, Unge P et al. Eradication of Helicobacter pylori using one-week triple therapies combining omeprazole with two antimicrobials: The MACH 1 Study. Helicobacter 1996; 1: 13844. Moayyedi P, Langworthy H, Shanahan K et al. Comparison of one or two weeks of lansoprazole, amoxicillin, and clarithromycin in the treatment of Helicobacter pylori. Helicobacter 1996; 1: 714. Suzuki M, Miura S, Mori M et al. Rebamipide, a novel antiulcer agent, attenuates Helicobacter pylori induced gastric mucosal cell injury associated with neutrophil derived oxidants. Gut 1994; 35: 13758.

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REFERENCES
1 Marshall BJ, Warren JR. Unidentied curved bacilli in the stomachs of patients with gastritis and peptic ulceration. Lancet 1984; 1: 131114. 2 Langenberg W, Rauws EAJ, Oudbier JH, Tytgat GNJ. Patient-to-patient transmission of Campylobacter pylori infection by beroptic gastroduodenoscopy and biopsy. J. Infect. Dis. 1990; 161: 50711. 3 Miyaji H, Kohli Y, Azuma T et al. Endoscopic crossinfection with Helicobacter pylori. Lancet 1995; 345: 464. 4 Sugiyama T, Naka H, Yabana T et al. Is Helicobacter pylori infection responsible for postendoscopic acute gastric mucosal lesion? Eur. J. Gastroenterol. Hepatol. 1992; 4 (Suppl.1): S936. 5 Marshall BJ, Armstrong JA, McGechie DB, Glancy RJ. Attempt to fulll Kochs postulates for pyloric Campylobacter. Med. J. Aust. 1985; 142: 4369. 6 Morris A, Nicholson G. Ingestion of Campylobacter pyloridis causes gastritis and raised fasting gastric pH. Am. J. Gastroenterol. 1987; 82: 1929. 7 Fennerty MB. Helicobacter pylori. Arch. Intern. Med. 1994; 154: 7217. 8 Formmer DJ, Carrick J, Lee A, Hazell SL. Acute presentation of Campylobacter pylori gastritis. Am. J. Gastroenterol. 1988; 83: 116871. 9 Sobala GM, Crabtree JE, Dixon MF et al. Acute Helicobacter pylori infection: clinical features, local and sys19

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