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Print version ISSN 1130-0108
Rev. esp. enferm. dig. vol.96 n.9 Madrid Sep. 2004
Incidence and factors influencing on Helicobacter pylori infection recurrence
B. J. Gómez Rodríguez, M. Rojas Feria, M. J. García Montes, R. Romero Castro, P. Hergueta Delgado,
F. J. Pellicer Bautista and J. M. Herrerías Gutiérrez
Service of Digestive Diseases. Hospital Universitario Virgen Macarena. Sevilla. Spain
Objectives: a) to determine the rate of H. pylori reinfection after successful eradication in a 4-year follow-up study; and b) to evaluate the contribution of different factors in the infection relapse.
Patients and methods: a total of 208 patients (age range 18-81 years; average 50 years; 87 women) who had been successfully treated for H. pylori infection were included. Annually, urea breath test was assessed to determine H. pylori status after eradication. Age, sex, rural/urban environment, smoking habit, treatment regimens against H. pylori and urea breath test values were evaluated.
Results: reinfection occurred in 9,6% of patients observed, 6,7% (14/208) in the first year, 1,9% (4/208) in the second year, 1% (2/208) in the third and 0% in the forth. Risk factors for infection recurrence were younger age and higher values of urea breath test in the multivariante analysis.
Conclusions: annual reinfection rate was 2,4 pacients-year. Younger patients and higher values of urea breath test were factors associated with a higher rate of reinfection relapse. Annually, urea breath test should be performed to detect reinfection in order to avoid ulcer complications.
Key words: Reinfection. Recrudescence. Recurrence. Eradication. Helicobacter pylori. Urea breath test.
Gómez Rodríguez BJ, Rojas Feria M, García Montes MJ, Romero Castro R, Hergueta Delgado P, Pellicer Bautista FJ, Herrerías Gutiérrez JM. Incidence and factors influencing on Helicobacter pylori infection recurrence. Rev Esp Enferm Dig 2004; 96: 620-627.
Correspondencia: Blas José Gómez Rodríguez. Servicio de Aparato Digestivo. Hospital Universitario Virgen Macarena. Avda. Doctor Fedriani, 3. 41071 Sevilla. Telf.: 955 008 801. Fax: 955 008 805. e-mail: email@example.com
Trabajo con soporte financiero mediante: Accésit al Premio al Mejor Proyecto de Investigación titulado: "Reinfección por Helicobacter pylori", otorgado en el año 2001 por la Sociedad Andaluza de Patología Digestiva. Premio para proyecto de Investigación titulado: "Reinfección por Helicobacter pylori", otorgado en el año 2002 por la Fundación Española de Patología Digestiva.
Helicobacter pylori infection is an essential factor in the pathogenesis of peptic ulcer disease, MALT lymphoma and gastric adenocarcinoma. Eradication heals active ulcers, and in the long term reduces ulcer relapse and complications (1).
There are two types of recurrence of H. pylori infection after successful treatment: recrudescence and true reinfection. Recrudescence is defined as a relapse of previous infection, whereas true reinfection is an infection with a new strain that is different from the former (2,3).
Reinfection rate is around 6.25% in some parts of Asia (4) and 2.4% in India (5). In developed countries the reinfection rate is lower than 1%. There are few studies regarding reinfection rates in Spain. Ramos et al. (6) found a recrudescence rate of 4.7%, and Gisbert et al. (7) recurrence rates of 3.6% at six months after eradication, 1.5% a year later, and 1.5% two years later, most of them recrudescences instead of true reinfections.
The main objectives of this study were to determine the annual reinfection rate within 4 years after successful treatment, and to evaluate the contribution of different factors to infection relapse.
PATIENTS AND METHODS
Two hundred and twenty-one patients successfully treated for H. pylori infection and under continuous monitoring in our GI Department were included. H. pylori infection eradication was diagnosed by using the urea breath test (UBT) or urease test, and histology in gastric ulcer patients.
Treatment indications were duodenal ulcer in 159 patients (73%), dyspepsia in 30 (12%), gastric ulcer in 18 (9%), dermatological disease in 8 (3%), and other in 6 patients (3%). Sixty-one percent of patients were treated with proton pump inhibitors (PPI), clarithromycin, and amoxicillin; 16% with ranitidine bismuth citrate, and one or two antibiotics; 9% with classic triple therapy (bismuth, ranitidine and metronidazole or tetracycline), and 14% with quadruple therapy and others.
Patients were monitored for recurrence with UBT annually for 4 years.
UBT was performed in patients after 6 hours fasting. After the administration of citric acid solutions (2 g of citric acid and 200 ml of water) a baseline breath sample was taken. Then, 100 mg of 13C-urea in 50 ml of water were given, and 30 minutes later a second breath sample was taken. Samples were analyzed using mass spectrometry. Results (difference between both samples) were expressed in delta units, defined as the patient's 13C/12C ratio versus standard values expressed in percentage (‰). Results were considered negative if they were under 5.
Patients were divided into two groups: reinfected, if a recurrence of H. pylori infection was observed by any test, and non-reinfected, if UBT was persistently negative. Age, gender, rural/urban environment, smoking habits, treatment regimens for H. pylori, diagnostic tests (UBT vs rapid urease test and histological examination), and UBT values were considered as predictors for H. pylori infection recurrence.
A multivariate logistic regression analysis was performed to evaluate the influence of variables in H. pylori infection recurrence. The Kaplan-Meier method was used to study the evolution of reinfection over time. The Local Ethics Committee approved the protocol study.
In all, 208 patients (121 males and 87 females, with a mean age of 50 ± 13 years, age range 18-81 years) completed the follow-up. Thirteen subjects (6%) were excluded as they did not show up for any of the annual clinical visits.
H. pylori was found in 20 of 208 patients (incidence of 2.4 patients/year). Probability of reinfection according to the Kaplan-Meier method was estimated as 6.7% (14/208 patients) in the first year, 1.9% (4/208) in the second year, 1% (2/208) in the third, and 0% in the fourth year.
Reinfected patients were younger than non-reinfected patients (44.25 years vs 21.5 years, p = 0.005). Age was considered a protecting factor in the multivariate analysis, with an odds ratio of 0.915 (95% confidence interval, 0.803 to 0.979) (Table I).
The Kaplan-Meier test applied by age groups showed that the highest percentage of reinfection (15.15%) occurred in subjects aged between 35 and 49; 65% (13/20) of reinfected subjects were under 49 (Table II).
UBT test value after eradication in reinfected patients was higher than in non-reinfected patients (1.8 vs 0.4, p = 0.042). In the logistics regression analysis UBT value after H. pylori treatment was shown to be a predictor for recurrence, with an odds ratio of 3.267 (95% confidence interval, 0.684 to 15.599).
No differences were found between both groups in gender, rural/urban environment, smoking habits, treatment regimens for H. pylori, or diagnostic tests used to confirm eradication. None of these variables were predictors of reinfection in the multivariate analysis.
During follow-up, one case of ulcer secondary to NSAID ingestion was diagnosed in the non-reinfected group. In the reinfected group 5 cases of duodenal ulcer and one of chronic urticaria relapse were diagnosed. All of them were treated successfully, and no ulcer complications were found.
In our study, the recurrence rate after eradication of H. pylori infection was 2.4%, similar to that in previous reports.
In a review that included countries with different levels of development, the annual incidence of recurrence was between 0 and 10% (8). Archimaditis et al. (9) found in 165 patients with duodenal ulcer a recrudescence rate of 9.7%, and a reinfection rate of 9.3% in the second year, of 2.3% in the third year, and of 0% in the fourth (9). In Spain, Mones et al. (10) calculated a recurrence rate of 3.4% during the first year for 85 patients with peptic ulcer. In Brazil, Della Libera reported a reinfection rate of 7.6% (11) one year after successful eradication. In Japan, a country with a high prevalence of H. pylori infection, the annual reinfection rate was 0.8% (12). There are some studies that analyzed reinfection rates in patients with MALT lymphoma associated with H. pylori infection (13-15). One of these studies (16) observed a high recurrence rate (14%) 22 months after the eradication therapy.
A detection of different H. pylori strains is necessary to differentiate between reinfection and recrudescence. Strains can be isolated using polymerase chain reaction (PCR) or restriction fragment length polymorphism (RFLP) analysis. However, it is controversial whether the definition requires the presence of similar or different strains with regard to the primary infection. Moreover, patients can be simultaneously infected by different strains (17-20). Since a genetic analysis was not performed in this study, we cannot distinguish between recrudescence and true reinfection.
Some factors have been proposed as adjuvant of infection recurrence, such as impaired immune response and low socioeconomic status (21). All patients in this study had the same socioeconomic status, so the influence of this factor has not been studied. We observed that reinfected patients were younger than non-reinfected ones, which is consistent with previous reports. H. pylori eradication at a young age can be a risk factor for infection recurrence (22,23). Some studies found dental plaque (24-26) or partner infection (27-29) was a potential risk factor for H. pylori recurrence.
Another controversial aspect is the clinical outcome of reinfection. Different situations may occur: infection relapse, symptomatic or not, without endoscopic findings; symptomatic ulcer relapse and its complications (mainly bleeding), and gastric MALT lymphoma recurrence after eradication success and histological improvement (13,14).
It has been reported that ulcer relapse in reinfected patients ranges from 3 to 60% (30-32); in this study we observed a rate of 20%. Some studies demonstrated that eradication therapy is more effective than PPI treatment to prevent ulcer relapse and its complications (33-36). We could avoid them by using a therapy against H. pylori infection in reinfected patients.
However, management of reinfected patients remains unclear as yet. Some authors have questioned if H. pylori status needs to be periodically tested and treated in case of infection, above all in the case of MALT lymphoma or bleeding ulcer (37-39).
UBT should be the first-choice test for detecting H. pylori reinfection, since it is a non-invasive method that explores the whole stomach. Recently, a multicentric study published in our country has validated this test for the diagnosis and eradication control of H. pylori infection (40), since its sensitivity is high in both cases. However, in the second case, it is recommended that the cut-off value be lowered to 4.6 atoms per thousand. In fact, some authors establish their cut-off value in 3.5 atoms per thousand (41). In our study, if we had established it in 3.5 atoms per thousand, 15% (3/20) of reinfected patients would have been diagnosed with failed eradication instead of infection recurrence. No differences were observed in the non-reinfected group. Therefore, values between 3.5 and 5 atoms per thousand should be considered indecisive, so another UBT, histological studies or rapid urease test should be performed.
In order to detect a recurrence of H. pylori infection and to retreat patients to prevent complications, we suggest an annual follow-up with UBT for patients under 50 who are asymptomatic and were successfully treated.
In conclusion, in our population the H. pylori recurrence rate is 2.4 patients/year within a 4-year follow-up period. This study has shown that reinfection depends on age, so we recommend an annual UBT for 3 years after eradication, above all in patients under 50 years of age.
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