2. TREATMENT RECOMMENDATIONS FOR HELICOBACTER INFECTION 491
These clinical practice guidelines are designed to as- TABLE 1. Summary of recommendations and the quality of
sist primary care physicians, nurse practitioners, physi- the supporting evidence
cian assistants, and pediatric gastroenterologists in the Quality of
evaluation and treatment of suspected or diagnosed H. Recommendations evidencea
pylori–associated disease. The desired outcomes of these
How reliable are tests for H. pylori infection?
recommendations are the detection of children and ado- Currently, the diagnosis of H. pylori-mediated disease
lescents with H. pylori who need treatment. These rec- can be made reliably only through the use of
ommendations are applicable to children in developed endoscopy with biopsy. II, III
countries where the prevalence of infection is low but Presently available commercial serologic tests are
frequently unreliable for screening children for the
may not be directly relevant to children living in com- presence of H. pylori infection. II
munities where there is a higher frequency of gastric Urea breath testing, although promising, has not been
colonization by H. pylori. These recommendations have studied sufficiently in children. II
been endorsed by the Executive Council of NASPGN When is testing indicated?
and by the American Academy of Pediatrics. They are It is recommended that testing be performed in
children with endoscopically diagnosed, or
general guidelines to assist medical care providers in the radiographically definitive, duodenal or gastric ulcers. I
diagnosis and treatment of H. pylori infection in chil- It is recommended that children with recurrent
dren. They are not intended as a substitute for clinical abdominal pain, in the absence of documented
judgment or as a protocol for the management of all ulcer disease, not be tested for H. pylori infection. II
Testing for H. pylori infection is not recommended in
patients. asymptomatic children. II
In its deliberations, the committee addressed four is- Routine screening of children with a family history of
sues about H. pylori infection in children: How reliable gastric cancer or recurrent peptic ulcer disease is
are tests to detect H. pylori? When is testing for H. pylori not recommended. II
indicated? When is treatment of H. pylori infection in- Testing following treatment of documented H. pylori
is recommended, especially with complicated
dicated? What is the preferred treatment of H. pylori? A peptic ulcer disease (i.e., bleeding, perforation, or
summary of the recommendations of the H. pylori Infec- obstruction). For patients who remain symptomatic
tion Guideline Committee is presented in Table 1. after treatment, it is recommended that endoscopy
and biopsy be performed to evaluate for the
persistence of H. pylori-associated peptic ulcer
METHODS disease. I, II
If pathological evidence of MALT lymphoma is
The H. pylori Infection Guideline Committee consisted of a documented, then testing for H. pylori is
primary care pediatrician, a clinical epidemiologist, and seven recommended. II
pediatric gastroenterologists. To develop evidence-based When is treatment of H. pylori infection indicated?
guidelines, articles published in English from January 1966 Eradication treatment is recommended for children who
through May 1999 on H. pylori in children were searched. have a duodenal ulcer or gastric ulcer identified at
endoscopy and H. pylori detected on histology. I
Articles on diagnosis and treatment were sought separately. A prior history of documented duodenal or gastric
Letters, editorials, case reports, abstracts, and reviews were ulcer disease is an indication for treatment if active
excluded. Evidence tables were prepared based on 16 articles H. pylori infection is documented. I
on clinical presentation, 9 articles on diagnostic studies, and 30 There is no compelling evidence for treating
articles on therapy. Subsequently, additional articles were iden- children with H. pylori infection and non-ulcer
tified and reviewed. When the pediatric literature was insuffi- dyspepsia or functional recurrent abdominal pain. III
cient, the adult literature was also considered. Articles were Treatment is not recommended for H. pylori-infected
evaluated using published criteria (13). The Committee based children residing in chronic care facilities; children
its recommendations on an integration of a review of the medi- with unexplained short stature; or children at
increased risk for acquisition of infection, including
cal literature and expert opinion. Consensus was achieved by asymptomatic children who have a family member
using the nominal group technique, a structured quantitative with either peptic ulcer disease or gastric cancer. III
method, as described previously (14,15). By using the methods What is the preferred treatment of H. pylori infections in children?
of the Canadian Preventive Services Task Force (16), the qual- It is recommended that treatment consist of three or
ity of evidence of each of the recommendations made by the four medications, given once or twice daily, for
committee was determined and is summarized (Table 1). one to two weeks. I
a
Categories of the quallity of evidence: I Evidence obtained from at
HOW RELIABLE ARE TESTS FOR least one properly designed randomized controlled study. II-1 Evidence
obtained from well-designed cohort or case-controlled trials without
H. PYLORI INFECTION? randomization. II-2 Evidence obtained from well-designed cohort or
case-control analytic studies, preferably from more than one center or
Several invasive and noninvasive tests are available to research group. II-3 Evidence obtained from multiple time series with
detect H. pylori infection (Table 2). An ideal test for H. or without the intervention. Dramatic results in uncontrolled experi-
pylori is noninvasive or minimally invasive, highly ac- ments (such as the results of the introduction of penicillin treatment in
curate, inexpensive, and readily available and enables the 1940’s) could also be regarded as this type of evidence. III Opinions
of respected authorities, based on clinical experience, descriptive stud-
differentiation between active or past infection with the ies, or reports of expert committees.
J Pediatr Gastroenterol Nutr, Vol. 31, No. 5, November 2000
3. 492 GOLD ET AL.
TABLE 2. Tests for Helicobacter pylori and study. The optimal staining of biopsy sections is best
Helicobacter-related disorders determined by local expert pathologists. Endoscopic ex-
Invasive tests requiring endoscopy
amination of and specimens obtained in the esophagus,
Biopsies and histology stomach, and duodenum also provide information about
Rapid urease testing other upper gastrointestinal disorders that may be the
Bacterial culture cause of clinical symptoms including, for example,
Polymerase chain reaction of bacterial DNA esophagitis and peptic ulcer disease that is not due to H.
Non-invasive tests
Serum and whole blood antibody pylori.
Saliva antibody There are drawbacks to diagnostic gastrointestinal en-
Urine antibody doscopy. It is a relatively invasive procedure requiring
Stool antigen sedation or anesthesia. Furthermore, the test remains
Urea breath testing
relatively expensive in many centers, and access to an
endoscopist with specific pediatric expertise is limited in
many geographic areas.
organism. In addition, such a test enables discrimination
between the presence of H. pylori infection and H. py-
lori–associated disease. Because no such ideal test cur- Rapid Urease Testing of Biopsy Tissues
rently exists, the advantages and drawbacks of tests that Urease testing (CLO, TriMed, Kansas City, MO; Hp-
are available require critical appraisal and must be as- Fast, GI Supply, Division of ChekMed Systems Inc.,
sessed for their suitability for use in children. Camphill, PA; PyloriTek, Horizons International, Agua-
Failure to reach an accurate diagnosis carries consid- dilla, Puerto Rico) provides indirect identification of H.
erable financial and social costs including the expense of pylori infection within a few hours of endoscopy (20).
more tests, repeated visits to health care providers, inap- However, these tests have a poor positive predictive
propriate treatment, and missed school or work. A de- value (as low as 50%) in children, even though the nega-
finitive test, even if it is expensive, may result in overall tive predictive value is high (97–98%) (20,21). The ac-
cost savings (17). curacy of the test is dependent on the number of tissue
It is important to emphasize that the accuracy of a specimens tested, the location of biopsy sites, bacterial
diagnostic test is greatly impacted by the prevalence of load, and previous usage of antibiotics and proton pump
H. pylori in the population tested. There is a need for inhibitors, as well as the prevalence of H. pylori in the
studies to assess the accuracy and potential utility of population tested.
various noninvasive diagnostic tests in populations in
North America that differ in demographic factors that
may influence the prevalence and natural history of H. Bacterial Culture
pylori infection (18). Culture of H. pylori from the gastric mucosa provides
an opportunity to obtain a profile of antibiotic sensitivity
Invasive Testing Through Endoscopy that could identify potential treatment failure due to an-
tibiotic resistance (22). Culture also provides a bacterial
Biopsies and Histopathology strain for use in epidemiologic studies to examine asso-
ciations of virulence characteristics with disease out-
The definitive diagnosis of H. pylori and the evidence come. However, bacterial culture for H. pylori is rela-
of the consequences of infection can be made reliably tively expensive and success rates for recovery of the
only by endoscopy with multiple biopsy specimens ob- organism in many clinical laboratories are low (23). Cur-
tained in one or more regions of the stomach including rently, standardization of culture procedures has not been
antrum, body, and transition zones (i.e., cardia and inci- established, and bacterial cultures are only obtained rou-
sura). Histology provides information regarding the pres- tinely in research settings.
ence of H. pylori and the severity and topographic dis-
tribution of gastritis including the presence of atrophic Polymerase Chain Reaction
gastritis, intestinal metaplasia, and mucosa-associated
lymphoid tissue (MALT) lymphoma (3). As in adults, Polymerase chain reaction (PCR) is a highly sensitive
biopsy specimens obtained in the prepyloric antrum have technique that can be used to detect the presence of H.
the highest yield in H. pylori infection. Tissue specimens pylori in body fluids (e.g., gastric juice and stool), tissues
often are also obtained from the body and the transition (e.g., gastric mucosa), and water (24). Testing of H. py-
zones of the stomach, particularly if the patient has re- lori genomic DNA by PCR can be used to advance
cently taken acid-suppressing medication (19). It is rec- knowledge at the molecular level—for example, by pro-
ommended that multiple biopsies be performed in chil- viding information about point mutations conferring
dren with endoscopically documented peptic ulcer dis- resistance to antibiotics and about putative bacterial
ease or peptic ulcer suspected as a result of radiographic virulence factors. However, PCR is expensive, the assay
J Pediatr Gastroenterol Nutr, Vol. 31, No. 5, November 2000
4. TREATMENT RECOMMENDATIONS FOR HELICOBACTER INFECTION 493
is difficult to set up, specificity may be compromised by cation therapy. However, patients may be reluctant to
inadvertent contamination, and it is not widely available collect stool specimens. In addition, refrigerated stools
outside the research laboratory. are more difficult to test. Additional pediatric studies
evaluating the accuracy of stool antigen testing for both
initial diagnosis and posttreatment follow-up are re-
Noninvasive Testing
quired before specific recommendations can be consid-
Immunoassay Tests to Detect H. pylori Antibodies ered (32).
Enzyme-linked immunosorbent assays (ELISAs) to Urea Breath Testing
detect H. pylori antibodies are relatively inexpensive and
easy to implement in the clinical setting. Many tests are
available for use to test whole blood, plasma, or serum. Urea breath tests are noninvasive and have high sen-
However, compared with histology, the sensitivity and sitivity and specificity (>95%) both in adults (33) and
specificity of serologic assays are poor in both adults and children (34,35). The test requires the ingestion of either
children unless used in the populations in which they radiolabeled 14C-urea or urea tagged with the stable iso-
were initially developed (25). In general, the accuracy of tope 13C. Test results may be influenced by concurrent
serum-based immunoassays and whole-blood tests for use of antibiotics and acid-suppressing medications and
use in the physician’s office in symptomatic children in by the presence of other urease-producing organisms
developed countries is poor, with a range of sensitivity of present in the oral cavity. Test parameters are currently
only 60% to 70% (26–28). Furthermore, age-related cut- laboratory-specific (e.g., dosages for differing ages of
off values for commercial immunologic tests have not children, cutoff values, duration of fasting, use of a test
been established for children. One immunoassay devel- meal, times of sampling, and timing of posttherapy test-
oped in a research center to detect H. pylori–specific ing) and have not been well standardized for children
immunoglobulin (Ig)G in children was 91% sensitive (36). In addition, urea breath testing is technically more
compared with sensitivity of less than 70% in three com- difficult to perform in small children and infants, with
mercially available assays (28). In areas with low preva- failure rates in collection up to 10%, especially outside
lence of H. pylori infection, such as in developed coun- the clinical research setting (34).
tries, testing of serum and whole blood is not sufficiently In summary, the diagnosis of H. pylori–associated dis-
accurate to diagnose H. pylori infection in children. Ac- eases currently can be made reliably only by endoscopy
cordingly, treatment regimens based on the results of with biopsies. The most commonly used noninvasive test
these tests cannot be recommended. Serologic tests may to screen adults for H. pylori infection is serology. Un-
not be used reliably to verify eradication of H. pylori, fortunately, currently available commercial serologic
because antibody titers can remain positive for months, tests are frequently unreliable for screening children for
despite resolution of infection. the presence of H. pylori infection. Current whole-blood,
saliva, and urinary immunoassays are insufficiently sen-
sitive or specific to be effective as diagnostic tools. In-
Saliva and Urine Tests for H. pylori Antibodies sufficient data are available in children to confirm the
accuracy of the recently approved H. pylori stool antigen
Similar to serologic tests, saliva-based tests also detect test. The urea breath test has the promise to provide
the presence of H. pylori–specific IgG antibodies. The noninvasive and accurate diagnosis of H. pylori infec-
tests are easy to perform, painless, and inexpensive. Sa- tion; but currently, there is insufficient evidence that it
liva tests are less sensitive than assays of serum or whole can be used to reliably diagnose or exclude H. pylori–
blood (29). The protein concentration of saliva appears to associated diseases.
affect the accuracy of test results. Urine-based assays are
easy to perform, require minimal labor for collection,
and are painless (30). However, these assays are highly
variable and are not yet commercially available. There- WHEN IS TESTING INDICATED?
fore, saliva and urine assays for the detection of H. pylori
antibodies cannot be recommended. The primary goal of testing is to diagnose the cause of
clinical symptoms and not simply to detect the presence
Stool Test for H. pylori Antigens of H. pylori infection. Testing is not helpful unless it will
alter the management of the disease.
Testing of H. pylori antigens in stools has shown A variety of invasive and noninvasive tests exist for
promising results in adults for the noninvasive diagnosis the detection of H. pylori infection, but their degree of
of gastric infection using a commercially available kit sensitivity and specificity vary, as do their suitability for
(31). Testing for H. pylori antigens in feces also appears clinical use in children. Thus, there is potential for inap-
to be accurate for use in monitoring the success of eradi- propriate testing or misuse of tests in children.
J Pediatr Gastroenterol Nutr, Vol. 31, No. 5, November 2000
5. 494 GOLD ET AL.
Endoscopically Diagnosed or Radiographically dicates that there is a link between gastric cancers (both
Definitive Peptic Ulcer adenocarcinoma and lymphoma) and H. pylori infection.
However, no studies have shown that H. pylori eradica-
The causal relationship between H. pylori infection tion during childhood prevents subsequent development
and primary duodenal ulcers is compelling (37). There- of gastric malignancies. Until evidence is available to
fore, it is recommended that testing for the presence of H. better define the role of H. pylori in a variety of gastric
pylori infection be performed in children with endo- cancers and the role of H. pylori eradication in disease
scopically diagnosed or radiographically definitive duo- prevention, routine screening of children with a family
denal ulcer. Although the data in children are less com- history of gastric cancer or recurrent peptic ulcer disease
plete, evidence from studies in adults (38) supports the is not recommended.
recommendation that testing for H. pylori also be per-
formed in subjects with a documented gastric ulcer.
Histologic Evidence of Lymphoma
Abdominal Pain Unrelated to Peptic Ulcers
In the rare circumstance in which histopathologic evi-
Several lines of evidence, including serologic surveys, dence of MALT lymphoma is documented in a child,
endoscopic evaluations, and treatment trials indicate that testing for H. pylori is recommended.
H. pylori is not a frequent cause of recurrent abdominal
pain in children. There have been six studies performed
in North America, Europe, and Australia, with 2715 chil- Follow-up of Therapy for H. pylori Infection
dren evaluated by esophagogastroduodenoscopy and bi-
opsy, serology, or urea breath test (39–44). Although 5% Testing to confirm eradication of infection and the
to 17% of children with abdominal pain had evidence of resolution of associated symptoms and disease sequelae
infection with H. pylori, 5% to 29% of children without is advisable in selected children. Guidelines in adults
abdominal pain were also infected with H. pylori. There recommend testing after treatment of complicated peptic
are no convincing data to support routine testing of chil- ulcer (52), but studies in children are limited. As such,
dren with recurrent abdominal pain (39–45). Investiga- few data are available on the effectiveness of therapy in
tors have also looked for specific symptom patterns in H. children, testing after treatment is recommended in those
pylori–infected children, but none so far has been de- with complicated peptic ulcer disease (i.e., bleeding, per-
tected (46–50). Future studies are needed to determine foration, or obstruction) or lymphoma. For patients who
whether subsets of children with abdominal pain can be remain symptomatic, it is recommended that endoscopy
identified in whom signs and symptoms are caused by H. and biopsy be performed to evaluate for the persistence
pylori infection. It is recommended that children with of H. pylori-associated peptic ulcer disease. For patients
recurrent abdominal pain, in the absence of documented with an uncomplicated ulcer who are asymptomatic after
ulcer disease, not be tested for H. pylori infection. completion of eradication therapy, testing for persistence
of infection is not necessary. However, some physicians
Asymptomatic Children, Including Those at advocate the use of urea breath testing in this clinical
Increased Risk of Acquiring H. pylori Infection setting.
There are no compelling data to support routine testing
in asymptomatic children. Testing for H. pylori infection WHEN IS TREATMENT OF H. PYLORI
is not recommended in children without clinical symp- INFECTION INDICATED?
toms, including those residing in long-term care facili-
ties, children with short stature, and those at increased Eradication therapy is recommended for children who
risk of acquiring H. pylori infection. In addition, pur- have both known active H. pylori infection and symp-
ported extraintestinal manifestations of H. pylori infec- tomatic gastrointestinal disease. Known active H. pylori
tion have not been demonstrated in a convincing fashion infection is defined as identification of the organisms by
(51). Accordingly, a test-and-treat approach is not rec- histopathologic examination or as a positive culture from
ommended in these circumstances. endoscopic gastric biopsy. Serology is not a reliable test
for active disease, because it may indicate past but not
Family History of Gastric Cancer or Recurrent current infection with H. pylori.
Peptic Ulcer Disease There are no randomized controlled trials in children
that determine the precise clinical settings in which
No currently available data support routine testing in eradication therapy is indicated. Although additional
children with a positive family history of diseases related studies in children are needed (53), the available evi-
to H. pylori infection (52). Epidemiologic evidence in- dence supports the following recommendations.
J Pediatr Gastroenterol Nutr, Vol. 31, No. 5, November 2000
6. TREATMENT RECOMMENDATIONS FOR HELICOBACTER INFECTION 495
Duodenal and Gastric Ulcers cost of care. Therefore, the H. pylori Infection Guideline
Committee concludes that there is insufficient evidence
Eradication treatment is recommended for children to support either initiating or withholding eradication
who have a duodenal ulcer or gastric ulcer identified at treatment in this situation.
endoscopy and H. pylori documented by histopathology.
A prior history of duodenal or gastric ulcer disease is also
an indication for treatment if active H. pylori infection is Recurrent Abdominal Pain and
documented. If a definitive ulcer is present on contrast
Asymptomatic Children
radiography (e.g., an ulcer crater is present), eradication
therapy is indicated if either a noninvasive or invasive
test result is positive for H. pylori. There is no compelling evidence, at the present time,
for treating children with H. pylori infection and either
Lymphoma nonulcer dyspepsia or functional recurrent abdominal
pain. There is also no convincing evidence currently
The rare child with pathologic evidence of MALT available that asymptomatic children who have a family
lymphoma and H. pylori infection should be treated with member with H. pylori infection, peptic ulcer, or gastric
eradication therapy. Further studies of pediatric patients cancer need treatment.
with lymphoma should be performed to monitor the re-
currence, progression, or remission of the tumor after
therapy. WHAT IS THE PREFERRED TREATMENT OF
H. PYLORI INFECTION IN CHILDREN?
Atrophic Gastritis With Intestinal Metaplasia
The optimum treatment regimen for eradicating H. py-
Eradication treatment is recommended for the rare lori in children has not been determined (59). Effective
child who has pathologically proven atrophic gastritis therapy in adults is defined as successful eradication of
with intestinal metaplasia, according to the updated Syd- H. pylori infection in a minimum of 80% of treated sub-
ney classification of gastritis (54), plus coexisting H. jects (60). Although it appears that treatment options that
pylori infection. Because of the preneoplastic nature of have been effective in adults will also be efficacious in
these pathologic changes, follow-up endoscopy is rec- children, controlled studies in pediatric populations are
ommended to confirm that the H. pylori infection has needed to confirm or refute this supposition. Unfortu-
been eradicated and to ensure that there is no subsequent nately, the limited data currently available in children are
progression of gastric mucosal disease. open-label, case series and uncontrolled, anecdotal ob-
servations that do not meet the minimum criteria for
Gastritis Without Peptic Ulcer Disease determining efficacy. In vitro sensitivity of H. pylori to a
specific drug does not guarantee that the bacterium will
The finding of H. pylori–associated gastritis in the be effectively eradicated from the human stomach.
absence of peptic ulcer disease during diagnostic endos- Therefore, current treatment strategies to eradicate H.
copy poses a dilemma for the endoscopist. The decision pylori have been developed primarily by trial-and-error
to treat H. pylori–associated gastritis without duodenal or methodology (61).
gastric ulcer in this situation is subject to the judgment of The single most important determinant of successful
the clinician and deliberations with the patient and fam- eradication therapy is compliance with the prescribed
ily. Studies in adults on the effect of eradication treat- combination treatment regimen (62). There are well-
ment on abdominal symptoms have produced conflicting described treatment failures due to suboptimal compli-
results (55–58). There are no randomized controlled tri- ance. To enhance adherence to the treatment regimen,
als in children. The long-term impact of the eradication the number of medications prescribed, the frequency of
of H. pylori and the healing of gastritis on the subsequent administration, and the duration of therapy are best kept
development of peptic ulcer disease, adenocarcinoma, or to the minimum required for successful treatment.
lymphoma is uncertain. Although there is a small life- It is recommended that initial treatment consist of
time risk of development of peptic ulcer disease associ- three medications, administered twice daily, for 1 to 2
ated with H. pylori gastritis, there are no randomized weeks (63). Specifically, as shown in Table 3, three first-
controlled trials demonstrating that eradication of H. py- line therapy options are recommended for use in children
lori results in prevention of peptic ulcer disease. In ad- and adolescents. For patients in whom initial treatment
dition, there are no data showing that eradication therapy has failed, two other options are recommended, includ-
influences the long-term risk for development of gastric ing one option with four medications. It is recommended
cancers. Antibiotic treatment can result in adverse drug that monotherapy and two-drug regimens be avoided,
reactions, promote antibiotic resistance, and increase the because they are ineffective and increase the likelihood
J Pediatr Gastroenterol Nutr, Vol. 31, No. 5, November 2000
7. 496 GOLD ET AL.
TABLE 3. Recommended eradication therapies for H. pylori pump inhibitor also reduces the effectiveness of eradica-
disease in children tion treatment protocols. Studies are needed to determine
First-line
the relative importance of these risk factors in pediatric
options Medications Dosage populations.
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J Pediatr Gastroenterol Nutr, Vol. 31, No. 5, November 2000