Naval Submarine Medical Research Laboratory

NSMRL REPORT 1210 25 AUG 1998

A New Strategy to Address Loss of Submarine Qualifications in Submariners

Who are Helicobacter Pylori Positive and Diagnosed with Peptic Ulcer Disease:

Background to the Change in Policy

LT Robert P. Jackman, MC, UMO, USNR

ENS Jeffrey J. Costello, MC, USNR

Released by

M. T. Wooster, CAPT, MSC, USN

Commanding Officer

Naval Submarine Medical Research Laboratory

Jw.v/iiiiD 1

Approved for public release; distribution unlimited
A New Strategy to Address Loss of Submarine Qualifications in Submariners

Who Are Helicobacter Pylori Positive and Diagnosed With Peptic Ulcer Disease:

Background to the Change in Policy

LT Robert P. Jackman, MC, UMO, USNR

ENS Jeffrey J. Costello, MC, USNR

Naval Submarine Medical Research Laboratory

Report 1210

Approved and Released by

M. T. Wooster

Commanding Officer

NavSubMedRschLab

Approved for public release; distribution unlimited
SUMMARY PAGE

PROBLEM:

It was USN policy to disqualify submariners from returning to submarine duty for two years

following a peptic ulcer. This resulted in a loss of experienced personnel which was considered

to be unnecessary given the current medical advances in peptic ulcer therapy. This is an

evaluation ofthe medical literature to provide background to why the current USN policy of

disqualifying submariners from submarine duty following the diagnosis of peptic ulcer disease

has been changed.

FINDINGS:

The medical literature shows that infection with Helicobacter pylori is causally related to the

majority of both duodenal and gastric ulcer cases. The second most common cause of peptic

ulcer results from the use of non-steroidal anti-inflammatory drugs such as Ibuprofen (Motrin,

Advil, etc). Repeated studies have demonstrated that eradication ofHelicobacter pylori infection

in patients with peptic ulcer disease results in a dramatic reduction of ulcer recurrence from as

high as 74 to 95% to between 1.1% and 8%. This recurrence rate includes duodenal, gastric, and

complicated ulcers. Re-infection with Helicobacter pylori is uncommon in western countries,

with rates ranging between zero and 6.25% during the first year. Longer term studies reveal

annual re-infection rates of 0.36% to 1.5%.

APPLICATION:

Results indicate that it is reasonable to return submariners to duty with a low expectation of

complications contingent upon eradication ofthe bacteria Helicobacterpylori and complete

healing ofthe peptic ulcer.

Acknowledgment and Disclaimer

This project was conducted under Naval Medical Research Development Command Research

Work Unit 63706N-M0096.002-5205, "Medical Conditions Affecting Submarine

Qualifications." The views expressed in this report are those ofthe authors and do not reflect the

official policy ofthe Department ofthe Navy, Department of Defense, or the US Government. It

was approved for publication on 25 Aug 1998 and designated NSMRL Report 1210. The author

would like to extend thanks to all those who aided, critiqued, and otherwise helped in the

preparation ofthis paper. In particular, thanks to LCDR Neal Carlson for editorial comments and

Susan Monty for preparing the manuscript.

ii
Background

Peptic ulcer disease (PUD) is a chronic

inflammatory condition of the stomach and

duodenum that affects 10% of people in the

United States at some time in their lives, and

has a point prevalence rate of 2% of the

adult US population (1,2). Over the past

fifteen years PUD has been variously

attributed to stress, diet, decreased mucosal

defenses, as being idiopathic in origin, and

medications. Each new theory led to the

development of novel therapies (i.e.

antacids, H2 blockade and proton pump

inhibition) which met with initial success,

but in the main each failed. Thus recurrence

rates are reported to be as high as 95% for

duodenal ulcers and 74% for gastric ulcers

(3).

Based on the "unpredictability and

seriousness of the major complications of

perforation, hemorrhage, and obstruction"

(4) and the limited medical care available

aboard submarines, prior US Navy policy

required that submariners diagnosed with

PUD be disqualified from submarine duty

until they were ulcer-free for two years.

From 1990 to 1996 COMSUBLANT/PAC

medical data indicated that 53 US Navy

submariners were disqualified from duty due

to PUD (5). Of the 48 submariners

disqualified for PUD from 1990 to 1995, 31

(65%) were of the rank E5 to E7. US Navy

Bureau of Personnel records show that

between 1 Jan 1996 and 1 Oct 1996 of the

212 men disqualified for medical reasons,

11% (6) were due to peptic ulcer disease.

The monetary and readiness-related cost of

training and replacing USN submariners

disqualified by the former policy was,

therefore, substantial.

Several recent advances in understanding the etiology and improved

management of the disease have markedly

changed the prognosis of PUD (1,3,7-14)

and justify the change of the disqualification

policy. First, Helicobacter (H.) pylori

infection has been noted in 95% of those

afflicted with duodenal ulcers and 74% of

those afflicted with gastric ulcers (8).

Second, the H. pylori bacterium has been

hypothesized and in some cases

documented, to produce ulcers by

mechanical, immunologic, and cytotoxic

means (15-26). Third, H. pylori is readily

eliminated with common antibiotics.

Fourth, eradication of//, pylori infection

results in a dramatic and persistent reduction

in the recurrence rate of duodenal and

gastric ulcers. As a result, eradication ofH.

pylori is now a major part of the accepted

medical practice in the treatment of peptic

ulcers.

The purpose of this report is to present

evidence supporting the relaxation of the

former US Navy policy of disqualifying

submariners diagnosed with PUD. The

argument is based on recent advances in the

management of PUD, particularly the

eradication of//, pylori which has markedly

improved the prognosis of the disease by

minimizing its recurrence. Specifically, this

paper summarizes the current understanding

of the characteristics, demographics,

treatment, and prognosis of PUD associated

with H. pylori infection. It also addresses

the relevance ofthe dramatically reduced

rate of recurrence of//, py/on'-induced PUD

demonstrated in civilian populations to the

submarine community. Lastly, guidance for

the medical management (diagnosis,

treatment, and follow-up evaluation) of

submariners with PUD is presented with

clarification orjustification for each element

of the guidance. The ultimate result of

instituting the guidance is an increase in the
retention of career submariners and a

decrease in the associated retraining costs.

Peptic Ulcer Disease: Description and

etiology

A peptic ulcer is a circumscribed erosion

of the mucous membrane penetrating

through the mucosa and superficial stomach

musculature and occurs in areas exposed to

acid. The natural history of peptic ulcer

disease is one of chronicity and recurrence

and occurs more frequently in males. The

pathogenesis of ulcers has been radically reexamined with the discovery of//, pylori.

Previously an excess of acid and gastrin (the

hormone responsible for acid secretion)

were considered the cause of most duodenal

ulcers and the breakdown ofmucosal

defenses the cause for most gastric ulcers.

Other suspected causes included stress, diet,

medications, and endocrine diseases. More

rare etiologies for ulcer include cancers such

as lymphoma and sarcoma, with duodenal

ulcers generally being benign, and gastric

ulcer malignant (27).

Peptic Ulcer Disease: Symptoms and

Complications

Symptoms vary with the ulcer's location

and the patient's age; symptoms can be

atypical and minimal. Only about 50% of

patients present with the characteristic

pattern of symptoms. Typically ulcer is

associated with pain which is burning,

gnawing or aching in character but may also

be described as soreness, emptiness, or

hunger. Pain is generally steady, located in a

well-circumscribed area, usually epigastric,

and is relieved by antacids or milk. In those

with duodenal ulcer, typically the pattern of

pain tends to be relieved by food but recurs

two or three hours following a meal. The

symptoms of gastric ulcer follow a different

pattern and are generally unrelated to meals

and the pain may be caused by food and not

relieved by it.

The complications of peptic ulcer

disease include perforation (rare),

hemorrhage, which is found in up to 50% of

civilian ulcers (28), and obstruction of the

gastric outlet (occasionally found in gastric

ulcers). The percent of bleeding ulcers in

the submarine force has not been studied but

it will be assumed to approximate that of the

civilian literature. Except for bleeding, the

complications secondary to ulcers are

generally rare.

Peptic Ulcer Disease: Diagnosis

Diagnosis is suggested by the symptoms

and confirmed by the studies described

below. Endoscopy usually can establish the

diagnosis and is useful for a number of

reasons. First, it can detect shallow ulcers

missed by radiologic contrast studies such as

barium swallow. Second, the endoscope can

reach places that are difficult to visualize via

x-ray studies, such as the posterior stomach,

duodenum, and surgical anastomosis.

Lastly, endoscopy enables one to biopsy the

ulcer to look for cancer and to test for H.

pylori via the CLO test (a colorimetric test

that relies on pH changes induced by the

urease producing H. pylori) or culture.

However, even in experienced hands up to

10% of ulcers can be missed by endoscopy

(27). Barium studies, prior to endoscopy,

were used to diagnosed ulcers, but given the

high false negative rate and the exposure to

radiation, this test has since become

secondary (1, 27).

Peptic Ulcer Disease: Treatment

Treatment of gastric and duodenal

ulcers, prior to knowledge about H. pylori's

role, was aimed at neutralizing or decreasing

gastric acidity (even though gastric acidity is

usually normal). This was accomplished by

neutralizing acid with antacids, blocking the

secretion of acid with H2 receptor blocking

agents or proton pump inhibition agents, or

coating the stomach with a protective barrier
such as the medication sucralfate. Other

medications used were anticholinergics and

certain prostaglandins. Surgery is generally

reserved for intractable ulcers. Indications

for surgery include perforation, obstruction,

no response to medical therapy, major
hemorrhages, and malignancy. Figure 1 is

an accepted algorithm for the medical

treatment of dyspepsia or upper

gastrointestinal problems (14,29, 30). This

algorithm is a diagram of information found

in the consensus statement regarding the

medical treatment of peptic ulcer disease

drawn up by the Practice Committee of the

American College of Gastroenterology in

1996 and an article by Dr Barry Marshall

delineating the characteristics and

relationship of H. pylori to peptic ulcer

disease (14, 29).

In the past, anti-ulcer medications could

only partially interrupt the natural history of

ulcer disease (27). Prolonging treatment to

greater than two years on antisecretory

agents did not reduce the risk of relapse,

which was up to 95% for duodenal ulcers,

one year after stopping therapy. This led to

the following options: retreat relapses,

continue therapy indefinitely, or consider

surgery. New insight was required before

new treatment options could be explored and

tested.

Helicobacter pylori: Description

Until recently PUD was not attributed to

an infectious agent because the prevailing

dogma was that the stomach was sterile and

could not support bacteria. However, over

the last 100 years, various medical journals

have described an unidentified curved spiral

bacterium that could be found in the

stomach (31). The spiral bacterium was first

isolated from gastric acid in 1886 originally

was named Campylobacterpylori and has

since been renamed H. pylori (31, 32). In

the early 1980's Robin Warren at the Royal

Perth Hospital in Western Australia

discovered a spiral bacterium in the stomach

of various patients with gastritis (31). In

1981, he and Barry Marshall, also of the

Royal Perth Hospital, began a collaboration

to attempt to culture the organisms that were

found in gastric secretions (33). In 1982,

they began a prospective study of 100

patients undergoing endoscopy for gastric

complaints (31). They obtained biopsy

specimens for culture and staining and read

the pathology sections blinded to any

clinical details. The investigators

hypothesized that the spiral bacteria was

related to Campylobacter organisms (a spiral

bacteria found in food, the gut of pets, and

those with poor dental hygiene). Many

different culture media were tried and after

much trial and error, H. pylori was isolated

and cultured using a microaerophilic bloodbased medium (34, 35).

The bacterium survives in gastric acid by

breaking down urea and generating an

alkaline microenvironment for itself. H.

pylori attaches only to the mucous-secreting

gastric epithelial cells that line the stomach

and in this location occupy a microaerophilic, pH-neutral environment at the

junction between the mucosa and the lumen.

Its spiral nature and corkscrew-like motility

permit it to penetrate the mucous gel

overlying gastric epithelium and to set up

residence adjacent and adherent to gastric

epithelium. Technically speaking, the

organism does not invade the tissues. This

may explain why the bacterium is not

eradicated by normal immune responses

(31).

Helicobacterpylori: Etiology

After identifying H. pylori in the

stomach it was necessary to see if it was

causally related to PUD. Robert Koch, a

19th century German physician and

pioneering microbiologist, formulated the

universally accepted criteria that provided

proof that a specific bacterium caused a

disease (36). In order to prove that#. pylori

was the etiologic agent of human gastritis

and ulcer, Marshall et al (37), and Morris
and Nicholson (38) independently satisfied

Koch's four postulates:

1. The organism was known to be found

in humans with gastritis and duodenal ulcer

and was essentially absent in those without

disease.

2. H. pylori was isolated from

symptomatic patients and grown in pure

culture.

3. Ingestion of the organism was

associated with reproduction of the disease.

4. H. pylori was re-isolated from

subjects who had ingested the organism.

This work conclusively demonstrated that

there was an association between the disease

state known as peptic ulcer disease and the

bacterium Helicobacterpylori.

Helicobacter pylori: Pathogenicity

H. pylori pathogenicity has been

attributed to mechanical, immunologic, and

cytotoxic factors (15-26). The first step of

infection involves colonization of the gastric

mucosa. This is accomplished by specific

attachment of the organism to the human

host as well as a urease enzyme (an enzyme

which breaks down urea to ammonia) that

creates a hospitable microenvironment.

Once colonization has been established the

pathogen must avoid the host immune

response. This is accomplished by a

protective enzyme, a catalase, which breaks

down damaging reactive oxygen metabolites

such as hydrogen peroxide, Superoxide, and

radicals subsequently protecting the

organism from the immune systems

phagocytic activity. Direct damage to the

host may play a role. A phospholipase,

vacuolating cytotoxin, and protease may

supply nutrients to the organism by

damaging the epithelial cells thereby

increasing the solubility of mucous. These

and other putative virulence factors are

listed in Table 1.

Table 1. Factors that might enhance virulence and pathogenicity in H. pylori

Factor Comments/Action

Spiral shape Allows motility in mucous

Flagella Efficient motility in mucous

Specific attachment to phosphatidyl

ethanolamine, GM3 ganglioside Lewis B

antigens

Selective colonization of gastric, mucous-secreting, epithelial cells

Urease Survival in gastric environment, ammonia is toxic to epithelial cells in

some animal models

Phospholipase Digestion of epithelial cell membranes and mucous layer. Increased

moistening of mucosa.

Catalase Survival in gastric mucosa and possibly within phagocytic vacuole

(protection from H202)

Protease Digestion of epithelial cell membranes and mucous layer. Increased

solubility of mucous.

Vacuolating cytotoxin Damage to epithelial cells, perhaps allowing egress of nutrients from

submucosa

Low molecular weight chemo-attractant Attraction of neutrophils and mononuclear proteins cells that release

reactive oxygen species and interleukins
Helicobacter pylori: Relationship to Peptic

Ulcer Disease

Once H. pylori had been associated

causally with PUD an intense amount of

research then ensued that demonstrated the

reduction of ulcer recurrence with the

successful treatment (eradication) ofH.

pylori. Various researchers have

investigated the epidemiology and

relationship of the bacterium to

gastrointestinal disease (Table 2) (15-26,

31). Although H. pylori is prevalent in all

populations studied (Figures 2 and 3), only a

small proportion (1%) of infected persons

will develop an ulcer during their lifetime

(7,31). However, almost all duodenal

ulcers and the majority of gastric ulcers are

associated with H. pylori infection. H.

pylori infection has been noted in 95% of

those afflicted with duodenal (the first part

of the small intestine) ulcers and 74% of

those afflicted with gastric ulcers (8). The

proportion of gastric ulcer patients infected

with H. pylori increases to 96%, if those

with other recognized causes, i.e., those

associated with non-steroidal antiinflammatory drug (NSAID) use, or

gastrinoma (a rare tumor that secretes excess

amounts of the hormone gastrin, such

tumors frequently occur in the pancreas) are

excluded (9).

With the discovery of the link between

an infectious agent and PUD, antibiotics

entered the treatment armamentarium of

physicians with dramatic results. Repeated

studies (Table 2) have demonstrated that

eradication ofH. pylori infection in patients

with PUD results in a dramatic reduction of

the rate recurrence of duodenal, gastric, and

complicated ulcers (3, 8, 12, 39, 40, 41).

Graham et al. (3) demonstrated that

following H. pylori eradication there was a

lasting decrease in the recurrence of ulcers

in 109 patients up to two years after healing

of ulcers. Recurrence rates were 12% versus

95% for duodenal ulcer, and 13% versus

74% for gastric ulcer. Hentschel et al. (12)

demonstrated that among patients given both

antibiotic and antisecretory agents ulcer

recurrence occurred in 8% versus 86% for

those receiving antisecretory therapy alone.

Ulcers recurred in only 2% of those who had

H. pylori eradication versus 85% recurrence

in those who did not have H. pylori

eradication.

A study by Sung et al. (8) also supports

the above premise. Among patients given

antibiotics 92% had H. pylori eradication

and 85% had ulcer healing; in the group

receiving antisecretory therapy alone 13%

had H. pylori eradication and 73% had ulcer

healing. One year after treatment, 5% (1/22)

of the antibiotic treatment group had ulcer

recurrence versus 53% (12/23) of the

antisecretory treatment group. A recent

study by Van der Hülst et al. (41) in 141

patients with duodenal ulcers and 45 patients

with gastric ulcers demonstrated that

recurrence of PUD (excluding patients

taking aspirin or NSAIDs) is completely

prevented after successful H. pylori

eradication for up to 9.8 years. These results

demonstrated that the probability of

recurrence for patients receiving various

antibiotic therapies along with antisecretory

therapy was significantly lower than for

patients who received antisecretory therapy

alone.

Three prospective trials have examined

the effect of H. pylori eradication on ulcer

recurrence and H. pylori recrudescence.

Borody et al. (42) examined 94 patients with

documented H. pylori eradication and ulcer

healing four years following treatment. They

determined that only 2.2% were H. pylori

positive and that the effective re-infection

rate was 0.36% per patient per year. Labenz

et al. (39) determined that with successful H.

pylori eradication the one year ulcer
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Specifically in U.S.

- In age > SO years, > SO% have H. pylori.

- In minorities 40 - 50% have H. pylori.

- Immigrants Latinos > 60%

East Europeans > 50%

- Affluent whites «= 40 years, 20% have H. pylori.

- 25% of U.S. troops deployed outside the U.S. have H. pylori.

Figure 2. World wide prevalence of//, pylori

recurrence rate decreases from 68% to 1.1%

and the three year ulcerrecurrence rate

decreases from 91% to 3%. In this study of

190 people, the H. pylori re-infection rate

was 2.6% the first year, 1.2% the second

year, and 0% in the third and fourth year.

Overall the re-infection rate was 1.5%.

Forbes et al (43), in a prospective doubleblind trial found that 92% (32/35) previously

rendered H. pylori negative remained

negative after 7.1 years. Duodenal

ulceration was found in 20% (5/25) of

patients found H. pylori positive, compared

to 3% (1/38) of//, pylori negative patients.

The strongest argument supporting a

change in the disqualification policy toward

those with ulcers is the decreased risk of

gastrointestinal hemorrhage following peptic

ulcer disease healing and H. pylori

eradication. Peptic ulcers are the most

common cause of acute hemorrhage in the

upper gastrointestinal tract, accounting for

about 35% to 50% of cases (44, 45).

Recently, a review article by Jaspersen

examined the occurence of acute

gastrointestinal hemorrhage following H.

pylori treatment (44). He found a number of

studies that indicate a reduced risk of acute

gastrointestinal hemorrhage with successful

H. pylori eradication: Graham et al (46)

randomized 31 patients with upper

gastrointestinal bleeding ulcers and found

that after successful H. pylori eradication the

recurrence of bleeding was 0%. Labenz et al

30% of US. is H. pylori positive

1% of H. pylori positive develop

peptic ulcers

95% of those with Duodenal

ulcers have H. pylori

74% of those with gastric ulcers

have H. pylori

Figure 3. Relationship between H. pylori and Peptic

Ulcer Disease
Table 3. Methods of diagnosing H pylori (69-75)

Method Specimen SENS/SP

EC

95%/

Comments

Quick Biopsy/Serum Advantages: Performed in 10 minutes. Gives

Serology/ CLO 85% qualitative answer. Can exclude or confirm H. pylori.

test Disadvantages: Is a local test therefore if correct area

not biopsied may miss diagnosis; an invasive test

Quick saliva Saliva (detect 90%/ Same as quick serology

test IgG) 85%

ELISA tests Serum 95%/ Advantages: Provides a quantitative titer; is a true test

95% for urease producing organisms; appropriate for serial

measurements.

Disadvantages: Titer falls with variability (12-18 mo.).

Urease breath Breath sample 95-98% / Advantages: A global test of gastric mucosa;

test 95-98% noninvasive; independent of antibody titer; is a true test

for urease producing organisms; appropriate for serial

measurements. Disadvantages: More complex;

requires special instruments; I3C test is expensive, C

test uses radioisotopes; false negatives occur if test

performed close to antibiotic or antacid treatment.

Urease test of Mucosal biopsy 90-95% / Advantages: Simple; quick; inexpensive.

biopsy 98% Disadvantages: Invasive; not suited for serial testing.

Histology Mucosal biopsy 98%/ Advantages: Simple; quick; accurate; provides a

98% permanent record.

Disadvantages: Invasive; not suited for serial testing.

Culture Mucosal biopsy 90-95% / Advantages: 100% specific; mav guide antibiotic

100% therapv. Disadvantages: Invasive; not suited for serial

testing.

Culture of stool Stool sample 30-50% / Advantages: 100% specific; may guide antibiotic

100% therapy

Disadvantages: Low sensitivity

PCR Stool, gastric 95%/ Advantages: None presently.

juice, or 95% Disadvantages: Experimental; false positive reaction

mucosal sample limit use.
(47) prospectively followed 66 H. pyloripositive patients with upper gastrointestinal

bleeding ulcers and found after a median

period of 17 months that the rebleeding rate

was 0% with successful H. pylori

eradication. Studies by Rokkas et al (48)

and Jaspersen et al (28) reported similar

results. At the time of writing this review

there were no published articles indicating

that ulcer rebleeding following H. pylori

eradication is increased or demonstrates

significant recurrence.

No published studies have been

conducted regarding the epidemiology of H

pylori in the US submarine community,

however, two studies have examined H.

pylori in the military. In the first, a

prospective study conducted by

Hammermeister et al., (49) a statistically

significant increase in the prevalence of

antibodies (IgG and IgA) to H. pylori was

observed in German submariners (38.1%)

compared to controls (20%). Among the

assumed risk factors for submariners were

the crowded conditions and the limited

sanitary facilities in their small,

conventional boats. In the second, a

prospective study conducted by Hyams et

al., (50) a 25% H. pylori prevalence was

found in US Marine Corps personnel. This

prevalence was higher than expected for the

demographics of the study population and

indicate that deployed military personnel

may be at increased risk for//, pylori

infection.

Helicobacter pylori: Diagnosis

The finding of a causal relationship

between H. pylori emphasized the

importance of accurately diagnosing and

characterizing the organism. Numerous

validated methods to diagnose patients with

H. pylori are available (Table 3). The choice

of a test is a balance among the ease of use,

cost, accuracy, safety, and ease of obtaining

the sample to be tested - i.e. whether it is

invasive or non-invasive (51-57). The two

main categories are invasive procedures,

such as endoscopy, and noninvasive assays

such as the urea breath test and serology.

Invasive tests have been considered the

"gold standard", but because they are more

local than global they may be less accurate

due to the patchy nature of some H. pylori

infections (30). Additionally, endoscopy is

more time-consuming and less cost-efficient

than either the breath test or serology.

Table 3 summarizes the advantages and

disadvantages of the various non-invasive

tests for H. pylori. We propose that the

urease breath tests be used as they do not

rely on antibody titers (which are variable in

magnitude and may not reflect current

infection), do not require withdrawal of

blood, and can be performed serially. As

Table 3 shows, the CLO test, quick saliva

test, and ELISA tests have similar

advantages and disadvantages to each other.

The disadvantages as compared to the breath

tests are a higher risk of false negative and

false positive results.

We proposed that a non-invasive method

for annually following those with H. pylori

be considered as it is easier, less expensive,

safer, and can be shown to have similar

sensitivity and specificity as endoscopy (see

Table 3). The initial diagnosis should be

made by endoscopy as it has the advantages

of examining the anatomy, obtaining biopsy

specimens for H. pylori culture, and treating

active bleeding by cauterization.

Helicobacter pylori: Carbon Isotope Urea

Breath Test

H. pylori manages to survive in the

acidic environment of the stomach by

converting urea into bicarbonate and

ammonium to create its own alkaline "safe

10
zone." Clinicians can take advantage of this

reaction by having patients ingest urea

containing labeled carbon, an isotope of

carbon that can be detected with

instruments. In the presence of H. pylori

most of the labeled urea is metabolized to

produce labeled carbon dioxide while in the

absence of the bacteria most of the urea is

excreted intact in the urine (58). Therefore,

the presence of an appropriate amount of

labeled carbon in the carbon dioxide of a

patient's breath is indicative of//, pylori

infection.

There are two types of carbon isotopeurea breath tests. One of the urea breath

tests uses the 13C isotope (

13C-UBT). The

other test uses the unstable, radioactive 14C

isotope (

14

C-UBT). Both tests have been

studied extensively and have high reported

sensitivities and specificities (30, 59-69). It

should also be noted that results of both 13C

and 14C urea breath tests can be adversely

affected by proton pump inhibitors

(omeprazol), bismuth containing

medications (Pepto-Bismol), and antibiotics,

all of which can lead to false negative

outcomes. A post therapy time interval of

four weeks is necessary to allow for accurate

confirmation of//, pylori eradication (65,

69). False negative results can be caused by

administration of carafate (an anti-ulcer

medication) or prevastatin (cholesterol

lowering medication) within one week prior

to the test, antacids or H2 blockers within

twenty four hours prior to the test, and a

failure to fast for six hours prior to the test

(69).

The advantages of the 13C-UBT include

the use of a stable, nonradioactive isotope

and its ability to accurately quantify gastric

mucosal urease. However, because 13C

comprises only 1.1% of all carbon in nature

and because the ratio of 13C to 12C in the

expired breath varies with diet and exercise,

a relatively large dose of 13C-urea is

necessary to measurably increase' CO2

excretion. Ingestion of a test meal is

necessary to delay gastric emptying of the

labeled urea, allow time for the reaction to

proceed, and for the labeled carbon to be

absorbed by the digestive mucosa.

Additionally, the 13C-UBT requires the use

of an isotope ratio mass spectrometer to

determine the amount of labeled CO2

expired (65).

The 14C-UBT takes less time and costs

less to perform. Hydrolysis of 14C labeled

urea peaks 10 to 20 minutes after ingestion,

negating the necessity of a test meal and

producing results much sooner than if the

13C labeled urea is used (60). The main

drawback of using the 14C isotope is its

unstable, radioactive nature but this hazard

can be considered negligible except for

pregnant women and children. It should be

noted at this time that only the 13C urease

breath test has been approved by the Federal

Drug Administration.

Urease Breath Test: Sensitivity and

Specificity

Both the 13C and 14C labeled urea breath

tests have reported sensitivities and

specificities in the 90 to 100% range with

mean values of 96 and 97%, respectively

(30, 59). Such high values compare

extremely favorably with other tests used to

diagnose H. pylori infection including both

invasive and noninvasive tests (Table 3) (51-

57). Chronic inflammation and WarthinBarry staining of gastric antral biopsy

specimens are generally considered to be the

most accurate diagnostic methods but both

are invasive techniques that require more

time to perform and are much more costly

(30). The urea breath test, as well as IgG

and IgA serology tests, are noninvasive, less

costly, and less time consuming while

11
producing results that are not significantly

different from the more invasive tests.

Urease Breath Test: Radiation and safety

concerns

Proponents of the 13C urea breath test

have promoted its stable, nonradioactive

nature, even though it is more difficult and

more expensive than the 14C version. Most

of the safety concerns regarding the 14CUBT center around the long half life of the

radioactive isotope used. Because of this

long half life, the activity of the 14C isotope

is regarded as constant while present in the

body (58). Moreover, because 14C-urea does

not have a major route of entry into

metabolic pathways and is rapidly excreted

as either C02 in the breath or as unchanged

C-urea in the urine, this concern is of little

practical relevance (58, 60).

Despite the lack of a major entry point

into metabolic pathways, there is ample

evidence that a health concern is still

unjustified based on direct radiation

exposure. In the United Nations Scientific

Committee on the Effects of Atomic

Radiation 1988 Report, the global mean

effective dose equivalent an average person

receives from natural sources was reported

to be 240 mrem per year (70). The largest

calculated effective dose equivalent for the

l4C-UBT is 8 mrem or 1/30 that of the

amount of natural radiation received

annually (58). Therefore, the greatest

effective dose equivalent ever received from

14,

a X-UBT delivers the same amount of

radiation as would be received naturally in

twelve days. Another study found that two

days worth of natural radiation provides a

greater dose equivalent to bone marrow and

gonads than a

14C-UBT (58). It was also

found that a single upper GI X-ray series

delivers more radiation exposure to bone

marrow than 100 14C-urea breath tests (60).

It should also be noted that a normal person

carries 0.07 microCi of naturally occurring

4C within their body tissues which is the

equivalent of 1/14 of a

14C-urea breath test

(69). With all the supporting data, it is

reasonable to conclude that the few

diagnostic breath tests that one may receive

will not provide a significant exposure to

radiation.

Table 4 compares the radiation dose (in

mrem) of a 1 microCi l4C microdose given

to a H. pylori positive man to that of several

other common sources of radiation (60, 69).

As the table shows, a single microdose

(which uses a mere 1 microCi instead of the

usual 1 to 5 milliCi) of 14C-urea actually

provides less radiation than is absorbed by a

day's worth ofsunlight. It is also much less

hazardous than other commonly used

diagnostic tests such as the chest X-ray and

the upper GI series.

Urease Breath Test: Administration of'3CUBT

Prior to receiving the 13C-urea breath

Table 4. Radiation dose (in mrem) of 1 microCi of 14CQ2 urease compared to common sources of radiation

Chest X-rav Upper GI Tissue

Bone

lungs

Thyroid

marrow

Testes

1 Ci 14CQ2

0.22

0.01

0.24

0.32

0.24

4.0

61.5

3.0

<0.01

476.0

7.0

114.0

0.4

1 day Natural

0.35

0.35

0.35

0.35

0.35

12
test, patients undergo an overnight fast and

are then given a fatty or high carbohydrate

meal, such as pudding, to slow gastric

emptying. A baseline breath sample is taken

and the labeled urea is administered. A

typical dose is 125-150mg 13C-urea mixed

with water (30, 60, 66). A second breath

sample is taken sixty minutes after the C

ingestion and is analyzed by an isotope ratio

mass spectrometer. H. pylori infection is

indicated when the value of 13C for the

1 %

second exceeds the baseline C levels by

0.24% (30, 66).

Urease Breath Test: Administration of CUBT

Following an overnight fast, a mixture of

14C labeled urea and tap water is ingested by

the patient. The dosage of I4C used varies

from 1 to 5 milliCi depending on the source

(59, 60,71) but will be relatively small

regardless. Breath samples are taken at 0,

10, 20, and 30 minutes by exhaling through

a membrane containing straw into a

benzethonium chloride or methanol

containing vial. Results are assessed in a

scintillation beta counter and can either be

expressed as counts per minute (cpm) or

disintegrations per minute (dpm). If cpm are

used as the units then a mean value of

4398cpm (SD +/- 2468) per mmol of C02 is

expected in a sample taken 20 minutes after

ingestion in an H. pylori infected individual.

Conversely, those not infected by the

bacterium will have a mean value of 340cpm

(SD +/- 196) per mmol of C02 (60). If dpm

are used as the units then an increase of

200dpm or more over baseline values is

considered to be positive, an increase less

than lOOdpm is considered negative, and an

increase of 100 to 200dpm is considered

inconclusive and a second trial is

recommended (59, 67). Additionally, a

study conducted by German researchers

found that a

14C-UBT can be considered to

be positive if a patient exhales more than 2%

of the oral 14C test dose within 60 minutes

(72).

A relatively new method for

administering the 14C-UBT has been

developed and involves the ingestion of the

isotope in the form of a quickly dissolving

capsule. This technique protects the urea

from exposure to the bacterial flora of the

oropharynx and insures that hydrolysis of

the urea is due solely to the presence ofH.

pylori in the stomach. Therefore, the test

can be done with a microdose (1 microCi) of

the isotope and with a single breath sample

(67, 68).

To perform the microdose test, fasting

patients ingest a

14C-urea capsule with 20mL

of water. Ten minutes after administration,

the patients hold their breath for ten seconds

to insure adequate carbon dioxide content of

the sample and then blow through a straw

into a 2L aluminized balloon. One mmol of

carbon dioxide is removed from the balloon

and assayed for beta activity using a

scintillation counter (67).

It was suggested that the C-urea breath

test be used to diagnose and serially follow

H. pylori status in submariners for the

following reasons. First, it is currently the

only FDA approved urease breath test, and

second, it does not require ingestion of any

radioactive labeled urease. If the 14C-urease

breath test is FDA approved this desicion

can be re-evaluated.

Helicobacter pylori: Treatment

Currently there are a number of

recommended and highly effective drug

regimens available to treat H. pylori infected

people (1,14,73). Because drug resistance

evolves and drug regimens change a specific

antibiotic recommendation will not be made.

As long as the standard of care is followed

and the H. pylori infection is eradicated, the

specific medications used will be up to the

13
Table 5. FDA-Approved treatment options for Helicobacter pylori as of Sept. 1997 (73)

1. Omeprazole 40 mg QD and clarithromycin 500 mg TID for 2 weeks, then omeprazole 20

mg QD for 2 weeks.

2. Ranitidine bismuth citrate d(RBC) 400 mg BID and clarithromycin 500 mg TID for 2

weeks, then RBC 400 mg BID for 2 weeks.

3. Bismuth subsalicylate 525 mg QUD and metronidazole 250 mg QID and tetracycline* 500

mg QID for 2 weeks and H2 receptor antagonish therapy as directed for 4 weeks.

4. Lansoprazole 30 mg BID and amoxicillin 1 g BID and clarithromycin 500 mg BID for 2

weeks.

5. Lansoprazole 30 mg TID and amoxicillin 1 g TID for 2 weeks.

QD = once a day, BID = twice a day, TID = three times a day, QID = four times a day

*Although not FDA approved, amoxicillin has replaced tetracycline for patients in whom tetracycline is not

recommended. Tetracycline not for use in children < 12 years.

Table 6. Antibiotic doses

Bismuth

Subsalicylate

(B)

Tetracycline

(T)

Metronidazole

(M)

QID

Clarithromysin

(C)

BID or TID

Amoxicillin

(A)

Omeprazole

(O)

QID QID QID BID

2 Tablets 4x 500 mg 4x 250mg 4x 500mg 2x or 3x 500mg 4x 20mg 2x

daily with meals

and at bedtime

daily with meals

and at bedtime

daily with meals

and at bedtime

daily with meals daily with meals

and at bedtime

daily with

meals

BID = two times a day, TID = three times a day, QID = four times aa day,

Table 7. Drug combinations and Helicobacter pylori cure rates

Drug Combination (duration)

BMT (1 week)

BMT (2 weeks)

BMT and 0(1 week)

BMA (1 week)

BMA (2 weeks)

MOC(l week)

AOC (1 week)

MOA* (1-2 week)

95% Confidence Intervals

86 - 90%

88 - 90%

94 - 98%

75-81%

80 - 86%

87-91%

86-91%

77 - 83%

76

77, 78, 79

77

77

77

12, 55, 76

12,55

12,55

* amoxicillin lg 2 x daily

Adapted from Soil AH. Consensus Statement: Medical Treatment of Peptic Ulcer Disease, Practice Guidelines

JAMA 1996 275; 622-629.

14
discretion of the treating Undersea Medical

Officer or cognizant medical provider.

Though specific antibiotic regimens will

not be required certain principles should be

kept in mind (29). Therapy should not be

given unless the clinician has a positive

result for H. pylori. In fact, if a patient

presents with an H. pylori negative ulcer it

may indicate an unusual and possibly more

serious disorder such as the ZollingerEllison syndrome (52). Treatments longer

than 14 days have a higher likelyhood of

creating drug resistant bacteria and have not

been associated with higher success rates

(29). Longer and more complicated

treatment regimens tend to decrease

compliance. This has the effect of

increasing the likelihood of developing drug

resistance and treatment failures.

If therapy fails the same drug regimen

should not be used again. H. pylori

resistance to metronidazole and

clarithromycin develops readily therefore

these agents should not be used twice.

Following therapy, a four week antibiotic

and antisecretory free period should be

observed prior to any additional diagnostic

testing to confirm eradi-cation.

A treatment regimen will not be

recommended but a brief description of the

current FDA approved options can be found

in Table 5 (73). A summary of other

treatment options as described in the 1996

Consensus Statement for the Medical

Treatment of Peptic Ulcer Disease is

presented in Tables 6 and 7 (14, 74-77). A

comparison of the two tables should make

apparent why a standard treatment regimen

will not be required. As H. pylori develops

resistance and as new antibiotics are

developed it appears prudent to remain

flexible as to which therapy is used by the

clinician.

Conclusions:

The recent advances in understanding

the etiology of PUD and improved disease

management argued for relaxation of the US

Navy's disqualification policy. It is now

widely accepted that H. pylori infection is

the cause of the majority of PUD cases.

When H. pylori is eliminated with common

antibiotics, dramatic and persistent reduction

in ulcer recurrence rate and associated

complications occur. The low recurrence

rate of PUD following eradication ofH.

pylori increases the predictability of the

disease and strongly suggests that the

disqualification period can be significantly

shortened with minimal risk to either the

patient or submarine mission. It was

therefore proposed that submariners with

PUD be allowed to return to duty no less

than two months after successfully

completing treatment. Successful treatment

is determined by complete healing of all

lesions confirmed by endoscopy and

evidence of H. pylori eradication

demonstrated by negative culture or the 13C

urease breath test.

Appendix A is the Naval Submarine

Medical Research Laboratory's

recommended guidance for disposition of

submariners with peptic ulcer disease. This

recommendation was accepted and

distributed to the fleet as Appendix XVIII of

the COMSUBLANT/PAC INSTRUCTION

6000.2B CHANGE TRANSMITTAL TWO

dated 20OCT97.

In order to minimize the risks and

quantify the outcome of returning

submariners back to duty following ulcer

healing, a prospective study following those

submariners was suggested. A study

examining the prevalence of H. pylori in the

USN submarine force (currently being done

at the Naval Submarine Medical Research

15
Laboratory) would further clarify the PUD

risk factors a waivered submariner is

exposed to upon return to duty. By

accepting a change in the USN's policy

regarding PUD, an effort to maintain pace

with current medical treatment outcomes

was established.

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B, Keller JJ, Bruno MJ, Tijissen JG,

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20
APPENDIX A

NSMRL'S RECOMMENDED GUIDANCE

FOR DISPOSITION OF SUBMARINERS WITH PUD

The following section presents the new guidance for returning submariners back to duty

following PUD. The bold boxed print is the actual proposed element of the guidance and the text

following the box is commentary.

1. ESTABLISH DIAGNOSIS: Document diagnosis and infection by endoscopy with

biopsy/culture, or CLO test. Perform a

13C urease breath test,

The first step in any waiver process is to accurately diagnose and characterize the illness in

question. The standard of care for diagnosing and treating peptic ulcer disease is summarized in

figure 1 and table 3. (14,27,29,30). In order to positively diagnose PUD and assess whether the

subject is H. pylori positive an endoscopy is required. Endoscopy is very sensitive and specific

in diagnosing ulcers. Biopsy tissue for malignant ulcers and to culture for//, pylori (or for a

CLO test) is also accessible via endoscopy. As the sensitivity and specificity of tissue culture

and CLO test are both very high either is considered acceptable.

In order to prospectively follow the waivered submariners and determine ulcer recurrence rate

a recently FDA approved I3C urease breath test will be performed yearly. This test was chosen

because it can globally test for//, pylori in the stomach, is safe, easy to administer, and is noninvasive. The initial breath test will serve as a baseline for future reference.

2. ADMINISTER APPROPRIATE TREATMENT: Several acceptable regimens are

available and as studies continue and drug resistance's change, treatment

recommendations will evolve. Therefore, no specific regimen is prescribed. The

appropriate regimen will be at the discretion of the treating gastroenterologist and

consistent with current clinical guidelines.

Currently there are a number of recommended and highly effective drug regimens available

to treat H. pylori infected people (1, 14). Because drug resistance evolves and drug regimens

change, a specific antibiotic recommendation will not be made. As long as the standard of care is

followed and the H. pylori infection is eradicated, the specific medications used will be up to the

discretion of the treating Undersea Medical Officer or cognizant medical provider.
3

- VERIFY ERADICATION: A minimum of 4 weeks following completion of treatment,

document via repeat endoscopy (with either biopsy or CLO test) and urease breath test

both complete healing ofthe ulcer and eradication of the H. pylori infection. Serological

testing typically shows decreasing titers over several months in individuals who have been

successfully treated, but its variability precludes reliable determination of H. pylori

eradication.

To remain conservative and accurately verify ulcer healing and//, pylori eradication a repeat

endoscopy, biopsy and culture, and urease breath test will be performed. Most uncomplicated

ulcers (80%) heal in 4 to 8 weeks (2), therefore the minimum amount of time prior to

documenting ulcer and H. pylori cure should be 4 weeks.

Serum antibody titers are not useful because the decline following successful eradication is

slow, variable in magnitude, and not reliable (30,78). Therefore the urease breath test, which is

only positive when urease producing organisms reside in the gut, is required.

4. INITIAL DISPOSITION:

a. Individuals in whom infection is not eradicated or ulcer has not healed

1. Provide treatment as medically appropriate

2. Process for submarine duty disqualification

b. Individuals in whom infection is eradicated and ulcer has healed

1. Submit request for waiver. Waiver will be conditioned upon no recurrence of

ulcer and compliance with prescribed treatments and follow-ups.

2. Instruct the patient to avoid non-steroidal anti-inflammatory drug use unless

prescribed by a physician aware of his peptic ulcer disease history.

3. Instruct patient to promptly report any recurrence ofsymptoms to the medical

department representative and cognizant Undersea Medical Officer.

4. Follow-up annually with interval history, a urease breath test, and additional

examinations or tests as clinically indicated.

Four weeks following treatment for both the H. pylori organism and PUD, and after repeat

endoscopy and H. pylori testing has been performed, the submariners disposition must be

considered. For refractory ulcers (nonhealing of ulcer following three months of appropriate

therapy (1)), or organisms unable to be eradicated, the submariner remains in either a continued

disqualified state (refractory ulcer) or is a high risk for recurrence (continued//, pylori

infection). With either of these situations the submariner will be disqualified according to the

current guidelines (79). Currently he would be eligible for a waiver following a two year ulcerfree period.

If the ulcer and H. pylori is eradicated, a waiver must be submitted to COMSUBLANT or

COMSUBPAC and then forwarded to BUMED. As a condition of the waiver the subject must

be counseled to avoid indiscriminate use of non-steroidal anti-inflammatory agents that may
increase risk of developing ulcers in susceptible individuals. The submariner is to report any

peptic ulcer symptoms (hematemesis, gnawing epigastric pain, or symptoms similar to those with

the initial ulcer).

5. FOLLOW-UP; Successfully treated individuals require annual urease breath test and

evaluation by an Undersea Medical Officer with emphasis placed on identification of

symptom recurrence. A positive urease breath test does not necessarily require further

study but should prompt a thorough search for symptoms. Other diagnostic testing will be

performed as clinically indicated. Asymptomatic individuals do not require annual

endoscopy or imaging. Individuals with recurrent ulcer should be provided appropriated

treatment and processed for submarine disqualification. _____

Given the evidence that ulcer recurrence is associated with//, pylori re-infection it is prudent

to track those individuals shown by their history to be prone to developing an ulcer. In order to

track waivered individuals a mandatory annual follow up will be required. Asymptomatic

individuals will be required to have documented evidence of a symptom-free interim history,

absence of physical signs, and a negative H. pylori I3C urease breath test. Endoscopy and

imaging will not be required. Endoscopy is indicated in those individuals exhibiting or suspected

of having an ulcer. Disposition of submariners with positive H. pylori tests will be up to the

Undersea Medical Officer's discretion.

An annual follow-up test for H. pylori is indicated as the relationship between H. pylori reinfection and ulcer recurrence is presently unknown, the mode of transmission is undetermined at

this time, the prevalence of//, pylori in the USN submarine fleet is unknown, and there is a 1%

chance of those infected with H. pylori progressing to peptic ulcer disease. The l3C urease breath

test has been chosen as the annual test for H. pylori because it tests for the presence of active and

current infection with H. pylori. Serum tests, as previously mentioned, are variable in

magnitude and not reliable (30,78). Furthermore, serum antibody tests remain positive in the

face of//, pylori eradication because antibodies to the bacteria remain in the bloodstream.

6. NAVAL SUBMARINE MEDICAL RESEARCH LABORATORY STUDY:

The Naval Submarine Medical Research Laboratory (NSMRL) has designed a research

protocol to scientifically evaluate recurrence rate and risk factors among submariners who are

granted waivers for PUD caused by H. pylori which has been successfully eradicated. The

protocol parallels the procedure outlined above, but in no way is the individual to be given the

impression that the waiver is contingent on his consent to participate in the NSMRL study.

Participation in the study should be offered only after the individual has been granted a waiver.

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TITLE (Include Security Classification) A New Strategy to Address Loss of Submarine Qualifications in Submariners Who are Helicobacter

Pylori Positive and Diagnosed with Peptic Ulcer Disease: Background to the Change in Policy

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