Path. Res. Pract. 187, 226-234 (1991)

Chronic Active Gastritis after Eradication of Campylobacter (now: Helicobacter) pylori . Results of a Medium Term Follow-Up Study G. H. Ruhl Department of Pathology, Ruhr University, Bochum, FRG

G. Borsch Department of Medicine, St. Josefs-Hospital, Ruhr University, Bochum, FRG

SUMMARY 11 patients with c.p.-associated chronic gastritis underwent a triple therapy with bismuth-subsalicylate, amoxicillin susp. and metronidazole. The c.p.-status and the inflammation parameters "polymorphonuclear leucocytes in the epithelium ". "polymorphonuclear leucocytes in the lamina propria", "lympho-plasmacellular infiltrate in the lamina propria ", "congestion and edema of the lamina propria" and "inflammatory alteration of the epithelium" were determined semi-quantitatively in semi-thin-sections by light microscopy in the same sections. The c.p.-status was verified further by means of the CLG-test and cultures. The biopsy probes were taken before treatment, immediately after treatment, 1 month following treatment and in differing time intervalls up to 9 months following treatment. Eradication of c.p. could not be attained in 2 of the patients. Spherical forms and vibrioforms of c.p. exhibiting degenerative alterations could be demonstrated by electron microscopy. Throughout the study the inflammatory parameters "intraepithelial polymorphonuclear leucocytes", "polymorphonuclear leucocytes in the lamina propria ", "inflammatory alterations of the epithelium" showed concordance in their reactions. They were closely correlated with the light microscopical demonstration of c.p.-organisms in the biopsy specimens. The regression of the lympho-plasmacellular infiltrate was still incomplete after 5 months of eradication. The time relationship between the end of treatment and complete remission differed. The results of our studies suggest that c.p. was the sole etiological factor for the development of chronic active gastritis in at least 4 of the 11 patients.

Introduction The infection of the gastric mucosa with Campylobacter pylori is of great interest from a morphological and clinical standpoint, as it allows a causal therapy of chronic gastritis type B9,16. The pathogenicity of c.p. has been verified indirectly by various studies of its treatment 8 , 17, 19,25. Taking the first antibacterial treatment results into account much thought has been given to the adequate 0344-0338/91/0187-0226$3.50/0

treatment of gastic ulcer disease and c.p.-associated gastritis5, 17,20. Information regarding the necessity and success of therapy will be demanded from the pathologist. Knowledge about the behaviour of the individual criteria of inflammation in chronological relation to the beginning and end of therapy must be acquired. After previous studies with bismuth, antibiotic monoand combined therapy with bismuth and an antibiotic resulted in a varying and often unsatisfactory rate of ©

1991

by Gustav Fischer Verlag, Stuttgart

Eradication of Campylobacter pylori· 227 eradication-defined as a c.p.-negative status four weeks after therapy-, the possibilities of an antibiotic triple therapy were to be explored. A long- and short-term post-treatment follow-up biopsy control of the patients was strived for as only little knowledge exists of the rate of exogenic reinfection following successful eradication7,24. The determination of the date for control-biopsies in relation to the beginning and end of treatment results in a preselection of the morphological pictures a pathologist evaluates. The purpose of the following study was to register different light microscopical parameters of inflammation and attempt a correlation of the findings obtained at close time-intervalls between the treatment and post-treatment phase. Further aspects to be studied were the optimal moment for bioptic control from a morphological view and, taking our experience from a previous therapy study26 into account, the portrayal of c.p. in patients exhibiting recolonisation (recrudescence) following insufficient eradication.

Material and Methods The course of the study covered a 14-day antibiotic triple therapy (bismuth-subsalicylate tbl 3 X 600 mg per day 60 min preprandial, amoxicillin susp. 3 x 500 mg per day 60 min postprandial, metronidazole tbl 3 x 500 mg per day 60 min postprandial) as well as gastroscopic examinations including biopsy control immediately prior to treatment, immediately after treatment and 4 weeks following treatment. The patients included in the study suffered from gastro-duodenal ulcers or from non-ulcerative dyspepsia. The patients underwent endoscopy by the second author and were informed about the course of the study if their CLO-test proved positive. If the patients agreed to at least two repeat-gastroscopies they were accepted in the study. Patients were included in the study until it could be foreseen that at least 10 patients would complete the study protocol. 9 of the 11 patients volunteered over a period of 5 to 9 months for 1 to 4 further biopsy controls following the end of treatment in the actual study. In each of the gastroscopic sessions at least 8 probes were obtained from the antrum and corpus ventriculi. 2 probes from both the antrum and corpus were prepared for examination by the semi-thin-sectioning-technique and electron microscopy. 2 probes served for the CLO-test and bacterial culture. The probes were preserved in a phosphate buffered mixture (pH 7.4) of 2.5% glutaraldehyde and 1.5% formalin. The probes were fixed further in 2% osmic acid for 4 h, washed, contrasted in a saturated aqueous uranyl acetate solution, washed and embedded in Epon over propylen oxide. Semi-thin sections of the epon-embedded material were prepared and stained with methylene blue in basic fuchsin 21 • Ultra-thin sections were stained with uranyl acetate and lead citrate and examined under a transmission electron microscope (Zeiss EM 10). The method of double contrasting the specimen with saturated aqueous uranyl acetate solution both prior to embedding in Epon and following ultra-thin sectioning for five minutes each has been applied in our institute for the past few years and has been proven its own worth. The morphological detection of c.p. in the semi-thin-sections was carried out by means of oil-immersion. The findings were interpreted as" +" when the bacteria could be sufficiently reliably identified as c.p. by their typical spirilli- or vibrioform and their typical topographical relationship to the gastric mucosal epithelium. They were interpreted as "( + )" when bacteria were evident,

which, where not clearly identifiable as c.p. 5 morphological parameters of inflammation in the gastric mucosa were evaluated semiquantitatively and three-step-gradation was performed: 1) polymorphonuclear leucocytes in the epithelium, 2) polymorphonuclear leucocytes in the lamina propria, 3) lympho-plasmacellular infiltrate in the lamina propria, 4) congestion and edema of the lamina propria, 5) inflammatory alteration of the epithelium. The parameter "inflammatory alteration of the epithelium" was defined by the degree of nuclear swelling, the size and increase of the nucleoli, the increase in the rate of mitosis, the enlargement of the mitosis-zone and the depletion of mucin granula. The number of incomplete and complete erosions of the gastric epithelium and foveolar microabscesses were also registered. Shortly after finishing the clinical part of the study the study group "Gastroenterologic Pathology" of the German Association for Pathology drew up a new grading and classification of gastritis II. The degree of chronic inflammation was divided into 4 grades (minimal, slight, moderate and severe) and the activity into 3 grades (A I-A 3: A 1: slight activity, A 2: moderate activity, A 3: severe activity). For the purpose of comparability retrograde diagnosis of the individual findings according to the new classification was performed. The inflammatory process was considered "active" when the parameters 1,2 and 5 listed above were pathologically altered. The highest degree of gastritis activity, which was found in the gastric antrum of all the patients, was taken into consideration.

Results

Morphology of Chronic Active Gastritis The characteristic of active chronic gastritis is the inflammatory migration of leucocytes, especially polymorphonuclear granulocytes, through the epithelium: The heaviest inflammatory alterations arise in the gastric antrum. Here the transitional area (isthmus zone) between the mucous antral glands and the foveolae and the depth and middle of the foveolae are involved. Light microscopically there is inflammatory alteration of the epithelium with swelling of the cell nuclei; altogether there is a picture of slight anisonucleosis and apical swelling of the cytoplasm as well as simultaneous reduction of mucous production. If intraepithelial microabscesses arise, localized epithelial necrosis occurs. Direct contact of c.p. with lymphocytes and granulocytes is possible here. The rate of mitosis is increased in active gastritis, the regenerationzone is broadened. The Imypho-plasmacellular infiltrate in the lamina propria always includes polymorphonuclear granulocytes.

Eradication In 9 out of 11 patients eradication of c.p. for at least four weeks was achieved (Fig. 1). In two of the 11 patients endogenic recolonisation (recrudescence) occurred. One patient was false c.p.-positive after therapy by light microscopy and correct negative in the CLO-test and in culture. In two of the patients demonstrating endogenic recolonisation following therapy no bacteria could be observed in the semi-thin sections after therapy; however, the CLO-test and culture were positive. In these patients

228 . G. H. Ruhl and G. Borsch Table 1. Diagnosis in accordance with the German Gastritis Classification before and after treatment Age

Sex

First diagnosis

1

34

m

Severe chronic active gastritis 10 months (A 2)

c.p. -

2

47

Moderate chronic gastritis

1 month

C.p.

3

57

Severe chronic active gastritis (A2)

9 months

c.p. -

Slight chronic gastritis

4

68

Severe chronic active gastritis (A2)

9 months

c.p. -

Moderate chronic gastritis

5

59

f

Moderate chronic active gastritis (A 1)

9 months

c.p. -

Slight chronic gastritis

6

45

m

Moderate chronic active gastritis (A 1)

9 months

c.p. -

Minimal chronic gastritis

7

41

Moderate chronic active gastritis (A 1)

5 months

c.p.

8

50

m

Severe chronic active gastritis (A 1)

1 month

c.p. -

Moderate chronic gastritis

9

40

m

Severe chronic active gastritis (A3)

9 months

c.p. -

Slight chronic gastritis

10

49

m

Moderate chronic active gastritis (A 1)

9 months

c.p. -

Moderate chronic gastritis

11

20

m

Severe chronic active gastritis (A 1)

9 months

c.p. -

Moderate chronic gastritis

Pat. Nr.

Interval Last c.p.-status

c .•

+

Moderate chronic gastritis Slight chronic gastritis

Moderate chronic active gastritis (A 1)

//1

C.P. +

c .•.I')

+

Last diagnosis

1

-I

BloPIY I

1 BloPIY II

................ ....:;....... ,0'

,0'

" ,

,'

BloPIY III

Fig. 1. Morphological detection of c.p. before (biopsy I), after treatment (biopsy II) and 4 weeks following treatment (biopsy III).

Fig. 2. Patient displaying endogenic recolonisation (recrudescence). Biopsy immediately following end of treatment. Spherical bacteria ~ on mucous-producing epithelium (a, b). Vibrioforms exhibiting degenerative changes (c). Transmission electron micrograph. a) X 2500, b) X 50100, c) X 10400.

Eradication of Campylobacter pylori . 229

230 . G. H. Ruhl and G. Borsch

a

...

...

numerous

.

I

I

I

mOderate~'L_~ ......... __ ....... . _ _ 111111"11'"111"'_'..... _ ,

Biopsy II

Biopsy I

b

. ...,... ,. .. ,,.. . ,.'. ,.

marked

".....

moderate _ _~~

slight I none

I

Biopsy III

I

I

I ________

·

Last Biopsy

""

-i - - - - - - - -JI

__~:~:.::-

-'"

....

"""~"":":

-,

.:'": "':. :

~~~~-=:-~~~:~-~~:~~~-~:-~:~:~-:~-~~-~-~-~-~-~-~-~~~ ..................................... .................................... .

Biopsy I

Biopsy III

Biopsy II

Last Biopsy

I

c marked

.. . . . ..

moderate

slight! none Biopsy I

Biopsy II

Biopsy III

Last Biopsy

Fig. 3. a: Polymorphonuclear leucocytes in the epithelium before treatment (biopsy I), after treatment (biopsy II), 4 weeks following treatment (biopsy III) and to the end of follow-up (last biopsy). - b: Inflammatory alteration of the epithelium. - c: Lympho-plasmacellular infiltrate in the lamina propna.

Eradication of Campylobacter pylori· 231

we observed c.p.-organisms via electron microscopy; they did not, however, appear in the typical combination of longitudinal-, diagonal- and cross-sections seen before treatment, but mainly as sections of spherical "coccoid" bacteria alongside of vibrioforms displaying degenerative alterations (Fig. 2a-c). Of the 9 patients available for further bioptic controls 8 were free of c.p. In one of the patients exogenic reinfection occurred three months after the end of treatment, which was successfully treated with a new triple therapy. The other 7 patients were free of bacteria during all of the 9 months follow-up.

Gastritis Morphology Following Treatment 10 out of 11 patients had chronic active gastritis, which became dormant following treatment (Table 1). The most distinctive feature was a marked reduction, in most of the patients even the disappearance of the polymorphonuclear leucocytes from the epithelium (Fig. 3a). The polymorphonuclear leucocytes in the inflammatory infiltrate of the

lamina propria reacted accordingly. In 9 out of 10 patients the change in activity occurred during therapy, as was demonstrated by a second bioptic examination immediately following therapy. The parameter "inflammatory alteration of the epithelium" was closely connected to the parameter "intraepithelial polymorphonuclear leucocytes" (Fig. 3 b). One successfully treated patient exhibited lymphocytic gastritis following treatment. The lymphoplasmacellular infiltrate in the lamina propria showed a reduction by at least one grade in 8 out of the 9 patients eradicated of c.p. (Fig. 3c). In contrast to the polymorphonuclear infiltrate its regression was very slow and variable in relation to the end of treatment, occurring in some of the patients not before several months following the end of treatment. 9 months following treatment, 4 of the 8 patients available for further follow-up - in one case following renewed triple therapy after exogenic reinfection - exhibited only a residual state of gastritis with a minimal to slight round cell infiltrate (Fig. 4, Table 1). The parameter "congestion and edema of the lamina propria"

Fig. 4. Patient Nr. 3. - a: Before treatment - severe chronic active gastritis (A 2). - b: Immediately following treatment - moderate chronic gastritis.

232 . G. H. Riihl and G. Borsch

Fig. 4. Patient Nr. 3. - c: 4 weeks following treatment - slight chronic gastritis. - d: 9 months following treatment - slight chronic gastritis. Semi-thin sections, methylene blue - basic fuchsin, X 125.

improved in 5 of the 8 patients under continued observation. A correlation of this parameter with other parameters of inflammation did not become evident. Discussion The present study is an independent morphological constituent of a larger, more clinically orientated therapy study involving 105 patients 6 . The rate of eradication of 82% reached (defined as a c.p.-negative status 4 weeks following the end of treatment) is in keeping with the rate of eradication reached in the total study (841105, 80%). The rate of eradication is thus considerably higher than the rate following a monotherapy or a combination therapy including bismuth and an antibiotic3, 4, 19, 30. A higher rate of eradication of 94 % was reached by Borody and Carrick, in 1988 7 . The course of the study has shown that a persistent eradication of c.p. and a decrease in the activity of gastritis up to a complete cure is principly possible.

These observations can be interpreted as evidence for the pathogenicity of Campylobacter pylori. The improvements in the findings were found in the C.p.-free patients during the total observation period. Avariable regression behaviour of the granulocytic infiltrate on the one hand and the lympho-plasmacellular infiltrate on the other hand became obvious. A reduction of the neutrophilic granulocytic infiltrate already occurs during treatment. If the patient is eradicated of c.p. the regression of the granulocytic infiltrate is complete by the end of treatment. This immediate effect of therapy has already been described by others 17,25. It can easily be verified by applying the chloroacetate esterase reaction 12 • The lympho-plasmacellular infiltrate in the lamina propria does not follow this set pattern. Its regression is rather a continual process and in some patients is not even completed after 4 months. The results correspond with the report of Marshall et al. 17 , who performed biopsy controlls 2 weeks and 8 weeks following successful treatment. They found complete absence of polymorphonuclear granulocytes within 2 weeks follow-

Eradication of Campylobacter pylori . 233

ing the end of treatment and a gradual reduction of the score for mononuclear cells even 8 weeks after the end of treatment. In this respect control biopsies in the posttherapeutic phase can only represent selective moments of a perpetual process. In 4 patients only a residual state of gastritis with a minimal to slight round cell infiltrate in the lamina propria could be found in the last bioptic control. This allows the conclusion that c.p. probably was the only etiologic factor causing the gastritis type B and that the lympho-plasmacellular infiltrate is an indicator for cellmediated immunity in the case of T-lymphocytes and for humoral immunity in the case of B-lymphocytes and plasma cells. The morphological picture in these patients is equivalent to the mucosa-status as it was depicted by Rauws et al. 1988 25 . We would not go so far as to refer to this state as a normal mucosa. We agree with Steininger and Becker 1988, who call for an "almost complete freedom of inflammatory cells" in the gastric mucosa to allow the designation "normal" 31. This view is also expressed in the German classification of gastritisll. Naturally there is only little knowledge regarding the rate of exogenic reinfection per patient and year following successful eradication. The results of the total therapy study involving patients obtained so far let a reinfection rate of 10% appear reasonable. According therapeutic experiences have been reported by other study groupsI8,24. Following bismuth therapy, antibiotic mono-therapy, or a combination of bismuth with an antibiotic, quick reinfection within 2 to 4 week often occurs 4, 26. In the vast majority of patients this is probably due to endogenic recolonisation (recrudescence) of the mucosa following incomplete eradication and only infrequently due to a quick exogenic reinfection. Therapy studies in which only one control was performed immediately following the end of treatment are thus not capable of a valid statement regarding the true rate of c.p.-eradication 1,8,13,19. Interestingly, c.p. can undergo metamorphosis in adverse environments. We observed this phenomenon for the first time light microscopically in the course of therapy study involving bismuth and a cephalosporin 26 . In 4 out of 10 patients, all of whom demonstrated a typical C.p.-flora with vibrio- and spirilliform bacteria prior to treatment, bacteria could be found by light microscopy immediately following therapy. Now, however, short rods and spherical bacteria in reduced numbers could be demonstrated, whereas only few spirilliform bacteria could be found. 4 weeks following therapy a typical C.p.-flora was restituted. Obviously a selection of the mentioned C.p.-forms or a metamorphosis of the spirilliform and vibrioform organisms had occurred under antibacterial therapy. In the present study "coccoid" bacteria alongside of vibrioform organisms displaying degenerative alterations could be found immediately following treatment by electron microscopy in 2 patients exhibiting endogenic recolonisation. It is naturally difficult to draw conclusions as to the three-dimensional form of bacteria from a two-dimensional electron micrograph. It is, however, to be expected that a solely therapeutically - induced reduction in the number of bacteria should not change the ratio of longitudinal-, diagonal- and cross sections of the bacteria. Coccoid

C.p.-forms can be induced by lack of organic substrate2, 15. We consider it possible that these milieu-adapted organisms play a role in endogenic reinfection (recrudescence). Much thought from several sides has been given to the formal pathogenesis of c.p.-gastritis and hypotheses have been proposed, which have in part arisen from a more biochemical, in part from a more morphological standpoint lO,23,28,29. From a morphological view Schiifer discusses the following forms of injury to the gastric epithelium: 1) A lesion of the surface epithelium by direct contact with the bacteria, e.g. by opening of the junctional complexes. 2) An autophagolysosymal degeneration of parietal cells and 3) a leucocytoclastic reaction in the epithelium in the course of the chronic active inflammation29 . Naturally the autophagolysosymal degeneration of parietal cells can only serve as a model for injury of the mucosa of the corpus region and does not explain the inflammatory alteration of the antral zone. We have found an opening of the junctional complexes only in the immediate surroundings of epithelial necroses and erosions (publication in preparation). A direct toxic influence of c.p. e.g. via humoral factors seems to be possible by means of a lively exo- and endocytosis activity. We consider the epithelial leucocytoclastic reaction for a further important mechanism of injury in c.p.-gastritis. This is indicated by the close correlation between the parameters of "inflammatory alteration of the epithelium" and the presence of polymorphonuclear granulocytes in the epithelium and the lamina propria. The mechanisms leading to a variably intense granulocytic reaction towards the C.p.-colonisation of the gastric mucosa are still not clear. It is true that according to studies by Stolte et al.3 3 and Steininger et al.3 2 the inflammatory activity in the antrum zone correlates significantly with the intensity of bacterial colonisation. Questions remain open regarding the group of patients displaying a dormant form of gastritis type B although they may exhibit a high degree of bacterial colonisation 14,22,27. Further studies, e.g. follow-up studies, but also studies regarding the chemotactic processes involved are essential.

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18 Marshall B], Goodwin CS, Warren ]R, Murray R, Blincow E, Blackbourn S, Phillips M, Waters T, Sanderson C (1987) Long term healing of gastritis and low duodenal ulcer relapse after eradication of Campylobacter pylori dis. A prospective doupleblind study (abstract). Gastroenterology 92: 1518 19 McNulty CAM, Gearty JC, Crump B, Davis M, Donovan lA, Meliakian V, Lister DM, Wise R (1986) Campylobacter pyloridis and associated gastritis: investigator blind, placebo controlled trial of bismuth salicylate and erythromycin ethylsuccinate. Br Med] (Clin Res) 293: 645-649 20 McNulty CAM: The treatment of campylobacter-associated gastritis. Am J Gastroenterol 82: 245-247 21 Morgenroth K jr, Schroder CHR, Themann H (1977) Doppelfarbung von Semidiinnschnitten mit basischen Farbstoffen. Mikroskopie 26: 260-263 22 Niedobitek F, Grosse G, Taube F, Volkheimer G, Fehrenbach FJ, Werner E (1987) Untersuchungen zur Frage der bakteriellen Besiedlung der Magenschleimhaut. Z. Gastroenterol 25: 98-106 23 Rathbone BJ, Wytt JI, Heatley RV (1988) Possible pathogenetic pathways of Campylobacter pylori in gastro-duodenal disease. Scand J Gastroenterol 23 (suppl 142) 40-43 24 Rauws EAJ, Langenberg W, Houthoff HJ, Tytgat GNJ (1989) Longterm follow-up of C. pylori-associated gastritis after treatment with colloidal bismuth sub citrate and/or amoxicillin. In: Megraud F, Lamouliatte H (Eds.) Gastroduodenal pathology and Campylobacter pylori, 633-636. Elsevier Science Publishers B.V., Amsterdam 25 Rauws EA, Langeberg W, Houthoff HJ, Zanen HC, Tytgat GNJ (1988) Campylobacter pyloridis-associated chronic active antral gastritis. Gastroenterology 94: 33-40 26 Riihl GH, Borsch G, Hackenberg K, Philippou S (1988) Campylobacter pylori-Infektion der Magenschleimhaut. Diagnostik, Morphologie, Therapieeffekte. Berichte Pathologie 107: 443-444 27 Riihl GH, Morgenroth K (1988) Campylobacter pylori Stand des Wissens aus morphologischer Sicht. Leber-MagenDarm 18: 17-28 28 Sarosiek J, Slomiany A, Slomiany BL (1988) Evidence for weakening of gastric mucus integrity by Campylobacter pylori. Scand J Gastroenterol 23: 585-590 29 Schaefer H (1987) Feinstrukturelle Untersuchungen zur Campylobacter pyloridis-Gastritis. Ver Dtsch Ges Path 71: 358 30 Schaub N, Stalder H, Stalder GA, Affolder H, Wegmann W (1987) Versagen von Doxycyclin bei Campylobacter-pyloripositiver Gastritis. DMW: 112: 117-118 31 Steininger H, Becker V (1987) Phanomenologie der chronischen Gastritis. Z. Gastroenterologie 25 (suppI4): 1-10 32 Steininger H, Schneider U, Bartz K, Simmler B (1989) Campylobacter pylori und Gastritis - Besiedlungsdichte und Grad der Entziindung. Semiquantitative und morphologische Untersuchung. Leber-Magen-Darm 2: 70-78 33 Stolte M, Eidt S, Ritter M, Bethke B (1989) Campylobacter pylori und Gastritis. Assoziation oder Induktion. Pathologe 10: 21-26

Received December 27, 1989 . Accepted in revised form August 8, 1990

Key words: Campylobaeter pylori - Helieobaeter pylori - Gastritis - Eradication

Dr. Georg H. Riihl, Institut fiir Pathologie, Ruhr-Universitat, UniversitatsstraRe 150, D-4630 Bochum, FRG