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Colitis caused by Escherichia coli 0157:H7:

A study of six cases

LB E1nus. MD, FRCPC , M G UIN[)! , MD, J DROUIN, MD, FRC PC, S GREGOIRE, MD, FRC PC, JR BARR, M B, C HB

ABSTRACT: The clinical and pathologic features of six pa tients with proven vcrotoxin-producing Escherichia coli colitis are described . C lin ical data, 25 biopsy ~recunens and two autopsies from these patien ts are reviewed. A ll presented with crnmpy abdomina l pain and bloody d iarrhea. Colonoscopic find ings included eJema, erythema, pseudomembranes and hemorrhage. O n hiopsy, two patients had ischemic colitis, one had pseudomembranous colitis and th ree had a com-1'ination of concurrent ischemic and pseudomem branous colitis. Four cases showed fibrin-platelet thrombi in mucosa! capillaries and submucosal a rte rio les. The classical patte rn of infect ious colit is was no t seen in these cases. Other niimpecific changes inc lud ed patchy mucosa! e<lema, congest ion, focally rrominent interstitial hemorrhage and mild, patch y increase of the lymphoplas­mocytic component of the lamina. Ischemic necrosis was present in 10 of 25 biopsies (40% ), pseudomembranes in seven of 25 biopsies (28%), and four of25 riopsies (1 6%) showed both. Colon from one aut0psy revealed edema, pseudo ­membranes and intramura l infarc tio n . Concurrent thro mbotic thro mbo­cytopenic purpura was clinically documented in three of six patients. It is concluded that, in the context of hemorrhagic colitis, the following observations are indicative of E coli Ol 57:H7: the combination of pseudomcmbranous and 1schemic colitis; ischemic colitis in a yo ung pat ient; or pseudo membranous colit is with Closcridium difficile-negative culture and toxin. Multiple biopsies are re­yuired to demonstrate the full-blown features. E coli 0 157:H 7 colit is should he aJJed to the differen tial diagnosis of submucosal edema. Can J Gastroenterol 1990;4(4): 141-146 (pour resume, voir page 142)

Key Words: E col i O 157: H 7, lschemic colitis, Pseudomembranous colitis, Verocoxin

University of Ouawa, Oc/)(lrtmenL~ of Pachology and Internal Medicine, Occawa General Hosp1cal; and Department of Paiholoi.,ry . Oua~,a Civic Hos/Jiwl , Ottawa, Ontario

Correspondence and reprmrs: Dr Leslie B Eidus , De/Jartmen1 of Pathology. Onawa General Hospiwl, 501 Smyth Road , Onawa , Ontario KI l-1 8L6

ThL1 paper was presented m pare ar the Canadian Con,1rress of Laboracory Mt!d1cine, Ottawa, Omario, June 1989

Received for publicatwn Ocwber 5, 1989. Accc/ncd December I 2. 1989

CAN J GASmOENTER()L VOL 4 No 4 M AY/JUNE 1990

v:EROTOX!N-PRODl.X::TNG ESC/ !ERIC/ /IA coli O 157:117 i~ an important cau~e

of hemorrhagic colitis which is he ing diagnosc<l with increasing frequency ( l ). The w mpl1cat ions a rc potent ially life th rea tenin g: hemo lyri v ure mtc syndrom e is we ll documented , and , more recently, th rombotic thrombo­cywpenic purpura has been observed (2-4 ).

The i<lenrifi cation of diagno~t ic pa t h n lo g1ca l les io ns t hat suggest verotoxin-produc ing E coli in fec tion is important hecause clin ical markers of the disease may be negarive or inap­parent. For instance, in the adu lt age group, hacteria arc shed in the ~tool only for a few Jays to a week after onset o f sy mp toms (4,5) . T h e assay fo r veroto xm is positive for only a few ad­dit ional days, and i~ not available in man y te rtiary care hospitals. Thus, de lay by the pat ient in seeking me<l ical attention, or by cl inicians in ohta ining stool for culture, reduces the likelihood of isolating the organism. Thrombotic t hrombocytopen ic purpura may dominate the clinical p icture to the ex­tent tha t co lit is is overlooked a l­together (4).

The authors previously reported two

141

E1nus et al

Colite causee par Escherichia coli 0157:H?: Etude de six cas

RESUME: L'etude Jccrit les manifestations clini4ues et pathologiques Je six patients atteints Jc colite a Escherichia coli pro<luisant <les vermoxincs. Les donnees cliniqucs, 2 5 prelevcmcnts biopsiques ct dcux autopsies sont passes en revue.Tousles sujets prescntaient Jes doulcurs abdominalcs a type de crampcs et Jes <liarrhces sanglantcs. La colonoscopie a rcvele de l'oedemc, <le l'erytbcmc, des pseudomcmbrancs ct des hemorragics intcstinales. D'apres les biopsies, Jeux patients souffraient de colitc ischcmique; un, de colitc pseuJomembrnneusc; ct trois, d'unc combinaison de colite ischemique et pscu<lomembraneuse. Quatre cas montraient des thrombi fibrinoplaquertaires Jans lcs capil laircs de la mu­queusc ct les arterioles de la sousmuqueusc. Aucun des cas nc prescntait la morphologie classiquc de la colitc infectieuse. Parmi les aurrcs changements non specifiques figurcnt l'oedcme disscminc de la muqucuse, la congestion, l'hemorragic interstitielle en foyers, er l'infilrration moderce et en aires de la lamina par Jes plasmocytes et des lymphocytes. Une necrose ischemiquc ctait prescntc Jans d1x des 25 biopsies ( 40%); Jes pseudomembrancs, Jans sept cas sur 25 (28%); ct les dcux phcnomencs ecaient manifesres dans quatre des 2 5 hiopsies (16%). Le colon d'un sujet autopsie a rcvele LIO oe<lemc, Jes pseu<lomembrnncs et unc infection intramurale. Un purpura thromhocytopcnique thrombotique a ete cliniquement confirme chez trois patients sur six. On conclut quc, dans le contexte de la colite hemorragique, les observations suivantcs in<liquent la presence d'E coli Ol 57:H7: une colite pseudomcmbraneuse ct ischemiquc combinec; unc colitc ischemiquc chcz un jcunc patient; ou une colite pseudo­membrancuse accompagnee d'unc culture negative de Clostridium difficile ct de toxine. De multiples biopsies sont necessaires pour reveler toutes lcs caracteristiques <le cette affection. E coli 0157:H? Jcvrnit figurer au diagnostic d1ffcrcntiel de l'oedeme de la sousmuqueuse.

cases of E coli 0 157: H7 colitis compli ­cated by thrombotic thrombncytopenic rurpura anJ briefly described the un­usual finding of simultnneous ischcmic and pscu<lomcmhranous colit is (3). In the present rcpon, several pathological alteratiom arc described, which, in comhination, strongly suggeM the diag­nosis of verotoxin-producing E coli.

PATIENTS AND METHODS Sixteen patients wnh positi ve Moo!

cultures for E coli 0157: 11 7 were iden­tified from the records of the microbiol­ogy labora tories of two teaching hospitals over a r eriod of one-and-a­half years. Six of these patients had a total of 25 colonic biopsies. T wn of the s ix patients died and the autopsy material was reviewed. The biopsies were seria lly sect ioned and stamed with hematoxylin and cosin. C linica l fea­tures, abdominal x-rnys, and endo­scopic findings of these six patients were reviewed.

RESULTS Clinical features: All six patients pre­sented with a one to five day history of

crampy abdominal pain, blnody diar­rhea, nau~ea ,md vomiting. There was no history of travel outside of Canada. Two patients received a few doses of c rythromycin. Four of the ca~cs were sporadic. In the o ther two cases, a milder, self- limited form of diarrhea de­veloped in other family members and soc ial contacts. Three patients de­veloped thrombotic thmmbocycopcnic purpura (as defined by the presence of thmmbocyropenia, microangiopathic hemolytic anemia, fever, normal pro­th rombin and partial rhromboplastin times, normc1I fibrinogen levels, and de­clining neurological and rena l func­tions). Dilated, edematous small and large howel ( with occasional thumb­printing) were seen on standard a bdomi­nal x- rays (Figure I) . C olonoscopy showed erythema , edema and hemor­rhage in all six patients and pseudo­membranes in two (Figure 2). There was pancolitis in on e patient with predominance on the right side. O nly the left colon was visua lized in the remaining five paticms. However, bleed­ing above rhc level of the colonoscope was repo rted int woof these fi ve patients.

Pathological findings: The hi ,ro­patholngical find ings arc shown in Fig­ure 3. Pscu<lomcmbranous coli tis wa, diagnosed whe n the type 2 lesion desc ribed by Price and Davies (6) wa, identified (Figure 3h) . This as well ,h

the other histological types I and~ were nmed in fourpmients. Mucosa! biopsic, in five patients revealed isc hem1c colitis defined ns va riable depth of coagulative necrosis, with or without type 3 pscudnmembranes (Figure k). In three pallcnts pseudomemhranou, colitis was seen concurrently with is­chemic coliti s. Pse u<lo mem bran nu, w litb and ischemic co lit is were present in seven of 25 (28%) and 10 of 25 (40%) biopsies, respective ly. The two processes occurred cont igunusly m four of 25 ( 16%) b1ops1es.

Platelet-fibrin rhromhi were visual· ized in the hinpsie., of four patient-. Patchy, sometimes prominent, mrcr stitial hcmorrhagt' and edema of rhe lamina was prcscm in a ll parienrs.

Ncut rophiliL infi lt ration of gland and lamina was not a feature of the biopsies, and only the rare microfocu, could be identified. The lymphopla,­mocytic component of the lamina was only foca lly and mildly increased . Sub­mucosa was included in two bior sies from the same patient and was markedly edematous.

Two patient~ died; both were elderly and both cases were complicated hy thrombotic rhromhocytopenic purpura. At autopsy, the colon of one patient showed o nly ede ma and petechial hemorrhages. The second patient died fo llowing central ne rvous system com­pl icatiom of thrombo ti c thrombo­cytopenic purpura. In this case, the colon sh owed extensive ischcmic necrosis with focal pseu<lomcmhrane formation (Figure 4 ).

DISCUSSION The sa I ient pathologic changes seen

in these six cases of E coli Ol 57:H7 infection were ischcmic col it is and all three morphological types of pseudo· membra nou s co liti s. Half of the patients h ad the unusual finding of simultaneous pseudomembranous and ischemic colitis. None of the biopsies showed the feature~ of infec tious colitis.

142 CAN J GAt,TRt)ENTEROL Vm 4 No 4 MAY/JUNE 1990

Figure 1) Abdominal x-ray showing tlnnnb/)nnting ( aiww) in the asceruling colon

fil(llre 2) Colonic endoscopy showing submucosal edema (Za) and /)seudumembranes, erythema an;/ hemorrhage ( 2 b)

Since ischemic colitis was iJcnrificd in only 10 of 2 5 biopsies anJ pseudo­membranous colitis in only seven of 25, 1r is evident that muluple samples arc necessary for demonstralion of lhe lesions and for aJequale evalumion of rhe colonic mucosa.

Concurrenl bowel infarction and pscudomembranc formatinn have been Jescnbed in a subset of ischemic bowel disease under Jiagnostic terms such as nonocclusive inteslinal ischemia and

pscudomcmhranous entcmcolilis. They occur a~ complications of various con­ditions such a~ shock, postoperative states and heart failure (6-9). ln con­trast with E coli 0157:1-17 colilis, small bowel involvement is common and the prognosb is poor. On ncca~ion, pseuJo­membrane~ can abo be seen associated wnh ischemic colitis in mesenteric artery occlusion. Usually only type 3 pscudomembranes, and not the full spectrum of types l to 3, are present in

CAN J GASTROENTl:RL)L Vm 4 No 4 MAY/JUNE 1990

E co/i0157:H7 colitis

occlusive ischemic colitis (8). In con­w1st, mucosa! hemorrhagic necrosis of the type seen in ischcmic bowel disease, as well as intramural and transmural infarction, arc not a feature of anti­biotic-associated pseudomem hranous colitis. Thus, in the context of hemor­rhagic coli tis, the simultaneous occur­rence of pscudnmembranous colitis and ischcmic colitis seems to be a distinc­tive finding of E coli Ol 57:H7 coli tb.

The clin ical prcsentntton m many previously reported cases of E coli 01 57:H7, as well as in the present stu<ly, suggested ischcmic rather than infec­tious colitis (1,3,4). Three of the present six patiems were under 50 years of age, anti mucosa! ischemia was a component of the hisropmholngy in five cases. lschcmic colitis is unusual in young patients. Thus, its presence in young patients would also suggest a diagnosis of£ coli 0157:l 17. Conversely, the possibility of an infectious etiology may be overlooked in the e lderly patient presenting clinically with is­chemic colitis.

A hiopsy showing pseuJo­membranous or pscudomembranous and 1schemic colitis may he the only clue ro E coli Ol 57:117 colitis. The tliag­nosis of E coli Ol57:Il7 is suggested in any patient with biopsies showing pseu­domem branous colitis but nega1 ive Clostridium difficile cultures or toxin.

Other pathological findings seen raJiologicall y and/or cntloscopically may also be helpful in pointing to the diagnosis of E coli Ol 57:I 17 . The dif­ferential diagnosis ofsuhmucosal edema of the colon b essentially limited to inflammatory bowel disease (particular­ly Cmhn 's disease), ischemic colitis, and pseudomembranous colitis. Since the basic pathology of E coli Ol57:H7 coli tis was that of ischemic, pscudo­membranous, or pseudomemhranous and ischemic colitis, it is not ~urprising t hat subrnucosal edema was also present. Other colonic lesions as­soci<1ted with 1~chem1c colitis were also found in the prescm study: focal inter­stitial hemmrhage (six cases) anJ small vessel fibrin-platelet thrombi (four cases). The rare section showed capil­lary thrombi in otherwise normal mucosa.

14}

EJL)US et al

3a

3e

3d

Figure 3) Colonic bio/Jsies . 3a Segment of colonic mucosa where pseudomembranous colitis ( long arrow) is continuous wi1h ischemic co/iris ( short arrow). 3b On higher magnification, the pseuclomembranous component is formed of rhe typical 'fire cracker' lesions and streaming exudate . 3c There is full thickness infarction of the mucosa in 1he ischemic />orrion of the biopsy with thrombi in submucosal vessels and mucosa! capillaries (arrows). 3d Several biopsies show a lesser degree of 1schemia identified only by aitenuation of the superficial portion of a few glands (arrows). 3e Microf oci of superficial hemorrhages are common and result from rupture of large, di/aced mucosa/ capillaries ( short arrows ouiline capillary, long arrow the dismpiion)

T he colonic patho logy obse rved here has been reported to a limited ex­tent in the literature. One case reported by Morrison et al (2) was associated with pseudomembranes identified his-

144

rologically but not recognized on endo­scopy. Richardson et al ( LO) described three cases of E coli 0157:H7 colitis complicated by he mo lytic-urem ic syndrome in the pediatric age group.

Pse udome mbran e fo rm atio n was present in one case, (again seen only on mic roscopic examination) and is­chemic necrosis (personal communic;i. tion) in two cases (10) . None of these

CAN J GASTROENTEROL VOL 4 NO 4 MAY/JUNE 1990

E co/i 01 57:H7 colitis

,. . . 4c

. . .. .. .. •

,, .. ~ '"

• . . ~ ..

.. w ..

" . ~ -... .• .. ' · • .

4b

\

Figure 4) Co/on removed at autopsy . 4a Variegated pmrem of mucosa/ infarction ( anow heads), ,dcerarwn (.1/inrtanow) and adherent exuaate fonning [!se11domembranes (long mww) . 4b .Secr,on wken m lite let•el uf rhe {)m1Jomemhrane. Then.' is <'xrcn.1i1•e rran.miural h1?1T1onltage (long anow) and m1ram11ral infarction extending inro rhc nmsculans /)m/Jria (shorr amiw) . 4c lschemu: necrosis (am>w) and hemcmhage of muscularis Jiro/Jria

TABLE 1 Algorithm for diagnosis of Escherichia co/i0157:H7 infection

Diagnosis of E co/i0157:H7 is suggested by biopsies showing· lschemic colitis in a young patient Simultaneous ischemic and pseudomembronous colitis Pseudomembronous colitis with negative Clostridium difficile culture/toxin Pseudomembronous colitis in elderly with c linical picture of ischemlc colitis

Diagnosis of E co/i0157:H7 should be included in the differential diagnosis if: Minimal findings on biopsy with rodiolog,colly or endoscopicolly proven submucosol

edema or hemorrhage Biopsy-proven ischemlc colitis in on elderly patient

report e<l cases s h owed pseu<lo­membranous and 1schemic colitis. In all other reported cases, the pathological alterations in mucosa! biopsies showed a spectrum, including: no altcratinns; nonspecific changes including intersti­tial hemorrhage, mi ld increase of the lymphoplasmocytic component of the lamina propria and edema; neurrophilic infiltrates of the lamina propria and

g la nd~ in the fashion of infectious col itis; and apL)pto:,is o f su rface epithelium ( 1,4,5, 11 ). It is surpnsing that on ly four of a ll of the reported cases showed ischemic colitis or pseudo, membranous colitis, and that pseudo­membranou:, and ischem ic colitis was not seen in any report of E coli O I 57:H7 infection; othcrassociated features such as submucnsal edema a nd hemorrhage

CAN] GASTROENTERl)L VL)L 4 NO 4 MA Y/JLJNE 1990

were prominent findings in most cases. Possible explanat ions for ch is dis­crepancy include mucosa I sampling limited to the distal colon (wirh the mo re seve re prox imal d isease nor visualized endoscopically) and a patient population with a milder form of colitis than observed in the present study. In ­deed, th ree of the six cases were compli ­cated by thrombotic thrombocywpen ic purpura and two of the six patients died, a far higher percentage of complica­tions than in ocher se ries.

The relationship betwee n pseudo­me m bra n o us col ir is and isch e mic colitis has heen extensively debated. So m e authors co n si d e r pseu<lo­me mbrano u~ col itis as pan of the spectrum of isch emic colitis, whereas o th ers regard pseudomembranous colitis and ischemic colitis as dist inct a nd sepa rate e ntiti es. T he findings

145

Eml sec al

JescribcJ in the present six cases sug­gest that pseuJomemhranous col it is and 1schemic colitis arc inJeed on a cnntinuum of the :mme disease. The mechan1,m hy whicL the pseudo­membrane forms has been suggested by Norris in h is review of the spectrum of ischemic bowel disease ( 12). Whereas total cessation of hloodflow to bowel results in coagulative necrosis, a n acute inflammatory in filtrate Jcvclops in bowel mucosa when colonic bloodtlow

REFERENCES I. Riley LW. The ep1dcm1nlogic, c.linilal,

and microb1olog1cal features llf hcmor­rhagll col itis. Annu Re\' M1Crnh1ol 1987;4 I: 383-407.

2. Morrison D, Tyrrell D, Jewell L Colonic h1opsy m vcmll)xin-mJuceJ hemorrhagic clllitis and thromhmic rhromht1Cytopen1c purpura (TIP). AmJ Clm Pathol 1986;86:108-12.

3. Kovacs M, Roddy J, Gregoire S, ct .ii. Thrombmic thromhocytopcm~ pur­purn fo llowing col itis J ue co E rnli 0157:11 7. Am J Med l 990;88: 177-9.

4. Ryan CA, Tm,xc RV, Ho,ck GW, ct al. facheric/1iu col, 0157:11 7 dh1rrhca in a nursmg home: C linical, cp1demiolog1cal, anJ p,1thological fmJ ­ings. J lnfocr Dis 1986; 154:6 31-8.

5. P.ii Cl I, Gordon R, Suns I IV. ct al. SporaJu.: cases of hcmorrhag1l col it is

146

ceases and is then re-established. N orris suggests that thb process evnlves m pseuJomem bra ne format ion.

The nuthurs have demonstrated in

these cases of E coli Ol 57:H7 colitis, disruption a nd /or thrombosis of mucosal cap1llan es and, to a lesser ex­tent, thrombosb of small submucosal arterioles. Lysb of these thrombi or col­latera l blood supply from the rich mu­cosa! plexus to the ,,chemic mucosa may result in reflnw uf blood, acute in-

""nuated wnh r\chenchw coli 0157:H7. Ann Intern Med l 984; LOI :738-42.

6. Price AB, [}.1\•1e, DR. Pst'11do­mcmbrnnou, colitis. J C'lm P,1thol [977;30:1-12.

7. Goul,ron SJM, McGovem VJ. Pscudo­memhranoll', rnliu,. G ut 1965;6:207 .-12

8. \Xlh,rcheaJ R. !,chemic cnrcronilit1s: An exprc,,ion of thl' incrava,cubr co.1gulmion syndrome. Ciu1 1971; 12:912-7.

9. Rl•edcrsJWAJ,Ty1garGNJ,Ro,en­bu,ch G, Gracam,1 S. bchem,c rnl,m. Boston: Martmu, N11ho(f Puhl,shcr~. 1984:23,29.

10. R,ch.irdl'(m SE, l<.anna li MA, 111:cker LE, Smith CR. The histllpathnlogy of the hemolytic uremic ,yndmmc as.,oc iatcJ with \'erotoxm produung E~clwrichia colr infections. I !um Pathol

flammatory infiltrate anc.l s11hsl'qt1ent pseudomembrane formation.

Fi na lly, in light of the preceding dis· cussion, the authors have found the ,11-gorichm presented in Tahle I usefu l in the diagnosis of E culr 0157:117 coliw,.

APPENDIX: While th,, work wa, 111 prcparatmn, two paper, ,hm, mg pathol,1g1-c;1 I findi ng,somcwhat "milar w I ho,c :ihove were prc,cnred ,lt thl· lntcrnauonal Academy of Pat ho logy, San Fr,lntl\CO California, March 1989 (I>, 14).

1988;19:1102 8. 11. Kelly JK, Pm CK, Jadrn,mgh 111, ct ,ii.

The histoparholngy of rccto,igmoid h1ops1c, from ,,dults w11h hloodv d,ar rhea due to vemtux 111-pmducing Eschmchia coli. Am J ('Im P,1thol I 987;88:78-82.

12. Norris I IT. Rccxam111ation of I he ,pccrrum of i,chem1c howcl dl'casc In: Norris I IT, ed. Pathology of thl· Colnn, Small lnre,tinc and Anus. New York: Churchill L1vmg,tonc, 1983: 109-20.

I 3. Olm,tc.1d LC, Petra, RE, Unffin PM. E.1cherich1a ml, 0 I 5 7: l 17-assoc ,aced col it is: A h isl ologit study of IO cases Lab Invest I 989;60:68A. (Ahst)

14. Kelly J, Wcnc,tck M, Ory,hak A, l't ,11. The rnlon ic pathology of fache1·1ch111 coli Ol 57:H7 1nfccr1,m. Lah Invest I 989;60:46A. (Ahst)

CAN JU I\STROENT! ROI Vt)L 4 Nt) 4 MAY/JUNI: 1990

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