On the Possible Relation of Bacillary Dysentery to Non-Specific Ulcerative Colitis

By

ABRAHAM PENNER, M.D. NEW YORK, NEW YORK

S I N C E its f i rs t descr ip t ion by Wilks and M0xon (1) in 1875 and by Hale-Whi te (2) in 1888, "ulcera t ive

colit is" has been a s to rm center among gas t roen te r - ologists. In his o r ig ina l paper, Hale-Whi te presen ted these cases, which form the first a t t empt to establ ish a group of ulcerat ive lesions of the in tes t ina l t r ac t wi th the widest possible var ie t ies of etiology, as a new ent i ty . Of his eleven cases probably only two or three would be considered as even fa i r ly typical today. The lesions found at necropsy var ied in d i s t r i bu t ion f rom j e j u n u m to anus showing the acu tes t lesions distal ly as a rule. This au thor remarks , " I t no more follows tha t because there is u lcera t ion of the in tes t ine which in some specimens r eminds one of dysen te ry tha t the dis- ease f rom which the p a t i e n t died is dysentery, than because a condi t ion of the l a rynx quite i nd i s t ingu i sh - able f rom dip there t ic u lcera t ion is found tha t there- fore the disease caus ing the u lcera t ion is d iph ther ia . "

In th i s fashion ulcerat ive colitis has come down to us t h rough the years, pass ing th rough repeated phases of recogni t ion as an ent i ty , followed by renewed at- t empts to include i t in other and more thoroughly es- tabl ished categories. These r ecu r r en t episodes have centered almost exclusively about a t t empts to prove a s ingle inclusive etiology for th is condit ion.

A brief and incomplete enumeration would include as sole causative factors: psychogenic, neurologic, unknown toxic, vitamin deficiency, endocrine deficiency, Bargen diplococcus, streptococcus, amoebic infestation, B. Coli in- fection, mercury or bismuth poisoning, tuberculous, syphi- litic or dysentery infection. In recent years, further at- tempts have been made to prove the dysentery bacillus to be the only factor involved. In the following an attempt will be made to present the evidence as proposed, evaluate it and discuss the difficulties and sources of error in the interpretation of the data presented.

D I A G N O S T I C C R I T E R I A

(A) Isolation and identification of B. dysenteriae: F r o m the point of view of scientific accuracy the ideal way to prove the dysenter ic o r ig in of a case of ulcera- t ive colitis would be the unequivocal demons t r a t ion of the presence of a s t r a i n of B. dysenteriae in the ex- cre ta or in the i n t e s t i na l lesion of the pat ient . The cul ture of these o rgan i sms f rom the stool or ulcera- t ions is f r a u g h t wi th difficulties, not only involving the method of ob t a in ing the type of specimen most l ikely to yield a posi t ive resul t bu t also the more de- tai led and complex technical procedures involved in choosing media, choosing suggest ive colonies, sub- cul ture, etc.

There is no doubt that the best results are obtained when the original culture material is removed directly from the bases of the ulcerations with the use of the proctoscope or

*From the Medical Services of the Mount Sinai Hospital, New York City.

Submitted July 1, 1936.

740

sigmoidoscope for visualization. This has been repeatedly emphasized by Seligman and Cossman (3), Seligman (4), Egan, et al (5), Fletcher and Mackinnon (6), Smyly (7), Hern (8), Mackie and Gaillard (9). Lacking the oppor- tuni ty to do this, one may still have a reasonable chance for success if cultures of the bloody mucus of a freshly passed stool are made.

Having begun in this fashion, we may then just ly en- quire as to the possibilities of recovering a specific organ- ism at various stages of the disease. In this connection we may refer to the experience of Martin and Williams (10), who, in repeated cultures taken in a series of 1050 cases occurring in connection with acute epidemic dysen- tery, were able to recover the specific organism in almost 70% of cases in the first week of illness dwindling to less than 10% by the end of the second week. Similar data are contributed by Seligman and Cossman (3) and Selig- man (4). In an especially thorough and important study of chronic dysentery, Fletcher and Mackinnon (6) were able to isolate a specific organism in 88 of 229 patients, (38.6%) who had been affected with dysentery from one to thirteen years previously. Four of these cases had been ill thirteen years before the follow-up examination was made and still presented positive stool cultures. In order to obtain these results we note that 13 of the cases were examined 469 times with positive results on 207 occasions, i.e. about 44% of the cultures were positive. In a some- what smaller series of cases of known chronic dysentery, varying in duration from three months to five years with an average of one and one-quarter years, Smyly (7) was able to recover specific organisms in 50 of 62 cases, i.e. in 80.6% of his series. Similarly, Thorlakson (11) was able to culture B. dysenteriae from the lesions of six of his nine cases (80%). Schiirer and Wolff (12) likewise were able to recover these organisms in seven out of nine cases of dysentery over six months in durations. It can be seen that, with the improvement in bacteriological tech- nique in recent years, the incidence of recovery of specific organisms has incresaed remarkably in cases which are known to have been Bacillary Dysentery from the onset.

Having placed the isolated material on Endo plates (or, if desired, on Conradi-Drigalski or Teague medium) these are frequently inspected and the pearly grey colonies iso- lated to the various sugar media for fermentation reac- tions as well as glucose agar slants in preparation for specific agglutination reactions. At this point we meet with our first major obstacle. This is due to the marked tendency shown by the various members of the dysentery group to differ from time to time in their fermentative abilities. To no less a degree it is due to the similar variability shown by the members of the B. Coli group so that when first isolated the latter may present fermenta- tion reactions identical with those considered typical of the dysentery group. This has been a matter of daily experience in routine stool cultures so that a uniform policy of repeated subculture has been adopted with re- sultant elimination of this source of error. Apparently Gardner (15) as well as Lentz and Prigge (16) and Egyedi and Kulka (17) have had similar experience.

Even within the dysentery group itself we find such extreme variability in fermentation reactions that these

PENNER--ON THE POSSIBLE RELATION OF BACILLARY DYSENTERY TO NON-SPECIFIC ULCERATIVE COLITIS 741

cannot be used as the sole mode of identification of mem- bers of this group. Subdivisions of the so-called parady- sentery group based on the fermentation of saccharose and maltose are frequently given. Thus we are told that the Park-Hiss type ferments neither maltose nor sac- charose while the Flexner variety ferments maltose but not saccharose. The unreliability of such criteria is well shown by the results of Sonn~ (18), on the influence of the time of incubation on carbohydrate fermentation. I-Ie showed that if the fermentation reactions are read in twenty-four hours 42 out of his 74 strains reacted as typically Park-Hiss and the remainder as Flexner, where- as if observed at the end of forty-eight hours the ratios were completely reversed. In addition the fermentation reactions will vary in successive tests at considerable in- tervals and these fermentation difference may show little correlation with antigenic differences. Such has been the experience of Busson (19), Sonne (18), Kruse (20), Man- teuffel (20a), Thomson and Mackie (21), Ledingham (22), Park and Casey (23), Shiga (24), Bauch (25), Gardner (15) and others.

We may then safely conclude that isolation of the bacillus is the only safe method for certain diagnosis of the type of organism causing the infection and that the cultural characteristics have only a very tentative value. The actual nature of the isolated bacillus can only be definitely ascertained by its agglutination by specific sera.

Here again we meet with several sources of error which are in all probability due to variation in the antigenic factors present in the bacilli. For this reason the organisms show a marked difference in their agglutinability with specific sera from strain to strain and from time to time in the strain. Thus we find, for example, an organism which culturally and fermentatively may be considered a member of the dysentery group and yet cannot be agglutinated by specific animal sera. This may be due to one of three factors: 1- -Fai lure to use the specific serum for this variety of organism, 2--Complete or partial tem- porary inagglutinability, or 3--Actual non-dysenteric nature of the organism which happens to have the cultural and fermentative reactions of the dysentery group. In the first instance, we may remedy matters by using a greater variety of sera so as to include the specific serum for the strain isolated. Real inagglutin- ability is by no means a rare phenomenon but is usually not permanent and disappears on repeated subculture. These wide variations in sensitivity to specific sera occur both in different races of a single serological group and in the same race at different times. In any case agglutinin absorption methods will almost invariably serve to identify the organism in such instances. The third group has been discussed above and needs no fur ther comment.

(B) The significance of the Agglutination Reaction: As of secondary importance and merely presumptive evidence of the presence of dysentery infection we may mention the agglutination reaction. Here again we have several serious sources of error to contend with. To begin with, positive agglutinations may be obtained with the sera of perfectly healthy individuals where no previous history of dysentery can be ob- tained. This has caused investigators to establish border line values which however are found to vary from strain to strain and even with a given strain with different authors. Thus the borderline value for B. Flexner has been placed at figures varying from 1/50-1/100 Barrensheen (26) to 1/300 (Egan et al (5)) , for B. Shiga 1/20 (Pfuhl (27)) , (Jacobwitz

(28)) and 1/100 (Egan et al (5)) , Schmidt and Uranus (29). This normal agglutinating power has been shown by Burgi (30), not to be attributable to subclinical infections. Healthy sera clump bacilli by virtue of their physico-chemical constitution and inde, pendent of any contact with the bacteria in the sense of a previous infection. The intensity of the aggluti, nation varies from species to species and f rom time to time in the same individual. Above all it varies with the agglutinability of the suspension used for testing the serum. Even in the higher titers one must be extremely cautious in at tr ibuting etiologic signifi- cance in individual, isolated cases. These positive agglutinations are of diagnostic value only in the presence of significant clinical and cultural support or in cases where definite evidence is presented of con- tact with a known case of dysentery proven by culture or where the clinical features are very typical.

The difficulty in the interpretation of agglutination reactions is fur ther increased by the frequent occur- rence of the phenomenon of cross agglutination. This, to be sure, is more prone to occur with infections caused by B. FIexner or the Hiss-Y organism but does repeatedly show itself with the other organisms as well and serves to confuse the interpretation of the results. The unreliability of the agglutination reac- tion is fur ther demonstrated by the occurrence of negative results in cases where the specific organisms may be repeatedly recorded from the stools (Seligman and Cossman (3)) . I t seems fair therefore to con- clude with Flexner that the presence in the blood of agglutinins for dysentery bacilli is of inconclusive value in diagnosis.

(C) Bacteriophagy: Bacteriophagy presents diffi- culties in interpretation similar to those of the aggluti- nation reaction. From the technical side the use of the plate method to determine lysis is so unsatisfac- tory and unreliable that results obtained from its use must be dismissed as subject to too great a chance of error. Even with a carefully titrated test tube series of bacteriophage experiments, we usually find so marked a cross lysis with the various dysentery strains that specific interpretation is practically im- possible. In addition, we usually find the lyric princi- ple present only during the acute period of the dis- ease as it is beginning to subside so that it is of relatively little value in chronic cases. Furthermore it has been found in "normal," "healthy" individuals fur ther confusing the issue. Thus, Feemster (31) in examining 111 stools none of which were from dysen- tery patients found bacteriophage present for dysen- tery organisms in the following proportions: B. Shige, 10 cases; Hiss-Y, 10 cases; B. Flexner, 9 cases; B. Sonne, 6 cases. I f one examines the data from thir- teen small epidemic outbreaks presented by this author one is struck by the fact that the bacteriophage in itself has no diagnostic value and that even in cases occurring in the course of an epidemic, is of diagnostic value only when a specific organism has been re- covered from another case occurring in the same epi- demic. These data may be contrasted with those of Winkelstein and Hirschberger (40) who, with a similar but not identical technique, were unable to isolate a bacteriophage from the stools of 45 patients who presented clinical evidence of dysentery.

(D) Incidence and Significance of Chronic Dysen- tery: The incidence of chronic dysenteric infection has naturally been a mat ter of great interest and obvi-

742 AMERICAN JOURNAL OF DIGESTIVE DISEASES AND NUTRITION

ously would have a direct bearing on the problem of the relationship of bacillary dysentery to chronic ulcerative colitis. This of course will depend upon our definition of chronicity and it may be well to take as a border line, an interval of three months from the onset of the original illness. There need not neces- sarily be continuous clinical manifestations of disease in these cases during the entire period of so called chronicity. However, as can be seen from the above data, recovery of the specific organisms may be suc- cessfully accomplished in as high as 80% of these cases, thus indicating their importance as dissemina- t ing loci for endemics or epidemics. Using these criteria Froensdorff (43), in a follow up of his war cases of acute bacillary dysentery, was able to find only three chronic cases in a total of 210 (1.43%). Albu (44), on the other hand, on the basis of sigmoido- scopic and clinical observations considers the complete cure and healing of the intestinal mucosa a rare event in bacillary dysentery. Clinically there remains a greater or lesser sensitivity of the colon, which, with a slight stimulus, causes a recurrence of symptoms. In addition he finds sigmoidoscopic changes which per- sist for years. However, in only two of his cases was he able to recover specific organisms. As a conserva- tive estimate we may take the figures of Leusden (13) who estimated that about 5% of cases of acute bacil- lary dysentery became chronic. Schurer and Wolff (12) consider that healing of the colon is prevented by the persistence of the original infections. Walko (14), in discussing chronic bacillary dysentery, points out that, in his experience, these cases are practically always infectious, whether merely healthy carriers or chronically ill with persistent or recurrent diarrhea.

( E ) Epidemiologic Data: Bacillary dysentery, generally considered a so-called tropical disease with occasional spreads to the temperate zones, is in reality a cosmopolitan disease, endemic practically the year round throughout the entire United States. The data for the State of California have been carefully com- piled by Reed (32) for the years 1917 to 1932 and show a wide distribution of the disease through this fifteen year period. An examination of the monthly data on the incidence of dysentery in this country as published in the United States Public Health Reports shows that cases are reported practically each month throughout the year in states from coast to coast. Fur the r investigation of this same source yields the interesting data on the incidence of diarrhea and enteritis for infants under the age of two years as follows :

Number of cases Rate per 100,000

1931 . . . . . . . . . . . . . . . . 18,704 . . . . . . . . . . . . . . . . . 15.7 1932 . . . . . . . . . . . . . . . . 14,375 . . . . . . . . . . . . . . . . . 12.0 1933 . . . . . . . . . . . . . . . . 15,706 . . . . . . . . . . . . . . . . . 12.5

These data may be compared with the dysentery rate for the same years in adults:

Rate per 100,000

1931 . . . . . . . . . . . . . . . . . . . . . 2.0 1932 . . . . . . . . . . . . . . . . . . . . . 1.7 1933 . . . . . . . . . . . . . . . . . . . . . 2.2

If, as we feel, we are justified in assuming that the vast majority of the infantile cases were in reality infec- tions with B. Dysenteriae as was shown by Wollstein (33) and Flexner (34), it can be seen how much more frequent are these infections in infancy, at least in these more severe forms, than in adults. This may be contrasted with the relatively infrequent occurrence of chronic ulcerative colitis in the infant age period. Further proof

of the endemic nature of these infections is presented by the data presented by Hassler (35) (Leipzig), Silverman (36) (New Orleans), Smyly (7) (Peiping), Smillie (37) (Boston), Thjotta (38) (Norway), Felsen (39) (Jersey City) as well as the data kindly placed at our disposal by Dr. Boldman of the New York City Department of Health which showed the presence of over 500 cases of proven bacillary dysentery in this city during the first ten months of 1935. These occurred in apparently isolated cases as well as in small epidemic outbreaks.

Bacillary dysentery is primarily a human disease widespread throughout the entire world and affecting mankind regardless of age, color, sex, or social status. As indicated above it has a tendency to occur more frequently in infancy and childhood, at least insofar as clinical manifestations are concerned, although no age period is exempt. In our forces overseas, it occur- red with almost equal frequency in both the colored and white troops, at times involving practically entire fighting units. On exposure, males and females are equally affected as shown by Hassler (35). In general the disease tends to occur in association with a lack of adequate hygienic facilities and is a disease of filth. Its transmission by food handlers and contaminated water is too well known to require comment. I t thus occurs less frequently in the higher social classes where contact infection is less likely to occur.

We thus find ourselves faced with a disease uni- versal in distribution, prone to have a protracted course with a period of potential infectivity commen- surate with the duration of the bowel lesions and affecting all age periods, regardless of sex or color but with a tendency to infect infants and young children especially those living in unhygienic sur- roundings.

COMMENT ON THE R E L A T I O N S H I P OF BACIL- LARY DYSENTERY TO CHRONIC

ULCERATIVE COLITIS The evidence adduced to prove the etiological re-

lationship between the dysentery group of bacilli and chronic ulcerative colitis consists mainly in the finding of positive blood agglutination reactions for this group of bacilli in cases of chronic ulcerative colitis. Such data have been brought forward by Mackie (9), Thor- lakson (11) and Winkelstein and Hirschberger (40). As pointed out above, this by itself cannot be consid- ered as adequate and conclusive proof of the relation- ship. Bacteriophagy, also employed by these authori- ties, has similar defects and cannot thus be considered satisfactory, sole evidence of such a direct relation- ship.

Thus far there have been too few studies carefully performed in accordance with the criteria mentioned above to permit us to evaluate the factor of dysentery infection in chronic ulcerative colitis. Mackie and Gaillard (10) were able to find 18 positive dysentery stool cultures in a series of 83 cases which clinically were considered chronic nonspecific ulcerative colitis. In these 18 positive cultures, there were 'included 5 strains of organisms which, though presenting typical fermentation reactions, showed no agglutination in the number of specific sera used in the tests. Making the necessary correction in the calculated percentage we find it necessary to reduce this from 22% to 16%. Similar results have been obtained by Winkelstein and Hirschberger (11%) (40). Both of these series con- sisted of cases which clinically, sigmoidoscopicaUy and roentgenologically were considered to be idiopathic

P E N N E R - - O N T H E P O S S I B L E R E L A T I O N OF B A C I L L A R Y D Y S E N T E R Y TO N O N - S P E C I F I C U L C E R A T I V E C O L I T I S 743

ulcerative colitis. We may thus draw the conclusion that about 10% to 15% of cases considered clinically to be idiopathic ulcerative colitis r ightful ly belong to the category of chronic bacillary dysentery. The resi- dual 85% to 90% still remain in the group of the etiologically unknown.

The gross clinical features and course of chronic bacillary dysentery and of non-specific ulcerative colitis resemble each other so closely tha t differentia- tion is impossible unless we t race a case to a known and proven ep idemic- -an unusual event. Similarly the sigmoidoscopic and roentgenologic fea tures are so similar tha t they cannot serve as reliable methods of differentiation. And finally we find tha t even on the autopsy table, there are few i f any features which serve as adequate cr i ter ia for purposes of differential diagnosis.

Despite these close resemblances there are other features which make one suspect tha t the two condi- tions are not dependent upon a common etiology. Thus, in contrast to the age distribution of bacillary dysen- tery as given above, we find a preponderance of cases of non-specific ulcerative colitis in the third and four th decades with surprisingly few cases in infancy and early childhood. In a series of 492 cases seen in the Mayo Clinic, only 19 occurred between the ages of 2 and 14 years. Another discrepancy is discovered in the sex incidence, in which it is found that the disease occurs about twice as often in women as in men. ( H e m (18)) . Fur thermore , despite the widespread distribu- tion of epidemic bacillary dysentery throughout the armies on all f ronts during the World War, the pre- ponderance of males is at present below the age of for ty and mainly in the third decade which did not see service overseas. In addition chronic non-specific ulcerative colitis insofar as it has been reported in the l i terature is not as prevalent in Central Europe as one would expect f rom the prevalence of acute epi- demic bacillary dysentery during the late war.

Finally, we must contrast the well known lack of infectivi ty of non-specific ulcerative colitis, for which no author i ty known to us has ever claimed infective

properties, with the equally well known infectivity of cases of chronic bacillary dysentery as pointed out by Walko (14) and Schtirer and Wolff (12). Bargen, in the larger series f rom the Mayo Clinic, was able to find but five instances of familial occurrence while Paulson in the Johns Hopkins Hospital series could uncover only one such instance. I t has been our ex- perience tha t where such cases occur we are much more likely to find a definite etiological agent such as amoebae or dysentery bacilli.

I t is our impression that taking the ulcerative coli- tides as a group there will be found definite etiological agents responsible for a relatively small number and tha t the larger residual group consists of a heterogene- ous conglomeration of conditions with variable eti- ology. As yet we are aware of no single comprehen- sive study under controlled conditions as described above, in which any single bacteriological agent has been proved to be the sole etiological factor concerned in the production of this syndrome. Certainly, the data presented as the case for B. Dysenteriae show such a variat ion in cri teria and control study tha t they as yet cannot be seriously considered as the final solution of the problem.

SUMMARY We have at tempted to summarize and evaluate the

data bear ing on the relationship of bacillary dysentery to chronic ulcerative colitis. There is presented evi- dence suggestive of such a relationship which how- ever is not sufficiently complete to be considered more than suggestive. Cri ter ia for the evaluation of rele- vant data are proposed. The widespread distr ibution of endemic and epidemic bacillary dysentery is no t ed - - a public health problem of grea t importance and magnitude. The tendency for acute bacil lary dysen- te ry to become chronic is discussed; it points to the necessity of carefully following all acute cases for at least five years in an effort more completely to study the relationship of these diseases to one another.

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