GASTROENTEROLOGY

CLINICAL

1991;101:254-262

CHALLENGES

Mark A. Peppercorn, M.D. Clinical Challenges Editor

Beth Isreal Hospital 330 Brookline Avenue Boston, Massachusetts 02215

Exacerbation of Ulcerative Colitis DONALD J. HERMENS

and PHILIP B. MINER, Jr.

Division of Gastroenterology, University of Kansas Medical Center, Kansas City, Kansas

Case Report A 17-year-old girl with a history of ulcerative colitis and a recent pilonidal cyst excision was admitted to the hospital with fever, severe abdominal pain, and frequent, bloody diarrhea. The diagnosis of idiopathic ulcerative colitis was made 4 years before admission and was based on colitis symptoms, endoscopic pancolitis, and unequivocal histological changes. The patient was started on sulfasalazine and prednisone therapy but failed to achieve a complete remission. One year before admission she was having three episodes of bloody diarrhea daily. Her medications were prednisone, 30 mg daily, and sulfasalazine, 1 g t.i.d. She complained of intolerable mood swings due to prednisone, but tapering resulted in continuous diarrhea. Her colonic mucosa was edematous, erythematous, granular, and friable from the mid-descending colon to the rectum. The patient responded well to the addition of one 4-g mesalamine enema per day, and steroid therapy was tapered off completely over the next 8 months. She experienced a brief relapse 3 months before admission manifest by abdominal cramping and two to three blood-streaked, loose stools per day. The patient attributed this relapse to a viral upper respiratory infection she had contracted several days earlier. She observed that her colitis flared “every time she had a cold.” This relapse resolved with an increase in oral sulfasalazine and mesalamine enemas. When the patient was seen 10 weeks before admission she was in clinical and sigmoidoscopic remission, with no complaints of pain, diarrhea, or bleeding on a regimen of sulfasalazine, 2 g daily, and mesalamine enemas, 2 g daily. The patient was scheduled to have a pilonidal cyst excised. The case was discussed with the surgeon, who agreed not to use antibiotics perioperatively unless treating a specific infection because of the concern about provoking antibiotic-induced diarrhea or Clostridium dijjkile colitis. Several days before surgery the patient developed recurrent fevers and pharyngitis. Her examination showed tonsilar hyertrophy, but there was no significant adenopathy or splenomegaly. Her white blood cell count was elevated to

1300 with 78% lymphocytes, most of which were atypical. Results of a mono spot test were positive, and infectious mononucleosis was presumed to be the cause of the patient’s fevers. Surgery was performed 7 weeks before admission. The patient’s ulcerative colitis remained in clinical remission throughout her febrile illness and during the immediate postoperative period. However, 2 weeks after surgery (5 weeks before admission) she developed abdominal cramping, tenesmus, and bloody stools. Her symptoms became worse despite an increase in her sulfasalazine to 4 g daily and mesalamine enemas to 4 g daily. A flexible sigmoidoscopy performed approximately 2 weeks before admission revealed mucosal edema, erythema, granularity, and friability from the rectum to the descending colon. The hematocrit was 29.5%, the white cell count was 8100, the platelets were 625,000, and the erythrocyte sedimentation rate was 58 mm/h. The differential white blood cell count showed 16% segmented neutrophils, 16% banded neutrophils, 39% lymphocytes, 9% monocytes, and 20% eosinophils. Because of the patient’s eosinophilia and worsening condition, the sulfasalazine dosage was reduced to 2 g daily. Abdominal pain, stool frequency, and bleeding all continued to increase. The patient, complaining of progressive weakness, was admitted to the hospital after a syncopal episode during a phlebotomy. Physical examination revealed a pale, thin, and mildly diaphoretic female patient. Her temperature was 37.8”C, her heart rate was 100 per minute, and her systolic blood pressure was 100 mm Hg supine but fell to 90 mm Hg in the sitting position. She had no ocular or oral lesions, and the chest examination results were normal except for tachycardia. The patient had active bowel sounds, and her abdomen was soft and nondistended with mild, diffuse tenderness. There was no rebound, guarding, or liver or spleen enlarge-

Abbreviations used in this paper: 5-ASA, 5-aminosalicylic acid; CDT, Clostridium dificile latex agglutination test; CW, cytomegalovirus. o 1991 by the American Gastroenterological Association 0016-5065/91/$X00

CLINICAL CHALLENGES

July 1991

255

ment. Levels of serum electrolyte, blood urea nitrogen, creatinine, and glucose were normal. The hematocrit was

developed diarrhea (2). Additional strong evidence that C. dificile may be hospital acquired is that up to

25.2%, the white blood cell count was 5600, the platelets were 686,000 and the erythrocyte sedimentation rate was 62 mm/h. The differential white cell count showed 19% segmented neutrophils, 13% banded neutrophils, 45% lymphocytes, 16% monocytes, and 8% eosinophils. Further diagnos-

30% of healthy neonates harbor the organism when they leave the hospital (3). Cytomegalovirus (CMV) may be responsible for severe relapses of ulcerative colitis. It is usually associated with a flulike illness and atypical lymphocytosis similar to that seen in this patient before her pilonidal cyst excision (4). Other bacterial, protozoal, and viral infections may mimic active ulcerative colitis or trigger a clinical relapse. In some cases, relapse can be directly attributed to the untoward effects of medical therapy (Table 3). Problems related to sulfasalazine and 5-aminosalicylic acid (5-ASA) were considered possible causes of relapse in this case. First, sulfasalazine commonly causes headaches, anorexia, nausea, and dyspepsia (5). These may result in medical noncompliance and relapse caused by discontinuation or reduction of the drug. Both the patient and her mother confirmed her compliance with the prescribed medications. The second concern, an idiosyncratic reaction to sulfasalazine or 5-ASA (6-lo), was considered when the colitis worsened following an increase in these medications. Antibiotics may provoke symptoms by allowing the growth of C. dijjkile and production of toxins (11) or by causing impaired carbohydrate salvage due to suppression of normal colonic bacteria (12). Antibiotics were avoided in this case, reducing the possibility of antibiotic-induced relapse. Ischemic colitis is considered a diagnosis of older individuals, although in young patients mesenteric venous thrombosis and resultant ischemia have been reported in association with various inflammatory states (13). Peritonitis due to appendicitis is the usual source of inflammation, but ulcerative colitis has also been implicated. Women taking oral contraceptives also carry a modest risk for ischemic colitis from either mesenteric venous thrombosis or, less commonly, mesenteric thromboembolism (14-18). Typically, mesenteric venous thrombosis results in the gradual onset of colicky abdominal pain, nausea, vomiting, and a change in bowel habits. Rarely, hematemesis or hematochezia may be present. Mesenteric venous thrombosis is most often diagnosed at the time of an exploratory laparotomy, although characteristic radiological findings have been described (lg.-21). This patient had no evidence of peritonitis and was taking no hormones when her ulcerative colitis relapsed, hence the likelihood of mesenteric venous thrombosis due to inflammation or hypercoagulability was very remote. Other vascular problems can present with a colitis picture. Systemic vasculitis involving the colon may cause abdominal pain, diarrhea, and rectal bleeding. In rare instances, systemic lupus erythematosus has been associated with granulomatous and ulcerative

tic studies were performed. Differential

Diagnosis

Dr. Donald Hermens: The pathogenesis of idiopathic ulcerative colitis and its relapses is not well understood, but in many disease exacerbations a precipitating factor may be identified. Often, this alters the therapeutic approach. Several potential causes of relapse (Table 1) could be ruled out in this case on the basis of history, physical examination, and admitting laboratory studies. The two principal concerns were (a) an exacerbation of symptoms due to infection and (b) an adverse reaction to medical therapy. The abdominal pain and frequency of diarrhea1 stools experienced by the patient before hospitalization were worse than she had experienced with any previous relapse of ulcerative colitis. These symptoms were accompanied by fever and a left shift in the differential white blood cell count. Although these findings are compatible with an uncomplicated relapse of ulcerative colitis, infectious diarrhea was a diagnostic possibility (Table 2). C. dificile is of particular concern because of the patient’s recent hospitalization and the ubiquitous presence of C. dificile on hospital floors, toilets, bedding, and furniture (1). In a prospective study, 21% of hospitalized patients acquired C. difficile following admission; of these, 37%

Table 1. Factors Associated With Relapse or Exacerbation of Ulcerative Colitis Symptoms Infections (see Table 2) Viral Cytomegalovirus Upper respiratory viruses Enteroviruses Bacterial

Clostridium dificile Enteric pathogens Myoplasma pneumoniae Entamoeba histolytica

Medications (see Table 3) Antibiotics Sulfasalazine 5-Aminosalicylic acid Azodisalicylate Ischemia Mesenteric venous thrombosis Mesenteric thromboembolism Vasculitis Neoplasia

256

HERMENS AND MINER

GASTROENTEROLOGY Vol. 101, No. 1

Table 2. Infections Associated With RelaDse or Exacerbation Infectious agents

of Ulcerative Colitis Svmotoms

Symptoms

Endoscopy

Clostridium dificile

Mild to severe colitis with prominent pain

Broad range of inflammation, pseudomembranes usually absent

Latex agglutination test (CDT): culture; cytotoxicity assay

Bacterial enteric pathogens

Severe colitis with constitutional symptoms

May be indistinguishable from underlying ulcerative colitis

Stool culture

Cytomegalovirus

Diarrhea and abdominal pain

Aphthous ulcerations to frank colitis

Intranuclear inclusions on biopsy; serology

Enteroviruses

Mild to severe ulcerative colitis symptoms

Mild to severe changestypical of ulcerative colitis

Serology: stool antigen testing

Mycoplasma pneumoniae and upper respiratory viruses

Mild to severe ulcerative colitis symptoms

Mild to severe changes typical of ulcerative colitis

Serology

Entamoeba histolytica

Severe colitis

May be similar to ulcerative colitis

Stool examination for parasites; serology

Diagnosis

Comments Higher incidence associated with antibiotics and hospitalization, but also occurs sporadically Incidence in ulcerative colitis probably similar to general population; culture stools if epidemiologic or clinical circumstances suggest a bacterial pathogen Typically associated with a flulike illness and an atypical lymphocytosis; steroids may predispose In one study, 8% of IBD relapses were associated with Norwalk agent and Rotovirus (41). Clinical correlation necessary; routine testing not indicated In two studies, 4O%60% of relapses associated with recent URI (37, 38) Should be investigated when there is a high endemic rate of infection or if there has been recent travel to an endemic area

URI, upper respiratory infection.

colitis (22). When vasculitis involves the colon there is almost always widespread systemic disease (23). The patient had an elevated erythrocyte sedimentation rate and a fever but no other manifestations of a systemic vasculitis.

Table 3. Medications Associated With Exacerbation

Increased diarrhea Increased symptoms of colitis

Antibiotics

Sulfasalazine

Azodisalicylate

of Ulcerative Colitis Symptoms

Symptom

Medication

and 5-ASA

Exacerbatiti

of bloody diarrhea

Exacerbation of bloody diarrhea

Increased watery diarrhea

Adenocarcinoma of the colon would be a diagnostic consideration in an older patient with long-standing ulcerative colitis. The risk of colon cancer increases with increasing extent and duration of disease. In patients with pancolitis there is a detectable increase

Mucosa

Mechanism

No change from preantibiotics Exacerbated colitis with or without pseudomembranes Typical ulcerative colitis changes ranging from mild to severe Typical ulcerative colitis changes ranging from mild to severe May actually be improved compared with pretherapy

Impaired carbohydrate salvage Clostridium dificile toxin Idiosyncratic

Idiosyncratic (same as sulfasalazine and S-ASA) Small intestinal secretogogue

CLINICAL

July 1991

in the incidence of colon cancer 8-10 years after the onset of symptoms (24), while in patients with colitis limited to the left colon a perceptible increase in incidence becomes apparent after 20 years (25). Although the patient had pancolitis when her condition was first diagnosed, her disease had been present for only 4 years. This fact and the clinical presentation requiring prompt admission virtually excluded the possibility of colon cancer.

Diagnostic Studies Stool cultures for enteric pathogens, including Campylobacter

jejuni, Salmonella,

Shigella, Yersinia,

and invasive Escherichia coli were negative. Results of stool examination for ova and parasites were also negative. Results of a C. diflcicile latex agglutination test (CDT) were negative, but stool cultures for C. difti’cile were positive. Proctoscopy showed severe edema, erythema, and extensive’pseudomembranes.

Discussion Dr. Philip Miner: This case illustrates the complexity of evaluating relapse in patients with chronic ulcerative colitis because several possible causes for relapse were present. The eosinophilia and clinical deterioration that occurred after doubling the patient’s sulfasalazine and mesalamine dosages suggested an adverse drug reaction, A relapse associated with sulfasalazine can present with symptoms indistinguishable from the underlying ulcerative colitis (6-10). One patient developed iridocyclitis following multiple challenges with sulfasalazine, indicating that extracolonic manifestations may accompany druginduced relapses. 5-ASA alone, administered orally or rectally, also causes exacerbation of ulcerative colitis symptoms, indicating that the 5-ASA moiety, is the most likely cause of relapse rather than sulfasalazine or sulfapyridine (26,27). Azodisalicylate, a new 5-ASA analogue, can provoke symptoms by an additional mechanism. This drug is a small bowel secretogogue (28) and caused exacerbation of diarrhea or loose stools in 15.5% of patients in its initial clinical trial (29). When the condition of a patient with inflammatory bowel disease deteriorates following the institution of a new medication, an adverse drug reaction should be considered. In some cases, it may be prudent to reduce or -stop the drug and observe,the patient before resorting to other therapy. In this case, reducing the sulfasalazine dose did not ameliorate the patient’s symptoms. Idiosyncratic reactions are not dose related, and it could be argued that the sulfasalazine and mesalamine should have been stopped completely.

CHALLENGES

257

C. jejuni, Salmonella, Shigella, Yersinia, and invasive E. coli may present with fever, abdominal pain, and bloody diarrhea, mimicking the presentation of ulcerative colitis. When these complaints appear de novo, stool cultures must be performed to exclude the possibility of infectious colitis. There are sparse data linking these organisms with relapse of ulcerative colitis, perhaps indicating their insignificant role in this regard. In one retrospective study, Salmonella was detected in 4.6% of ulcerative colitis flares (30), but eradication of the organism with antibiotics generally had no impact on the course of the disease and standard therapy, including prednisone, was often required to achieve remission. Interestingly, erythromycin does appear to shorten the clinical course of relapses associated with C. jejuni (31). Although frequently sought, these enteric pathogens are rarely found in relapses or exacerbations (4,32), questioning the practice of performing routine stool cultures (4). Given the high cost and the low yield of stool cultures, this test should probably be deferred in patients with relapsing ulcerative colitis unless standard medical therapy fails or epidemiological or clinical circumstances suggest the possibility of irifectious diarrhea. Amebiasis (Entamoeba histolytica) may simulate the clinical presentation of ulcerative colitis and can be difficult to distinguish endoscopically. However, amebiasis was unlikely in the case presented. The carrier rate of E. histolytica is probably far below 5% in the United States (33), and in most regions of the country patients with ulcerative colitis are rarely exposed. Although there are anecdotal reports of ulcerative colitis patients undergoing proctocolectomy for what ultimately proved to be amebic colitis, routine screening for this organism in nonendemic areas is unwarranted. In cases in which amebic dysentery is a diagnostic consideration, either because of recent travel or because of a high endemic rate of infection, protozoa1 stains on three separate stools and a hemagglutination test for antibodies to E. histolytica should be performed. The ameba titer may help to separate the more common carrier state from true infection with mucosal invasion (33,34). Elevated serum eosinophil counts are associated with many parasitic infections. However, amebiasis does not cause blood eosinphilia (35) and therefore was not a likely source for the eosinophilia seen in this case. Other protozoa were also unlikely causes of symptomatic relapse. Although giardiasis has been linked with Crphn’s disease (36), there has been no indication that this organism causes relapses of ulcerative colitis. The mild relapse our patient- suffered several weeks before her pilonidal cyst excision may well have been related to her “cold.” Mee and Jewel1 (37) found that 60% of patients with relapsing ulcerative colitis had experienced an upper respiratory infection in the

258

HERMENS AND MINER

month preceding relapse compared with only 23% of patients in remission. None of these patients received specific antibiotic therapy for their upper respiratory infections, reducing the possibility that these relapses were due to C. dificile. In children, Kangro et al. demonstrated that up to 40% of acute exacerbations of inflammatory bowel disease were temporally related to common upper respiratory infections (38). It is not known how an upper respiratory infection can cause inflammatory bowel disease (IBD) to relapse, but an immunologic mechanism seems plausible. Both IBD and upper respiratory infections have been connected with deficiencies in the cellular immune system (39,40). Viral gastroenteritis may also account for many relapses. In 54 patients with IBD, Gebhard et al. (41) documented positive seroconversion to either Norwalk agent or Rotavirus in 5 of 65 (8%) of disease exacerbations. Exacerbations of IBD associated with positive seroconversion lasted weeks to months, much longer than symptoms usually experienced with viral enteritis. It has been suggested that up to 30% of relapses may be caused by gastrointestinal viruses (42).

There is good evidence that CMV may cause relapses of ulcerative colitis. Using serology, tissue culture, and electron microscopy, Farmer et al. (43) detected a significantly higher incidence of CMV in ulcerative colitis patients than in controls. They proposed that CMV might induce relapse. Cooper et al. (44) evaluated colon specimens from ulcerative colitis patients following colectomy. They found CMV inclusion bodies in five of seven patients who had developed toxic megacolon. The mucosal inflammation and granulation tissue associated with ulcerative colitis may predispose to CMV infection (44,45). The mechanism of exacerbation is not clear, but steroids or other immunosuppressive therapy may be additional predisposing factors (45-48). Bartlett et al. (4) provide anecdotal reports of ulcerative colitis complicated by CMV. In each of several cases, relapse was ultimately shown to be caused by CMV and improved after stopping systemic corticosteroids. A striking feature in these cases was the appearance of a flulike syndrome associated with The authors suggest that atypical lymphocytosis. most relapses of ulcerative colitis involving CMV present in this fashion. Because effective management of CMV may entail reducing steroid medications, or instituting therapy with gancyclovir in severely immunocompromised individuals, early recognition of this entity in relapses may prevent subsequent development of severe complications. The role of C. diffi’cile in relapsing ulcerative colitis has stirred considerable controversy (Table 4). The published data suggest that C. difficile can be incriminated in relapses of ulcerative colitis but probably

GASTROENTEROLOGYVol.

101,No.l

does not cause ulcerative colitis. The association of C. and IBD was first suggested by LaMont and Trnka (49). They found C. dificile toxin in six patients during symptomatic relapse of IBD. In each case, improvement coincided with the disappearance of C. dificile from the stool. In a later, expanded analysis they reported C. dificile toxin in 11 of 59 IBD patients (19%), including 9 of 15 patients experiencing severe flares (60%) (50). Five of eight patients treated with vancomycin improved, and in every case toxin disappeared from the stool once remission was achieved. Bolton et al. (51) found C. difficile toxin in 5 of 26 IBD patients, and each of the 5 toxin-positive patients was in symptomatic relapse. Improvement occurred in 4 with the institution of either metronidazole or vancomycin therapy: the fifth received no specific therapy and improved only slowly with conventional therapy. In subsequent case reports, metronidazole was used successfully to treat toxic megacolon in patients with ulcerative colitis complicated by C. dificile (52). McLaren et al. (53) found C. dijfkile toxin in 18 of 112 relapsing IBD patients, whereas none of the 20 patients in remission excreted toxin. Greenfield et al. concluded that C. dificile was common in IBD patients (13.4%), but in their study C. dificile did not correlate with symptomatic relapses in outpatients (54). However, the organism was detected in 12 of 24 patients hospitalized during the course of the study, including 5 of 6 patients who required colectomy. These data suggest the association of C. diffi’cile with relapse severe enough to require hospitalization. Keighley et al. performed both cultures and toxin assays on 43 patients with relapsing IBD (55). Fourteen of these patients (33%) were culture positive, and 4 had positive toxin assays. An additional culture-negative patient who underwent colectomy was found to have C. dificile in the submucosa of the resected colon. Each of the 4 patients with positive toxin assay results had prior exposure to antibiotics. Three patients received early vancomycin treatment and improved promptly, whereas the fourth remained symptomatic due to a delay in beginning vancomycin therapy. Tremaine et al. (56) also used both culture and toxin assay to detect C. dificile in 22 of 150 (15%) patients with symptomatic IBD. There was not a significant correlation between the severity of the relapse and C. diffi’cile. Meyers et al. (57) reported that the toxin assay was positive in 3 of 18 patients with symptomatic ulcerative colitis (17%) and in 5 of 21 diarrhea1 controls (24%).All patients with positive assays had received antibiotics in the preceding 6 months. The IBD patients with C. diffi’cile were not taking sulfasalazine or metronidazole. Specimens were obtained during symptomatic relapse, but dificile

July 1993

CLINICAL

Table 4. Association of Clostridium

difficile

Source Bolton

4/l 7

et al. (51)

Culture only

Prior treatment

method

Assay only

Both culture and assay

Sulfasa lazine

0

0

4

ND

4

ND

NM

ND

3

ND

4

0

1

0

Antibiotics 2

No. treated for C. dificile 3

(24%)

Trnka

and LaMont

(50)

NM

NM

0

3

NM

0

0

4

0

0

0

1

NM

0

ND

2

ND

0

0

0

14

4

12

NM

3

0

1

3

1

1

0

0

0

NM

0

0

18/112

ND

18

ND

NM

15

NM

(16%) 22/150

NM

NM

NM

NM

NM

NM

4135 (11%)

Meyers

et al. (57)

3118 (17%)

Keighley

et al. (55)

4121 (19%)

Gurian

et al. (32)

Rolny et al. (58)

l/21 (5%) 2143 (5%)

Greenfield

et al. (54)”

30/219

NM

NM

(14%)

Burke and Axon (59)

41128 (3%)

Bartlett

et al. (4)”

o/14 (0%)

McLaren Tremaine

et al. (53)” et al. (56)”

259

and Ulcerative Colitis

Detection No. positive/ total

CHALLENGES

(15%)

“Data include patients with Crohn’s disease. “Number of specimens, not patients, recorded. NM, not mentioned; ND, not done: culture, C. difficile culture;

assay,

the presence of C. dificile toxin did not correlate with the severity of the relapse. Few studies suggest that C. dificile is an uncommon bacterium in patients with ulcerative colitis. Rolny et al. (58) detected C. di’cile toxin in only 3 of 57 samples (5%) obtained from 53 IBD patients, including 2 of 43 samples from ulcerative colitis patients. Both of the toxin-positive ulcerative colitis patients had severe disease, one eventually requiring colectomy. Burke and Axon (59) performed cultures and toxin assays on patients with documented relapses of ulcerative colitis. C. difficile was detected in only 2 of 62 patients (3%) before hospitalization. Gurian et al. (32) found C. dijficile in only 1 of 32 patients with relapsing IBD. This patient had undergone a recent course of antimicrobial therapy. Bartlett et al. found no C. dijficile in 14 relapses (4).

cytotoxicity

Comments on patients positive for C. dificile Treated patients responded rapidly, and recovery corresponded to the disappearance of toxin from the stool. 5 of 8 IBD” patients responded to specific treatment for C. diffitile. Only 3 of 11 had prior antibiotic therapy. All 3 had received recent antibiotics, but not sulfasalazine or metronidazole. Cultures became negative after 4-6 weeks, but 1 patient requiring colectomy had C. difficile submucosa despite a negative culture. Single patient had a severe relapse. One patient went on to colectomy, the other improved after intensive standard therapy. Infection correlated with hospitalization and colectomy in IBD” patients. Results include studies done on presentation and during treatment. C. dificile was cultured from 2 Crohn’s patients in remission. 3 of 18 patients had received no recent antibiotics. Incidence of infection significantly lower with sulfasalazine, significantly higher with other antibiotics.

assay.

Nearly all ulcerative colitis patients take either sulfaslazine or 5-ASA compounds to reduce the likelihood of relapse (60,61). Several reports have suggested that the sulfapyridine moiety of sulfasalazine may alter the normal bowel flora and thereby predispose to C. dificile overgrowth (50,51,54). This conclusion was supported when Clostridium welchii was cultured more frequently from ulcerative colitis patients taking sulfasalazine than from those who were not (62). However, Sandberg et al. demonstrated that sulfasalazine and its metabolites, including 5-ASA, inhibit C. dificile growth in vitro (63). In another study, the incidence of C. di#icile was significantly lower in patients taking sulfasalazine than in those not taking the drug (56). Studies demonstrate that the 5-ASA moiety is responsible for inducing remission of active disease (5). However, it is possible that both the

260 HERMENS AND MINER

sulfapyradine and 5-ASA moieties of sulfasalazine prevent relapses by inhibition of C. dificile growth. It is generally accepted that C. dificile may cause diarrhea when measurable toxin is present. The role C. dificile plays in culture-positive, toxin assaynegative diarrhea is uncertain. At least one study suggests that C. difieicilemay be an etiologic factor in diarrhea1 syndromes despite the absence of measurable toxin (64). In the case presented, results of the C. dificile culture were positive, but the CDT results were negative. This underscores an important point: while the CDT was developed to measure C. difti’cile toxin A, what it really measures is an antigen of the organism itself (65). A positive CDT result infers only the presence of the organism, not the presence of C. dificile toxin. Hence, a positive CDT result has the same diagnostic implications as a positive culture. The cytotoxicity assay using cultured fibroblasts and Clostridium sordelli antitoxin remains the only reliable means of detecting C. dificile toxin. The clinical efficacy of the CDT and the cytotoxicity assay may be less than optimal. There is a disturbing lack of concordance in CDT and cytotoxicity assays when used in a clinical rather than a research setting (66). There are several possible explanations for this observation. The bleeding that frequently accompanies ulcerative colitis may result in plasma proteins binding to the toxin or CDT beads, thereby rendering a false-negative toxin assay result. The increased volume of diarrhea resulting from the underlying disease may dilute the toxin to undetectable levels. Finally, it is conceivable that lower, and possibly undetectable, concentrations of C. diffi’cile toxin may cause disproportionately greater symptoms in patients with mucosa damaged by ulcerative colitis than in individuals with no mucosal injury. The patient presented received no antibiotics other than sulfasalazine for at least several months before stool collection. C. dificile infection often occurs in patients with ulcerative colitis who have not had a recent antibiotic exposure. Bolton et al. discovered C. di$icile in five IBD patients. Two were taking sulfasalazine and none had received other antibiotics for at least 3 months (51). In the series reported by Trnka and LaMont, 7 of the 11 cytotoxicity assay-positive patients had received no antibiotics other than sulfasalazine in the 2 months before stool collection (50). Greenfield et al. reported that 89% of IBD patients with C. dificile (positive culture and/or CDT assay) had received no recent antibiotics other than sulfasalazine (54). Tremaine et al. found a significantly higher incidence of C. dij@ile in IBD patients taking antibiotics, but the incidence in those not taking antibiotics was still nearly 10% (56). Pseudomembranes are unusual when C. dificile complicates ulcerative colitis, although cases have

GASTROENTEROLOGY Vol. 101,No.

1

been reported (4950). The pathogenesis of pseudomembranes is not known, but it is possible that the inflammed colonic mucosa associated with ulcerative colitis will not support their formation. An alternative explanation is that the inflammed mucosa of patients with ulcerative colitis is susceptible to injury by C. dificile at concentrations too low to provoke pseudomembrane formation. Even in previously normal colons, C. dificile diarrhea is not always associated with pseudomembrane formation (2). In these individuals, absent pseudomembrane formation may be.a function of host defense factors or of C. dificile concentration adequate to cause diarrhea but not adequate to cause pseudomembranes. It is possible that drugs used to treat C. dificile have an unrelated therapeutic effect on IBD. The usefulness of metronidazole in Crohn’s disease is well documented (67-69); however, investigations using oral, suppository, and IV forms of metronidazole in ulcerative colitis have shown no benefit (70-72). Metronidazole’s efficacy in eradicating C. dificile is the only reasonable use in ulcerative colitis patients. Similarly, vancomycin has only questionable benefit for relapsing ulcerative colitis (73) unless it is used for patients with C. dificile infection. Cholestyramine helps to eradicate C. dificile by a different mechanism. This medication binds the toxins of C. dijjkile and prevents toxin-induced injury to the colon while allowing restitution of the normal colonic flora (74). Normal flora suppress C. difficile growth. Specific treatment for C. dificile improves management of some relapses and avoids the adverse effects of increasing other medications. The patient presented was treated with IV steroids and oral vancomycin. The C. dificile was eradicated and the patient’s condition improved dramatically. Sulfasalazine and mesalamine enemas were briefly discontinued while the patient was in the hospital but later resumed when her condition improved. Oral steroids were gradually tapered. Six months after discharge, the patient had normal-appearing colonic mucosa. The IV and oral steroids undoubtedly contributed to the rapid clinical and endoscopic improvement seen. It is also likely that the eradication of C. dificile using oral vancomycin was an important adjunct to her recovery. Final Diagnosis The final diagnosis was relapse of ulcerative colitis complicated by C. dificile infection. Referencb 1. Fekety R, Kyung-Hee K, Brown D, Batts D, Cudmore M, Silva J. Epidemiology of antibiotic-associated colitis. Am J Med 1981; 70:906-906.

CLINICAL

July 1991

2. McFarland LV, Mulligan ME, Kwok RYY, Stamm WE. Nosocomial acquisition of C. difficile infection. N Engl J Med 1989;320: 204-210. 3. Viscidi R, Wiley S, Bartlett JG. Isolation rates and toxigenic potential of Clostridium dificile isolates from various patient populations. Gastroenterology 1981;81:5-9. 4. Bartlett JG, Laughon BE, Bayless TM. Role of microbial agents in relapses of idiopathic inflammatory bowel disease. In: Bayless

TM, ed. Current

management

of inflammatory

disease. St. Louis: Mosby, 1989:86-91. 5. Peppercorn MA. Sulfasalazine and related

new drugs.

bowel J Clin

Pharmacol 1987;27:260-265. 6. Werlin SL, Grand RJ. Bloody diarrhea-a new complication of sulfasalazine. J Pediatr 1978;92:450-451. 7. Schwartz AG, Targan TR, Saxon A, Weinstein WM. Sulfasalazine-induced exacerbation of ulcerative colitis. N Engl J Med 1982;306:409-412. 8. Adler R. Sulfasalazine-induced exacerbation of ulcerative colitis (letter). NEngl JMed 1982;307:315. 9. Ring FA, Hershfield NB, Machin GA, Scott RB. Sulfasalazineinduced colitis complicating idiopathic ulcerative colitis. Can Med Assoc J 1984;131:43-45. 10. Shanahan F, Targan S. Sulfasalazine exacerbation of ulcerative 455. 11. Bartlett JG. Antimicrobial difficile toxin associated J 1981;149:6-9.

and

salicylate-induced

colitis (letter). N Engl J Med 1987;317: agents diarrhea

implicated or colitis.

in Clostridium

Johns Hopkins

Med

12. Rao SSC, Edwards CA, Austen CJ, Bruce C, Read NW. Impaired colonic fermentation of carbohydrate after ampicillin. Gastroenterology 1988;94:928-932. 13. Grendell JH, Ockner RK. Mesenteric venous thrombosis. Gastroenterology 1982;82:358-372. 14. Kilpatrick ZM, Silverman JF, Betancourt E, Farman J, Lawson JP. Vascular occlusion of the colon and oral contraceptives. N Engl J Med 1968;278:438-440. 15. Cotton PB, Thomas ML. Ischaemic colitis and the contraceptive pill. Br Med J 1971;3:27-28. 16. Prust FW, Kumar GK. Massive colonic bleeding and oral contraceptive “pills.” Am J Obstet Gynecol 1976;125:695-698. 17. Nesbit RR, DeWeese JA. Mesenteric venous thrombosis and oral contraceptives. South Med J 1977;70:360-362. 18. Barcewicz PA, Welch JP. Ischemic colitis in young adults. Dis Colon Rectum 1980;23:109-114. 19. Clemment AR, Chang J. The radiologic diagnosis of spontaneous mesenteric venous thrombosis. Am J Gastroenterol1975;63: 209-215. 20. Tey PH, Sprayregen S, Ahmed A, Chan KF. Mesenteric vein thrombosis: angiography in two cases. Am J Radio1 1981;136: 809-811. 21. Rosen A, Korobkin M, Silverman PM, Dunnick NR, Kelvin FM. Mesenteric vein thrombosis: CT identification. Am J Radio1 1984;143:83-86. Kurlander DJ, Kirsner JB. The association of chronic “nonspecific” inflammatory bowel disease with lupus erythematosus. Ann Intern Med 1964;60:799-813. 23. Ferrari BT, Ray JE, Robertson HD, Bonau RA, Gathright JB. Colonic manifestations of collegen vascular disease. Dis Colon Rectum 1980;23:473-477. 24. Nugent FW, Haggitt RC, Colcher H, Kutteruf GC. Malignant potential of chronic ulcerative colitis. Gastroenterology 1979; 76:1-5. 25. Greenstein AJ, Sachar DB, Smith H, Pucillo A, Papatestas AE, 22.

Kreel I, Geller SA, Janowitz HD, Aufes AH. Cancer in universal and left-sided ulcerative colitis: factors determining risk. Gastroenterology 1979:77:290-294.

CHALLENGES

261

CD. Exacerbation 26. Austin CA, Cann PA, Jones TH, Holdsworth of diarrhoea and pain in patients treated with 5-aminosalicylic acid for ulcerative colitis. Lancet 1984;1:917-918. induced by 27. Pearson DJ, Stones NA, Bentley SJ. Proctocolitis salicylate and associated with asthma and recurrent nasal polyps. Br Med J 1983;287:1675. 28. Goerg KJ, Wanitschke R, Diehl PH, Meyer Zum Buschenfelde KH. Secretory effect of azodisalicylate (azodisal sodium) on the short circuited mucosa of the rat ileum in vitro. Gut 1988;29: 336-341. 29. Sandberg-Gertzen H, Jarnerot G, Kraaz W. Azodisal sodium in the treatment of ulcerative colitis. Gastroenterology 1986;90: 1024-1030. RJ, Weinstein L, Levitan R, Patterson JF. Ulcerative 30. Lindeman colitis and intestinal salmonellosis. Am J Med Sci 1967;254: 855-861. 31. Newman A, Lambert JR. Campylobacterjejuni causing flare-up in inflammatory bowel disease. Lancet 1980;2:919. 32. Gurian L, Klein K, Ward TT. Role of Clostridium diftkile and Campylobacter jejuni in relapses of inflammatory bowel disease. West J Med 1983;138:359-360, 33. Krogstad DJ, Spencer HC, Healy GR, Gleason NN, Sexton DJ, Herron CA. Amebiasis: epidemiologic studies in the United States, 1971-1974. Ann Intern Med 1978;88:89-97. 34. Markell EK, Voge M, John DT. Medical parasitology. 6th ed. Philadelphia: Saunders, 1986. 35. Krogstad DJ, Spencer HC, Healy GR. Current concepts in parasitology: amebiasis. N Engl J Med 1978;298:262-265. 36. Scheurlen C, Kruis W, Spengler U, Weinzierl M, Paumgartner G, Lamina J. Crohn’s disease is frequently complicated by giardiasis. Stand J Gastroenterol 1988;23:833-839. 37. Mee AS, Jewel1 DP. Factors inducing relapse in inflammatory bowel disease. Br Med J 1978;2:801-802. 38. Kangro HO, Chong KF, Hardiman A, Heath RB, Walker-Smith JA. A prospective study of viral and mycoplasma infections in chronic inflammatory bowel disease. Gastroenterology 1990;98: 549-553. 39. MacDermott RP, Bragdon MJ, Kodner IJ, Bertovich MJ. Defi-

40.

41.

cient cell-mediated cytotoxicity and hyporesponsiveness to interferon and mitogenic lectin activation by inflammatory bowel disease peripheral blood and intestinal mononuclear cells. Gastroenterology 1986;90:6-11. Askenase PW. Effector and regulatory mechanisms in delayed type hypersensitivity. In: Middleton E, Reed CE, Ellis EF, Adkinson NF, Yuginger JW, eds. Allergy, principles and practice. Volume I. 3rd ed. St. Louis: Mosby, 1988:247-274. Gebhard RL, Greenberg HB, Singh N, Henry P, Sharp HL, Kaplan L, Kapikian AZ. Acute viral enteritis and exacerbations of inflammatory bowel disease. Gastroenterology 1982;83:12071209.

42. Gorbach SL. Viral infections and inflammatory bowel disease. Gastroenterology 1982;83:1318-1319, 43. Farmer GW, Vincent MM, Fuccillo DA, Horta-Barbosa L, Ritman S, Sever JL, Gitnick GL. Viral investigations in ulcerative colitis and regional enteritis. Gastroenterology 1973;65:818. 44. Cooper H, Raffensperger EC, Jonas L, Fitts WT. Cytomegalovirus inclusions in patients with ulcerative colitis and toxic dilation requiring colonic resection. Gastroenterology 1977;72: 1253-1256. 45. Goodman ZD, Boitnott JK, Yardley JH. Perforation of the colon associated with cytomegalovirus infection. Dig Dis Sci 1979;24: 376-380. 46. Cunningham M, Cantoni L, Humair L. Cytomegalovirus primoinfection in a patient with idiopathic proctitis. Am J Gastroenter01 1986;81:586-588. 47. Powell RD, Warner NE, Levine RS, Kirsner JB. Cytomegalic

262

48.

49.

50.

51.

HERMENS AND MINER

inclusion disease and ulcerative colitis. Am J Med 1961;30:334340. Keren DF, Milligan FD, Strandberg JD, Yardley JH. Intercurrent cytomegalovirus colitis in a patient with ulcerative colitis. Johns Hopkins Med J 1975;136:178-182. LaMont JT, Trnka Y. Theraputic implications of Closfridium dificile during relapse of chronic inflammatory bowel disease. Lancet 1980;1:381-383. Trnka Y, LaMont JT. Association of Clostridium dificile toxin with symptomatic relapse of chronic inflammatory bowel disease. Gastroenterology 1981;80:693-696. Bolton RP, Sheriff RJ, Read AE. Clostridium dificile associated diarrhea: a role in inflammatory bowel disease? Lancet 198O;l:

383-384. 52. Bolton RP, Read AE. Clostridium dificile

53.

54.

55.

56.

57.

58.

59. 60.

61.

in toxic megacolon complicating acute inflammatory bowel disease. Br Med J 1982;285:475-476. McLaren L, Bartlett JG, Gitnick G. Infectious agents in inflammatory bowel disease: collaborative studies (abstr). Gastroenterology 1981;80:1228. Greenfield C, Aguilar Ramirez JR, Pounder RE, Williams T, Danvers M, Marper SR, Noone P. Clostridium dificile and inflammatory bowel disease. Gut 1983;24:713-717. Keighley MRB, Youngs D, Johnson M, Allan RN, Burdon DW. Clostridium dificile toxin in acute diarrhoea complicating inflammatory bowel disease. Gut 1982;23:410-414. Tremaine WJ, Bille J, Huizenga KA, Washington JA, Ilstrup DM. Factors which influence the occurrence of Clostridium dificile infections in inflammatory bowel disease (abstr). Gastroenterology 1983;84:1337. Meyers S, Mayer E, Buttone E, Desmond E, Janowitz HD. Occurrence of Clostridium dificile toxin during the course of inflammatory bowel disease. Gastroenterology 1981;80:697700. Rolny P, Jarnerot G, Mollby R. Occurrence of Clostridium dificile toxin in inflammatory bowel disease. Stand J Gastroenterol 1983;18:61-64. Burke DA, Axon ATR. Clostridium difficile, sulphasalazine, and ulcerative colitis. Postgrad Med J 1987;63:955-957. Dissanayake AS, Truelove SC. A controlled therapeutic trail of long-term maintenance treatment of ulcerative colitis with sulphasalazine (Salazopyrin). Gut 1973;14:923-926. Riley SA, Mani V, Goodman MJ, Herd ME, Dutt S, Turnberg LA. Comparison of delayed-release 5-aminosalicylic acid (mesalamine) and sulfasalazine as maintenance treatment for patients with ulcerative colitis. Gastroenterology 1988;94:13831389.

62. Cooke EM. Faecal

during treatment 565-568.

flora of patients with ulcerative colitis with salicylazosulphapyrine. Gut 1969;lO:

GASTROENTEROLOGY

Vol. 101, No. 1

63. Sandberg-Gertzen H, Kjellander J, Sundberg-Gilla 8, Jarnerot G. In vitro effects of sulfasalazine, azodisal sodium, and their metabolites on Clostridium dificile and some other faecal bacteria. Stand J Gastroenterol 1985;20:607-612. 64. Lashner BA, Todorczuk J, Sahm DF, Hanauer SB. Clostridium dificile culture-positive, toxin negative diarrhea: a review of 45 cases (abstr). Gastroenterology 1985;88:1465. 65. Lyerly DM, Wilkins TD. Commercial latex test for Clostridium dificile toxin A does not measure toxin A. J Clin Microbial 1986;23:22-23. 66. Biddle WL, Harms JL, Greenberger NJ, Miner PB. Evaluation of antibiotic-associated diarrhea with a latex agglutination test cell culture cytotoxicity assay for Clostridium difficile. Am J Gastroenterol 1989;84:379-382. 67. Ursing B, Kamme C. Metronidazole for Crohn’s disease. Lancet 1975;1:775-777. 68. Ursing B, Alm T, Barany F, Bergelin I, Ganrot-Norlin K, Hoevels J, Huitfelt B, Jarnerot G, Krause U, Krook A, Lindstrom B, Nordle 0, Rosen A. A comparative study of metronidazole and sulfasalazine for active Crohn’s disease: the cooperative Crohn’s disease study in Sweden. Gastroenterology 1982;83: 550-562. 69. Bernstein LH, Frank MS, Brandt LJ, Boley SJ. Healing of perineal Crohn’s disease with metronidazole. Gastroenterology 1980;79:357-365. 70. Gilat T, Suissa A, Leichtman G, Delpre G, Pavlotsky M, Grossman A, Fireman Z. A comparative study of metronidazole and sulfasalazine in active, not severe, ulcerative colitis. J Clin Gastroenterol 1987;9:415-417. 71. Davies PS, Rhodes J, Heatley RV, Owen E. Metronidazole in the treatment of chronic proctitis: a controlled trial. Gut 1977;18: 860-861. 72. Chapman RW, Selby WS, Jewel1 DP. Controlled trial of intravenous metronidazole as an adjunct to corticosteroids in severe ulcerative colitis. Gut 1986;27:1210-1212. 73. Dickinson RJ, O’Connor HJ, Pinder I, Hamilton I, Johnston D, Axon ATR. Double blind controlled trial of oral vancomycin as adjunctive treatment in acute exacerbations of idiopathic colitis. Gut 1985;26:1380-1384. 74. Taylor NS, Bartlett JG, Binding of Closfridium di’cile cytotoxin and vancomycin by anion exchange resins. J Infect Dis 1980;141:92-97.

Received September 12,199O. Accepted November 16,199O. Address requests for reprints to: Philip B. Miner, Jr., M.D., Professor of Medicine, Director, Division of Gastroenterology, University of Kansas Medical Center, 39th and Rainbow Boulevard, Kansas City, Kansas 66103.