FULMINATING NONINFECTIVE PSEUDOMEMBRANOUS COLITIS

Transcription

1 GASTROENTEROLOGY Copyright 1970 by The Williams & Wilkins Co. Yol. 58, No.1 Printed in U.S.A FULMINATING NONINFECTIVE PSEUDOMEMBRANOUS COLITIS A. GROLL, M.B., CH.B., M. J. VLASSEMBROUCK, M.D., S. RAMCHAND, M.D., AND L. S. VALBERG, M.D. Division of Gastroenterology, Department of Medicine, and Department of Pathology, Queens University, Kingston, Ontario, Canada Two women, who were previously in good health, developed severe diarrhea and circulatory failure during the administration of antibiotics. Typical gross and microscopic features of pseudomembranous colitis were found in the rectum and later throughout the colon of both patients. No pathogenic organisms were found in the stool or in the rectal biopsy. Initially, dehydration occurred but, later, fluid retention and marked edema predominated. Severe hypoproteinemia appeared to play an important role in the development of edema, reduction in effective plasma volume, and the rapid progression of shock. The 1st patient died of shock despite intensive therapy with parenteral fluids, plasma, and albumin, whereas the 2nd patient survived with a combination of intensive medical therapy and ileostomy with subtotal colectomy to correct the hypoproteinemia. The survival of this patient provided a unique opportunity to study the progress of the disease in the rectum. The pseudomembrane and edema of the mucosa rapidly resolved and there was a gradual diminution in the hypersecretion of the goblet cells and the inflammatory response. At the time of restoration of the continuity of the bowel, the rectal mucosa was still friable and mild inflammation persisted. Our interest in pseudomembranous colitis was stimulated by 2 patients who presented with diarrhea and subsequently developed marked hypoproteinemia, pleural effusions, ascites, and rapidly progressive circulatory failure that was refractory to treatment. The 1st patient died but the 2nd survived with a combination of intensive medical therapy and partial colectomy. The survival of this patient provided a unique opportunity to study the evolution of the disease and subsequent resolution of the disorder in the rectum and sigmoid colon. It is the purpose of this paper to draw Received June 19, Accepted July 28, Address requests for reprints to: Dr. A. Groll, Department of Medicine, Etherington Hall, Queens University, Kingston, Ontario, Canada. The authors wish to thank Dr. H. H. Westenberg and Dr. J. Kerr for referring the second patient. Dr. Kerr also performed the surgery. 88 attention to the importance of hypoproteinemia in this disorder and to discuss medical and surgical therapy of the shock that occurs in the severe form of the disease. Case Reports Patient 1 A 52-year-old Caucasian woman was admitted to the Belleville General Hospital on September 14, 1966, with a 10-day history of watery diarrhea characterized by the passage of 10 to 12 bowel motions per day which contained mucus but no blood. She had been treated with neomycin and kaolin without improvement. She had had similar less severe attacks lasting a day or so on many occasions during the previous 20 years but otherwise she had been in good health. Physical examination disclosed a thin woman weighing 112 lb. The temperature was 96.4 F, pulse, 80 per min, blood pressure, 118/62 mm Hg, and respirations, 17 per min. There was no edema or cya-

2 January 1970 CASE REPORTS 89 nosis. The abdomen was distended, soft, and tympanitic, and there was some tenderness in the left iliac fossa. The rest of the examination was normal. The hemoglobin was 16.4 g per 100 ml and the white cell count was 41,000 per mm". Urinalysis showed a trace of proteiu. and sugar and an occasional white cell per high power field. She was treated with parenteral fluids and Chloromycetin, 1.0 g daily, intramuscularly, for 6 days. The diarrhea persisted, marked edema of the lower limbs and presacral region appeared, and large bilateral pleural effusions developed in the absence of congestive heart failure. On September 19 a barium enema demonstrated dilation of the large bowel with irregularity of the colon and rectum, suggesting either overlying exudate or ulceration of the mucosa (fig. 1). The hemoglobin declined to 11.0 g per 100 ml and the serum protein concentration was only 4.0 g per 100 ml (table 1). The blood urea nitrogen and serum electrolytes were normal. No occult blood was fgund in the stools and no pathogens were isolated in stool cultures. On September 20 the Chloromycetin was discontinued and erythromycin, 2.0 g intramuscularly daily, was substituted. The patient's condition continued to deteriorate and she went into a state of shock. Some improvement occurred following the administration of 1500 ml of blood and 50 g of salt-free albumin, but the hypoproteinemia persisted (table 1), the edema became more generalized, and marked ascites, dyspnea, and peripheral cyanosis developed. She was transferred to the Kingston General Hospital on September 23 in a semicomatose condition. The blood pressure was 120/80 mm Hg and the central venous pressure was 2 cm of water. The pulse was 95 per min, respiratory rate, 20 per min, and temperature, 99 F. Bilateral pleural effusions, ascites, and gross peripheral edema were present, but she was not in cardiac failure. The hemoglobin was 11.0 g per 100 ml and the white blood count, 40,850 per mma, remained elevated. The concentration of plasma electrolytes in milliequivalents per liter were as follows: sodium, 121 ; potassium, 4.1; chloride, 87; and bicarbonate, 24. No gram-positive cocci or other pathogens were found in either repeated smears or cultures of the stool. Proctoscopy showed thick mucoid material in the rectum and markedly edematous and thickened mucosa covered by yellowish exudate.. Her condition deteriorated further and she was given 500 ml of blood and 125 g of al- FIG. 1. Barium enema roentgenogram showing dilation of the large bowel with marked irregularity of the colon and rectal mucosa. bumin in an attempt to restore the central venous pressure to normal and to reverse the shock. Dexamethasone, 8 mg daily, and mannitol were given as well, but she failed to improve and died on September 24. A limited autopsy was performed. The colon contained thick yellow mucus. The most striking features were edema of the entire wall of the bowel and the innumerable, irregular, yellowish plaques which were adherent to the mucosa. On microscopic examination, the plaques were composed of mucus, fibrin, variable numbers of leukocytes, occasional grampositive and gram-negative bacilli, and a few gram-positive cocci. In the underlying mucosa the number of goblet cells was greatly increased and in many areas there was degeneration of the epithelium and destruction of the mucosa. The lamina propria was edematous and infiltrated by large numbers of neutrophils. The small bowel was edematous, and the lumen contained yellow mucoid material, but o ~ histological section the mucosa showed only a mild degree of inflammatory cell infiltration. Patient 2 On May 3, 1968, a 20-year-old Caucasian student in her 8th month of pregnancy was

3 90 CASE REPORTS Vol. 58, No.1 TABLE 1. Results of investigation and treatment in patient 1 Date in September 1966 Albumin Therapy Blood Hemoglobin g ml g% Hematocrit Total Serum protein [ Albumin I Globulin % g/100 ml admitted to the Kingston General Hospital with a 5-day history of abdominal pain associated with the passage of frequent small loose stools that contained mucus. Ten days prior to the development of these symptoms she had been given ampicillin, 1 g daily, for the treatment of a urinary tract infection. On examination she appeared healthy, a 36-week parturient uterus was palpable, there was generalized abdominal tenderness, and no ascites were detected. On rectal examination the wall of the rectum felt irregular and thickened; proctoscopic examination was not performed. The hemoglobin was 11.2 g per 100 ml, white blood count, 7100 per mm', and sedimentation rate, 78 mm in 1 hr. Direct smear of the stools showed no gram-positive cocci, and no pathogenic organisms of fungi were found in repeated stool cultures. The diarrhea became progressively worse and by May 6 she had developed dehydration, tachycardia, and fever of 101 F. A urinary tract infection was found and treatment with both penicillin G, 6 million U, and streptomycin, 1 g daily, intramuscularly, was given. On May 7 she spontaneously delivered a live male infant. In the postpartum period the diarrhea continued, her general condition deteriorated further, and despite the vigorous administration of intravenous fluids she became hypotensive and oliguric. The extremities were clammy, the abdomen diffusely tender, and bowel sounds inaudible. A direct smear of the stool showed a mixed bacterial flora; a moderate number of yeasts and cultures grew no pathogenic organisms. The hemoglobin was 15.7 g per 100 ml; hematocrit, 44.5%; and white blood count, 25,350 per mm' with 89% segmented neutrophils, 1 % lymphocytes, and 2% eosinophils. The plasma electrolytes in milliequivalents per liter were as follows: sodium, 130; chloride, 103: potassium, 4.2; and bicarbonate, The plasma urea nitrogen was 21 mg per 100 ml. A diagnosis of peritonitis and septic shock was made and a laparotomy was performed. The peritoneal cavity contained 3 liters of ascitic fluid, and the entire colon was markedly edematous and thickened, but the small bowel appeared normal. Following closure of the abdomen a proctoscopy was performed. The rectal mucosa was covered with numerous, small, yellow-white patches of exudate. Histological sections made of a biopsy of the rectum showed that the exudate was composed of fibrin, mucus, red blood cells, and neutrophils. There was superficial ulceration of the underlying mucosa and the glands were hypersecretory and distended with mucus. The lamina propria was edematous but inflammatory cell infiltration was minimal. No bacteria or fungi were identified in special stains of the mucosa. The patient was transferred to the Gastroenterology Service at Kingston for further care. She was given 2400 ml of plasma and 25 g of albumin over the next 12 hr, but the hypotension, low central venous pressure, peripheral cyanosis, and oliguria persisted. Marked respiratory difficulty resulted from massive ascites and pleural effusions (fig. 2). Measurement of the total plasma protein made at this time showed a level of 3.7 g per 100 ml with 3.5 g per 100 ml of albumin and 0.2 g per 100 ml of globulin (table 2). To increase the central venous pressure and restore the arterial blood pressure, an additional 100 g of albumin and 2200 ml of plasma were given. The antibiotics were stopped and hydrocortisone hemisuccinate, 100 mg, was given intravenously every 6 hr. During the next 48 hr she was given an additional 400 g of salt-free albumin and 900 ml of plasma for the treatment of shock. Despite this intensive therapy her condition continued to deteriorate, the hypotension grew worse, and the total serum protein fell to 3.4 g per 100 ml {table

4 January 1970 CASE REPORTS 91 2). On May 11 a subtotal colectomy and ileostomy were carried out and the proximal end of the sigmoid colon was brought out through the anterior abdominal well. Like the bowel in the previous patient, the colon was thickened and markedly edematous (fig. 3). The mucosal surface was covered by firmly adherent irregular plaques of yellowish exudate and marked edema, and acute fibrinopurulent inflammation was present in the underlying mucosa (fig. 4A). Gram-positive organisms with the configuration of staphylococci and many yeast forms were noted in the superficial exudate, but not in the deeper layers of the mucosa. Eight hours postoperatively, severe intraabdominal bleeding commenced and another laparotomy was carried out. No definite bleeding point was identified, blood transfusions were continued, and the bleeding ceased spontaneously. The patient gradually improved, the ascites and pleural effusions rapidly disappeared, and the concentration of total serum protein increased to 5.9 g per 100 ml (table 2). Ten days following the operation proctoscopy was repeated. The pseudomembrane covering the rectum had disappeared and the rectal mucosa was less edematous and inflamed. There was also improvement in the inflammatory reaction in microscopic sections of a rectal biopsy, although the glands were still hypersecretory and distended with mucus (fig. 4B). The patient was discharged from hospital on June 5 and when seen again 10 weeks later she was in good health. The gross appearance of the rectal mucosa was unchanged and, microscopically, mild inflammation and edema were still evident (fig. 4C). Total serum protein level was normal and electrophoretic pattern was within normal limits (table 2). On review of her condition in February 1969, the rectal mucosa on sigmoidoscopic FIG. 2. Portable X-ray film of chest, demonstrating large bilateral pleural effusions. TABLE 2. Results of investigation and treatment in patient 2 Therapy Serum protein Date in 1968 Hemoglobin Hematocrit Albumin Plasma Blood Total I Globulin I Albumin g ml ml g% % g/100 May Partial colectomy June August

5 92 CASE REPORTS Vol. 58, No.1 FIG. 3. Macroscopic appearance of the sectioned colon. The marked thickness and edema of the wall and the elevated mucosal plaques are indicated by the arrows. examination was moderately friable and mild inflammation was still present in histological sections of the mucosa (fig. 4D). The continuity of the intestine was restored by an ileocolic anastomosis and she made an uneventful recovery. Ten days following the operation the rectal mucosa was similar in appearance to that observed prior to operation. When discharged from hospital she was having two to four semi formed bowel motions daily. Discussion The diagnosis of pseudomembranous colitis in these 2 patients was established from the macroscopic and microscopic appearances of the colonic mucosa. In the 1st patient the diagnosis was made at autopsy when the typical raised plaques of yellowish green exudate were seen covering the mucosa. In the 2nd patient a typical pseudomembrane was seen at proctoscopy and later in the surgical specimen. This distinctive feature and the histological findings (fig. 4) distinguished the disorder from ulcerative colitis, granulomatous colitis, ischemic colitis, and colitis due to Amoeba histolytica, Salmonella, and Shigella.! The survival of the 2nd patient provided a unique opportunity to follow the course of the disease in the rectum and sigmoid colon. The gross and microscopic changes noted in the rectum prior to operation were identical with those described in autopsy specimens obtained from patients with postoperative enterocolitis 2 and in post antibiotic pseudomembranous colitis. 3 Following operation the first abnormality to disappear was the pseudomembrane overlying the mucosa. This was accompanied by a gradual diminution in the number of hyperactive secretory glands and a reduction in the edema and inflammatory infiltration of the lamina propria. Although recovery was rapid it was not complete. Nine months later the mucosa of the rectum was still granular in appearance and friable when touched; mild inflammatory reaction was still present in histological sections of the mucosa (fig. 4). In the short period of observation following restoration of the

6 January 1970 CASE REPORTS 93 FIG. 4. Photomicrographs of colon mucosa. All sections were stained with hematoxylin, Phloxine, and saffron. A, hypersecretory mucus glands with streaming of mucus into lumen. Mucus admixed with fibrin and blood is infiltrated with large number of inflammatory cells to form the pseudomembrane (X 50). B, 10 days after colectomy. The pseudomembrane has disappeared. Marked decrease in the cellular content of the lamina propria with persistence of hypersecretory glands has occurred (X 50). C, 10 weeks after colectomy. Similar features as in figure 4B seen at higher magnification (X 125). D, 9 months after colectomy. The glands are quiescent in contrast to hypersecretory activity in figure 4C. A mild increase of lymphocytes and plasma cells are still present in the lamina propria (X 125). continuity of the intestine there was no flare-up of the disease, but a longer period of follow-up will be required to assess the effect of the operation fully. The etiology of pseudomembranous colitis in the 2 patients is not clear. It is unlikely that infection played a part because Staphylococcus aureus was not found in smears and cultures of the stool or in sections of the rectal biopsy. The failure to find pathogenic organisms or fungi when the disease was florid suggests that the gram-positive cocci found in the resected specimen of the 2nd patient invaded the abnormal mucosa late in the course of the disease. Pseudomembranous colitis has been reported in patients given antibiotic therapy in the absence of an identifiable infective agent 3-6 but a cause and effect relationship has not been established. Although both of our patients received antibiotics, the role that they played in the development of the disease is unknown. Debilitating diseases,7 intestinal obstruction,l. 8 and surgical operations 2 9 have been reported to antedate the development of pseudomembranous colitis, but none of these conditions was present in our patients. Hardaway and McKaylO considered shock to be an important factor because of its frequent association with pseudomembranous colitis. However, shock is a frequent complication of this disorder and in most cases where shock has been

7 94 CASE REPORTS Vol. 58, No.1 incriminated it is not evident that it actually preceded the onset of the colitis. Shock occurred late in the course of the disease in both of our patients and there was no evidence of vascular thrombosis in the colon. The major therapeutic problem in both of our patients was the rapid development of shock. In the early phase of the illness this was associated with marked dehydration and electrolyte imbalance due to the loss of water and electrolyte in the bowel motions, whereas in the late phase diarrhea was not marked and parenteral fluid given to correct the dehydration accumulated in the pleural cavities, abdomen, and tissues. Severe hypoproteinemia secondary to the loss of plasma protein into the colon contributed to the escape of the intravascular fluid into the tissues, reduction in the effective plasma volume, and consequent shock. Adequate treatment of pseudomembranous colitis depends on the replenishment of the fluid, electrolyte, and protein that are lost from the gastrointestinal tract. Plasma has been advocated as the fluid of choice at the onset. ll The severity of the hypoproteinemia in our patients suggests that this may be inadequate in severe cases. Under circumstances where the plasma protein concentration is low, the plasma infusions should be supplemented with salt-free albumin. If plasma protein is adequately replaced in the early phase of the disease it may be possible to reduce the subsequent development of edema and prevent the diminution in effective plasma volume. We have not encountered previous reports of the use of surgery to correct the outpouring of plasma into the gastrointestinal tract in pseudomembranous colitis. The decision to carry out a partial colectomy in our 2nd patient was influenced by the relentless deterioration of her condition despite intensive therapy, the absence of infection and underlying disease, and the knowledge gained at laparotomy that the disease appeared to be confined to the colon. The prompt improvement in the hypoproteinemia and edema following partial colectomy and gradual improvement in the patient's condition lend support to the use of surgery under these circumstances. It would seem reasonable, therefore, that surgery be considered in patients with noninfective pseudomembranous colitis without any predisposing debilitating disease when adequate medical therapy fails to correct the shock. A factor which will influence the outcome of the operation is the extent of the involvement of the intestinal tract. Although extensive disease may occur in both the small and large intestine, there are a number of cases similar to ours in which the disease has been confined to the colon. 1, 6, 12 REFERENCES 1. Goulston, S. J. M" and V. J. McGovern Pseudomembranous colitis. Gut 6: Penner, A., and A. 1. Bernheim Acute post-operant enterocolitis; a study on the pathologic nature of shock. Arch. Path. (C hicago) 27: Reiner, L., M. J. Schlesinger, and G. M. Miller Pseudomembranous colitis following aureomycin and cloramphenicol. Arch. Path. (Chicago) 54: Altemeier, W. A., R. P. Hummel, and E. O. Hill Staphlococcal enteritis following antibiotic therapy. Ann Burg. 157: Dearing, W. H., and F. R. Heilman Micrococcic (staphylococcic) enteritis as a complication of antibiotic therapy: its response to erythromycin. Proc. Mayo Clin. 28: Valberg, L. S., and S. C. Truelove Noninfective pseudomembranous colitis following antibiotic therapy. Amer. J. Dig. Dis. 5: Birnbaum, D., A. Laufer, and M. Freund Pseudomembranous colitis. A clinicopathologic study. Gastroenterology 41: Kleckner, M. S., Jr., J. A. Bargen, and A. H. Baggenstoss Pseudomembranous enterocolitis: clinicopathologic study of 14 cases in which the disease was not preceded by an operation. Gastroenterology 21: Pettet, J. D., A. H. Baggenstoss, E. S. Judd, Jr., and W. H. Dearing Generalized

8 January 1970 CASE REPORTS 95 post-operative pseudomembranous enterocolitis. Proc. Mayo Clin. 29: Hardaway, R. M., and D. G. McKay Pseudomembranous enterocolitis. Are antibiotics wholly responsible? Arch. Surg. (Chicago) 78: Bockus, H. L. [ed.] Gastroenterology, Vo!' 2, p W. B. Saunders Company, Philadelphia. 12. Bloomfield, D. A., and M. N. I. Walters Pseudomembranous enterocolitis. Med. J. Aust. 2: