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Serum immunoglobulin and immunoglobulin G subclasses in children with allergic colitis.

Serum immunoglobulin and immunoglobulin G subclasses were measured in thirty children with histologically proven allergic colitis and twenty age matched controls. Serum immunoglobulin A (mean +/- sd) (0.45 +/- 0.25 vs 87 +/- 0.41 Gm/L), IgG2 (29.2 +/- 13.1 vs 49.5 +/- 12.8 mg/dL), and IgG4 (7.58 +/- 3.01 vs 11.2 +/- 2.59 mg/dL) were significantly lower in allergic colitis than in the controls respectively (p < 0.001). There was a significant elevation of serum IgE in those with allergic colitis (p < 0.01). The serum IgG1 and IgG3 levels were not significantly different in allergic colitis and the controls (p > 0.10). Immunoglobulin A, IgG2 and IgG4 subclasses were low in 43.3%, 75.0% and 55.0% of cases of allergic colitis respectively, compared to 5.0% of the controls with low IgG2 and IgG4 (p < 0.005). The IgG1 and IgG3 subclasses were normal and comparable in both groups. Children with food allergic colitis in this study have low levels of IgG A, IgG2 and IgG4 subclasses. IgA, IgG2 and IgG4 subclass deficiency probably have a role to play in the pathogenesis of allergic colitis an mucosal immune defense mechanism.

Case-Control Studies↗

Severe Clostridium difficile colitis.

PURPOSE: Reports of fatality related to Clostridium difficile colitis and a sharp increase in prevalence of this infection prompted a study of patients who develop a more aggressive form of this disease. METHODS: Over 38 months, 710 patients at our institution developed C. difficile colitis. Twenty-one (3 percent) of these patients either required intensive care unit admission or died as a result of their infection. A retrospective, case-controlled study was undertaken to compare these patients, who were considered to have severe C. difficile colitis, with the remaining patients with milder disease. RESULTS: Factors that predisposed to the development of severe C. difficile colitis included intercurrent malignancy, chronic obstructive pulmonary disease, immunosuppressive and antiperistaltic medications, renal failure, and administration of clindamycin (P < 0.05 for all). Patients with severe C. difficile colitis were more likely to have abdominal pain, tenderness and distention, peritonitis, hemoconcentration (> 5 points), hypoalbuminemia (< 3 mg/dl), and elevated or suppressed white blood cell count (> 25,000; < 1,500; P < 0.05 for all). These factors were used to create a scoring system that could distinguish between patients with severe C. difficile colitis and those with mild disease. Thirteen patients in the late stages of terminal illness with metastatic malignancy or age > 90 were considered poor or inappropriate surgical candidates. Only the remaining eight patients could have potentially recovered from operation with hope for long-term survival. Of these, seven were treated without colonic resection, and six of the seven survived, whereas one patient underwent colectomy and did not survive. CONCLUSIONS: Patients with severe C. difficile colitis can be readily identified. Often they have coexisting illness that precludes operation. In this series, only 1 of 21 patients with severe C. difficile might have benefited from an aggressive surgical approach.

Age Factors↗

Clostridium difficile-associated diarrhea and colitis: clinical manifestations, diagnosis, and treatment.

PURPOSE: This review examines the pathogenesis, clinical manifestations, diagnosis, and current medical and operative strategies in the treatment of Clostridium difficile diarrhea and colitis. Prevention and future avenues of research are also investigated. METHODS: A review of the literature was conducted with the use of MEDLINE. RESULTS: C. difficile is a gram-positive, spore-forming bacterium capable of causing toxigenic colitis in susceptible patients, usually those receiving antibiotics. Overgrowth of toxigenic strains may result in a spectrum of disease, including becoming an asymptomatic carrier, diarrhea, self-limited colitis, fulminant colitis, and toxic megacolon. Diagnosis requires a high index of suspicion and depends on clinical data, laboratory stool studies (enzyme-linked immunoabsorbent assay and cytotoxin test), and endoscopy in selected cases. Protocols for treatment of primary and relapsing infections are provided in algorithm format. Discontinuation of antibiotics may be enough to resolve symptoms. Medical management with oral metronidazole or vancomycin is the first-line therapy for those with symptomatic colitis. Teicoplanin, Saccharomyces spp. and Lactobacillus spp., and intravenous IgG antitoxin are reserved for more recalcitrant cases. Refractory or relapsing infections may require vancomycin given orally or other newer modalities. Fulminant colitis and toxic megacolon warrant subtotal colectomy. Cost, in terms of extended hospital stay, medical and surgical management, and, in some cases, ward closure, is thought to be formidable. Review of perioperative antibiotic policies and analysis of hospital formularies may contribute to prevention and decreased costs. CONCLUSION: C. difficile diarrhea and colitis is a nosocomial infection that may result in significant morbidity, mortality, and medical costs. Standard laboratory studies and endoscopic evaluation assist in the diagnosis of clinically suspicious cases. Appropriate perioperative antibiotic dosing, narrowing the antibiotic spectrum when treating infections, and discontinuing antibiotics at appropriate intervals prevent toxic sequelae.

Clostridioides difficile↗

Clostridium difficile colitis: correlation of CT findings with severity of clinical disease.

Clinical records and abdominal CT scans from 64 patients with documented Clostridium difficile disease were reviewed to determine if any correlation existed between CT findings of colitis and severity of clinical disease. Clostridium difficile disease was documented with stool toxin titre levels and CT scans were performed within 3 days of stool sample. Clinical disease severity was estimated by tabulating the degree of fever, WBC count, frequency and duration of diarrhoea. Thirty-nine of 64 patients showed CT evidence of colitis of which 28/39 showed evidence of focal colitis and 11/39 had pancolitis. CT findings suggesting colitis included colonic wall thickening (39 patients), nodular mucosal thickening (11 patients), the 'accordion pattern' (3 patients), pericolonic oedema (27 patients) and ascites (10 patients). Twenty-five of 64 patients showed no CT evidence of colitis. The clinical severity of disease did not statistically differ (P < 0.05) between patients with CT evidence of colitis and those without colitis. The only CT finding that correlated with clinical severity of disease was nodular mucosal thickening which was found with significantly (P < 0.05) more frequency in patients with a WBC count > 11,000 mm3. CT changes with Cl. difficile disease correlate poorly with the clinical severity. This and negative findings do not exclude the disease.

Adult↗

Nonlymphocyte-derived tumor necrosis factor is required for induction of colitis in recombination activating gene (RAG)2(-/-) mice upon transfer of CD4(+)CD45RB(hi) T cells.

In this study, we addressed the role of tumor necrosis factor (TNF)-alpha and lymphotoxin (LT)-alpha in the development of colitis and defined the cellular sources (T cells versus non-T cells) of TNF (TNF-alpha and LT-alpha) relevant to disease development. After adoptive transfer of TNF(+/+) CD4(+)CD45RB(hi) splenocytes into TNF(+/+) recombination activating gene (RAG)2(-/-) mice, the recipients develop massive inflammation of the large intestinal mucosa concurrent with massive weight loss. In contrast, clinical signs of disease are completely absent in TNF(-/-)RAG2(-/-) recipients of TNF(-/-) CD4(+)CD45RB(hi) T cells, although elevated numbers of interferon-gamma-producing cells are present in the colonic mucosa. Surprisingly, upon transfer of TNF(-/-)CD4(+)CD45RB(hi) T cells into TNF(+/+)RAG2(-/-) recipients, colitis develops with kinetics similar to those upon transfer of TNF(+/+)CD4(+)CD45RB(hi) donor cells. In contrast, no clinical signs of colitis are observed in TNF(-/-)RAG2(-/-) recipients of TNF(+/+)CD4(+)CD45RB(hi) T cells. This protection from colitis is not a consequence of the absence of LT-alpha, as TNF-alpha(-/-)RAG2(-/-) recipients of TNF-alpha(-/-) CD4(+)CD45RB(hi) T cells are also protected from colitis induction. These results demonstrate the importance of TNF production by non-T cells of the colonic mucosa in the pathogenesis of colitis and provide direct evidence for a nonredundant role of TNF-alpha in this mouse model of colitis.

Adoptive Transfer↗

The role of the resident intestinal flora in acute and chronic dextran sulfate sodium-induced colitis in mice.

OBJECTIVE: There is increasing evidence that the intestinal microflora plays an important role in the pathogenesis of inflammatory bowel disease. In the present study, we examined the role of the resident intestinal flora in our model of dextran sulfate sodium (DSS)-induced acute and chronic colitis in mice. METHODS: Acute colitis was induced in BALB/c mice with 5% DSS in their drinking water for 7 days. Chronic colitis was established after four cycles of feeding 5% DSS for 7 days and water for 10 days. For eliminating intestinal bacteria, mice were injected intraperitoneally with metronidazole and ciprofloxacin. We analysed four parameters: (1) body weight, (2) length of the colon, (3) histological score, and (4) myeloperoxidase activity. RESULTS: In acute DSS colitis treatment with antibiotics led to an improvement of the histological parameters (epithelial damage, P< 0.05; inflammatory infiltrate, P< 0.05) and colon length (P < 0.0028). A significant reduction in granulocyte infiltration was indicated by a 52.6% reduced myeloperoxidase activity in colonic biopsies. By contrast, in chronic colitis, treatment of mice with antibiotics failed to show significant effects. CONCLUSION: In acute DSS-induced colitis bacteria and/or bacterial products play a major role in initiation of inflammation but not in chronic DSS colitis.

Acute Disease↗

Faecal diversion for Crohn's colitis: a model to study the role of the faecal stream in the inflammatory process.

The high incidence of clinical remission after faecal diversion for Crohn's colitis suggests the faecal stream may play a part in the inflammatory mechanism. The effect of faecal diversion (n = 22) and restoration of intestinal continuity (n = 10) was assessed in patients with Crohn's colitis and compared with controls. Faecal diversion produced significant improvement in the disease activity index mean (SEM) (before 176 (9); after 114 (9), p < 0.01) and serum albumin concentrations (before 33 (3.0); after 38 (3.0), p < 0.05) in all patients with Crohn's colitis. The crypt cell production rate (CCPR) was maintained after faecal diversion for Crohn's colitis but fell in the control group (before = 3.6 (0.8)), at two (1.4 (0.4), p < 0.02), and six weeks (1.6 (0.4), p < 0.05). Mucosal glucosamine synthetase activity, reflecting glycoprotein synthesis, was significantly lower in patients with Crohn's colitis (analysis of variance p < 0.05) after diversion but was maintained in the control group. Restoration of intestinal continuity failed to produce reciprocal changes. The sustained cellular proliferation and fall in glycoprotein synthesis in Crohn's colitis after faecal diversion may represent the end of an exaggerated protective response and regenerative hyperplasia after exclusion of the faecal stream. This study suggests the faecal stream may participate in the inflammatory process in Crohn's colitis. The underlying mechanism is unknown.

C-Reactive Protein↗

Role of T lymphocytes in rat 2,4,6-trinitrobenzene sulphonic acid (TNBS) induced colitis: increased mortality after gammadelta T cell depletion and no effect of alphabeta T cell depletion.

BACKGROUND AND AIM: Indirect evidence suggests that CD4+ T cells have a pathogenic while gammadelta T cells have a protective role in the initiation and perpetuation of inflammatory bowel disease. To define the role of T cell subsets in a rat colitis model (2,4,6-trinitrobenzene sulphonic acid (TNBS)) we analysed colitis severity after effective depletion of T helper cells, alphabeta T cells, or gammadelta T cells. METHODS: T helper cells, alphabeta T cells, or gammadelta T cells were depleted using previously described monoclonal antibodies directed at the CD4 molecule (OX38), the CD2 molecule (OX34, both depleting CD4+ T cells), the alphabeta T cell receptor (R73), and the gammadelta T cell receptor (V65). Depletion was verified by flow cytometry and/or immunohistology. Colitis was induced using intracolonic application of TNBS. RESULTS: Surprisingly, depletion of T helper cells or alphabeta T cells had no influence on survival, macroscopic or microscopic scores, or myeloperoxidase activity following colitis induction. In contrast, depletion of gammadelta T cells resulted in significantly increased mortality (V65: 73%, n=15) compared with controls (30%, n=13; p<0.03). In addition, colitis was histologically more severe in the gammadelta T cell depleted group compared with controls (p<0.05). CONCLUSIONS: T helper cells or alphabeta T cells did not influence the initiation or perpetuation of rat TNBS colitis. In contrast, gammadelta T cells had a protective role in rat TNBS colitis as depletion caused increased mortality.

Animals↗

Acute abdomen and Clostridium difficile colitis: still a lethal combination.

BACKGROUND: With the steadily prevalent appropriate and inappropriate use of antimicrobial agents, Clostridium difficile colitis has continued to be noticed as a common problem in hospitalized patients. The aim of this communication is to highlight a subset of C. difficile colitis patients who presented with an acute abdomen. METHODS: This is a retrospective study of 10 patients who underwent laparotomy for an 'acute abdomen' with an intraoperative or postoperative diagnosis of C. difficile colitis. RESULTS: All patients received antibiotics (mean 9.5 days) for other illnesses. The mean APACHE II score was 18.8 (range 8-25) and the mortality rate was 80%. Two patients had colostomies created. One patient underwent a subtotal colectomy, and another underwent a Hartmann procedure; the rest had a nontherapeutic procedure. CONCLUSION: We conclude that C. difficile colitis presenting as an 'acute abdomen' still represents a lethal entity. Patients who present with an 'acute abdomen', with a history of recent or current antibiotic intake, and without findings which mandate an exploration should have C. difficile colitis urgently excluded. Timely diagnosis of C. difficile colitis through bedside sigmoidoscopy or a CT scan could spare the critically ill patient an unneccessary and risky operation. Furthermore, if laparotomy is subsequently needed then having a preoperative diagnosis of C. difficile colitis will allow appropriate surgical therapy to be implemented.

Abdomen, Acute↗

Monocyte chemotactic protein-1 in a randomized placebo controlled study of canine plasmacytic-lymphocytic colitis.

The purpose of this study was to determine serum and colonic monocyte chemotactic protein-1 (MCP-1) concentration in dogs with plasmacytic-lymphocytic (PL) colitis, as well as to demonstrate if the concentration of MCP-1 may be an accurate diagnostic and prognostic marker for PL colitis in dogs receiving three different therapeutic protocols. Serum and colonic MCP-1 concentration were measured in 18 dogs with PL colitis and in 6 controls. Dogs with PL colitis were randomly divided in 3 groups and for a period of 30 days received the following: Group 1, sulfasalazine, prednisone and placebo; Group 2, placebo and &#x03C93/&#x03C96 fatty acids, and Group 3, sul-fasalazine, prednisone and &#x03C93/&#x03C96 fatty acids. Colonic and serum MCP-1 concentration were de-termined at the beginning and at the end of this period. Serum MCP-1 concentrations at the be-ginning were not significantly increased in dogs with PL colitis compared to the controls. On the contrary, colonic tissue MCP-1 concentrations at the beginning were significantly increased in the same dogs compared to the controls. Moreover, the colonic tissue MCP-1 concentration in the dogs of group 3 was significantly decreased (P&#x003C0.001) at the end of the experiment. The same observations were obtained from dogs of groups 1 and 2, in which the colonic MCP-1 concentra-tion also significantly decreased (P&#x003C0.01). These data demonstrate that in canine PL colitis, colo-nic MCP-1 concentration is increased in comparison to those of controls and suggest that the colonic MCP-1 concentration may aid in the diagnosis of canine PL colitis.

Journal Article↗

[Pseudomembranous colitis: clinical, endoscopic and radiological correlation--a 2-year experience].

The incidence rates of pseudomembranous colitis are rising. Early diagnosis and treatment are required for management of this potentially life-threatening disease. This report outlines our 2-year experience (1997-1998) at the gastrointestinal institute with 43 patients diagnosed with pseudomembranous colitis and describes the clinical course and imaging studies. The group consisted of 25 women and 18 men, aged 34-93 years (mean: 67). Thirty-nine patients were treated with antibiotics. Twelve patients were referred directly to an endoscopic examination with a presumed clinical diagnosis of pseudomembranous colitis (diarrhea, fever and abdominal pain) that was confirmed by colonoscopy. Thirty-one were referred to colonoscopy following abdominal imaging performed to clarify cause of fever and abdominal pain. Twenty-nine patients had an abdominal CT, one had an US and one a barium follow-through. The CT finding suggesting pseudomembranous colitis included colonic mural thickening in 28 patients (71% diffuse versus 29% segmental colitis), with an average wall thickness of 16 mm. Sixteen patients (59%) had pericolonic fat changes and 15 patients (51%) had ascites. All of these patients, except one, had endoscopic findings consistent with pseudomembranous colitis. Five patients (11.6%) died due to the severe PMC. To conclude, as an abdominal CT is often performed in the acutely ill patient, it may arouse the diagnosis of pseudomembranous colitis in the proper clinical setting. Such a suspected diagnosis justifies endoscopic evaluation, which is the most reliable diagnostic examination.

Adult↗

Ulcerative colitis exacerbation associated with cytomegalovirus infection.

There is an increasing prevalence of ulcerative colitis in Hong Kong and cytomegalovirus infection is an important factor in the exacerbation of the disease. We report on a 33- year-old Chinese man with ulcerative colitis in remission, who presented with bloody diarrhoea that failed to respond to an intensive regimen of oral and rectal steroid. Colonoscopy was performed and biopsy specimens showed signs of cytomegalic colitis in association with ulcerative colitis. Administration of ganciclovir and the gradual termination of steroid treatment resulted in remission of the colitis. The clinical course suggested an exacerbation of ulcerative colitis due to cytomegalovirus infection. The relationship between ulcerative colitis and cytomegalovirus is discussed.

Journal Article↗

[Levels of cytokines in mucosal biopsies of Crohn's colitis. Physiopatological observations].

BACKGROUND: It is well known that mucosal concentrations of many pro and anti-inflammatory cytokines are elevated in diseased segments of colon in Crohn's colitis. The present study, showing preliminary results, aims to determine whether the IL-1beta, IL-6 and IL-8 levels are increased throughout the entire colon in patients with Crohn's colitis. METHODS: Five patients with active Crohn's colitis and five controls were studied by mucosal biopsies. In the diseased patients IL-1beta, IL-6 and IL-8 levels have been measured in both pathologic and normal appearing colonic mucosa. The concentration of these cytokines was assessed using ELISA and compared. Histological sections were also performed to confirm diseased segment of colon. RESULTS: The concentrations IL-1beta and IL-8 were much more higher in patients with Crohn's colitis when compared to controls. Moreover IL-1beta and IL-8 were more elevated in uninvolved colonic segments than on diseased segments. CONCLUSIONS: Our results confirm the finding of other authors that, although Crohn's colitis is a segmental disease, the concentration of IL-1beta and IL-8 in mucosal biopsies is increased throughout the entire colon. In particular our study shows that the concentrations of IL-1b and IL-8 is higher in uninvolved than involved colonic segments. These appearances favour the physio-pathologic hypothesis that Crohn's colitis involves the entire colon even when is not clinically or histologically apparent, and they suggest that uninvolved parts of colon may not be free of disease. Further studies are required to better understand the higher levels of cytokines found in macroscopically normal when compared to pathological mucosal in patients with Crohn's colitis.

Adolescent↗

Antibiotic-associated pseudomembranous colitis.

This review defines the entity pseudomembranous colitis and briefly outlines the supposed etiologic causes of pseudomembranous colitis including antibiotics. The incidence, mortality rate, and natural history of antibiotic-related pseudomembranous colitis is contrasted with other forms and causes of pseudomembranous colitis. The clinical spectrum of antibiotic-related pseudomembranous colitis, ranging from a nonbloody, watery diarrheal state to a life-threatening condition mimicking an acute surgical abdomen, is reviewed. The classic proctoscopic and pathologic findings, as well as common problems encountered in interpretation, are discussed. A complete review of the spectrum of radiographic findings is presented from the nonspecific to the quite characteristic radiographic findings, including both plain film and contrast studies of the colon. These findings are contrasted with the X-ray features of other inflammatory and ischemic colitides and a differential diagnosis is discussed. A section dealing with the treatment of antibiotic-associated pseudomembranous colitis will be included. This section will review the various modes of therapy that have been employed. Finally, a brief section will speculate on the possible etiologic role that antibiotics play in pseudomembranous colitis, including the alteration of the bacterial flora and possible effect on bile salt metabolism.

Administration, Oral↗

Progression and prognosis of Crohn's colitis.

BACKGROUND: Inflammation refractory to medical treatment frequently characterizes the course of Crohn's colitis, often leading to colectomy and need for a stoma. The influence of disease extent within the colon on prognosis and disease progress over time has not been studied so far. AIMS: We evaluated the disease progress and the long-term outcome in 323 patients with Crohn's colitis followed-up for a mean of 9.8 years. METHODS: The charts were analyzed retrospectively, the mean number of documented examinations was 18.5 per patient. The influence of disease pattern, rectal disease and perianal fistulas on the long-term outcome was evaluated using actuarial methods and independent factor analysis. RESULTS: The probabilities of having pancolitis or rectal disease were 77.1% and 78.8% after 15 years, respectively, and higher in patients with initially left-sided or segmental colitis compared with right-sided colitis. The chance of having perianal fistulas was 43.3% after 15 years. The risk of undergoing resectional colonic surgery was 62.2% after 15 years and higher in the presence of right-sided colitis. The cumulative risk of colectomy was 18.2% after 15 years and higher in patients with pancolitis, left-sided colitis or in the presence of perianal fistulas. The 15-year probabilities of proctectomy (12%) and of having a temporary stoma (21%) were only influenced by the presence of perianal fistulas but not by rectal disease or pattern of colitis. CONCLUSIONS: Most patients with colonic Crohn's disease will eventually have pancolitis but only 20% of them will loose the colon. The proctectomy rate is low despite a high frequency of rectal disease. Perianal fistulas and the presence of total or left-sided colonic involvement are adverse risk factors with regard to preservation of colonic length.

Adult↗

Natural history of indeterminate colitis.

The long-term outcome of patients with a pathological diagnosis of indeterminate colitis on a colectomy specimen was investigated. The case records of 46 such patients operated on for inflammatory bowel disease between 1960 and 1983 were reviewed. Using the preoperative clinical information, pathological and radiological reports, it was possible to divide the patients into three groups: group 1, probable Crohn's disease (19 cases); group 2, probable ulcerative colitis (11 cases); and group 3, indeterminate colitis (16 cases). The patients were followed for a minimum of 2.5 years (median 10, range 2.5-28 years). During this period the probable diagnosis changed in five cases only. One patient in group 1 (Crohn's disease) was subsequently considered to have ulcerative colitis (group 2). The other four patients were all in group 3. Three were reclassified as ulcerative colitis and the fourth as Crohn's disease on the finding of a single granuloma in a rectal biopsy. No case in group 3 required subsequent small bowel surgery. These data suggest that patients continuing with a diagnosis of indeterminate colitis in spite of careful preoperative and postoperative assessment are unlikely to show features of Crohn's disease in the long term. This may be important when considering a subsequent restorative proctectomy.

Adolescent↗

Frequency and spectrum of microorganisms isolated from biopsy specimens in chronic colitis.

In 109 patients with chronic diarrhea colonic biopsies were examined for the presence of specific microorganisms. A positive result was obtained in 48% of patients with ulcerative colitis, 50% with Crohn's disease, 21% with non-specific colitis and 36% with non-specific proctitis. Chlamydiae were found most frequently in all groups. Obligate enteropathogenic bacteria were isolated in only three cases of nonspecific colitis. Of the facultatively enteropathogenic organisms Klebsiella and Pseudomonas aeruginosa were isolated in 31% and 24%, respectively, of patients with ulcerative colitis, in 21% and 7% of patients with Crohn's disease, and in 10% and 6% of patients with non-specific colitis. Whereas chlamydial proctitis is a well-known disease, the results of this study point also to a possible pathogenic role of chlamydiae in the proximal colon. Facultatively enteropathogenic organisms causing acute diarrhea might have aetiologic relevance in some cases of chronic non-specific colitis.

Adolescent↗

Histopathological diagnosis of microscopic colitis.

A typical symptom of microscopic colitis (MC) is chronic watery diarrhea with normal endoscopic findings and characteristic inflammatory changes in histopathology. Treatment of the disease is mainly empiric. MC has two main subtypes: lymphocytic colitis and collagenous colitis. There are also untypical histopathological forms of MC: MC with giant cells, MC not otherwise specified (NOS) and cryptal lymphocytic coloproctitis. Some other histopathological changes in MC have been observed, especially Paneth cell hyperplasia or epithelial degeneration. Eosinophilic colitis, acute colitis, amyloidosis, ulcerative colitis and Crohn's disease should be taken into consideration in differential diagnosis. The most reliable biopsy material for histopathological examination are samples obtained from transverse colon. Some studies proved that treatment of MC makes it possible to reduce not only clinical, but also histopathological, manifestations.

Colitis, Collagenous↗