Clinical Presentations Diarrhea

Preparative Period

The preparative regimen is the most common cause of diarrhea occurring within the first 2 weeks after bone marrow infusion. Drug-induced diarrhea occurs commonly in response to the preparative regimen that includes high dose cyclophosphamide and busulfan and may persist for 2 to 3 weeks. Sandostatin (Octreotide) (250 |g subcutaneously 3 times per day) has been reported by Morton and Durrant (1995) in a small series as being effective in loperamide-resistant preparative regimen related diarrhea. Oral gluta-mine supplementation has yielded mixed results when studied to determine if it could improve the nutritional status and diarrhea frequency in SCT patients (Coghlin Dickson et al, 2000). Mycophenolate mofetil causes diarrhea in a third of patients, inducing an enterocolitis characterized by the presence of patchy inflammation and focal crypt distortion (Maes et al, 2003). As this drug is used increasingly for GVHD prophylaxis, differentiating GVHD from the effects of the drug through use of a drug holiday is critical.

Acute GVHD

Diarrhea occurring after bone marrow engraftment (about the third week after SCT) is most likely due to acute GVHD, an immune mediated process triggered by activation of donor lymphocytes. Acute GVHD is a multisystemic process affecting the skin, liver, and gut. At Johns Hopkins, SCT patients with stages 2,3, and 4 acute GVHD had median survivals of only 5.4, 3.6, and 2.5 months, respectively, despite treatment (Arai and Vogelsang, 2000). Gut involvement does not require the presence of skin or liver involvement, although when these organs are affected, suspicion is raised for GVHD. Acute GVHD ranges from mild, with only small increases in stool volume occurring, to severe, with the passage of several liters of watery stool per day. In its most severe form, desquamation of the gut mucosa occurs and the diarrhea is complicated by severe losses in electrolytes and albumin.The presence of abdominal cramping is highly variable, particularly in the less severe form of gut GVHD. However, when desquamation occurs, affected individuals may have severe abdominal pain, requiring the use of narcotics for relief.

The diagnosis of acute GVHD can only be made by endoscopic biopsy, particularly if only subtle endoscopic changes are present since there is little correlation between endoscopic appearance and degree of histologic abnormality (Cruz-Correa et al, 2002). When present in the gut, in general, the stomach, small intestine, and colon are simultaneously affected, although the extent of histologic inflammation and injury may vary from one part of the gut to another. Although acute GVHD is panintestinal, involvement may be associated with only upper or lower Gi symptoms exclusively, and, therefore, endoscopic evaluation should be directed by the patient's symptoms and the need to exclude infectious etiologies. in the upper Gi tract, the duodenum is often the segment that gives the most dramatic endoscopic appearance of GVHD (Figure 48-2). Excessive GI bleeding from duodenal biopsies rarely occurs if the platelet count is above 50,000/mm3. The histologic diagnosis is based on the presence of apoptotic colonocytes, loss of crypts, and, at times, a neutrophilic or eosinophilic infiltrate. Although no definite pathognomonic endoscopic appearance of GVHD has been conclusively established, the appearance of widespread desquamation in the esophagus, duodenum or colon, is highly suspicious for the severest form of GVHD (Cruz-Correa et al,2002).

Treatment of acute GVHD begins with high dose steroids, followed by the addition of other immunosuppressive agents, such as mycophenolote mofetil (Cellcept) or pento-statin. Oral beclomethasone should be reserved for patients that have mild to moderate GVHD isolated to the GI tract and present primarily with nausea, vomiting, or anorexia (McDonald et al, 1998). For steroid refractory GVHD, response to a TNF-a monoclonal antibody (Infliximab) has been encouraging (Kobbe et al, 2001). Although no randomized controlled studies exist, control of the voluminous diarrhea associated with acute GVHD has reportedly been achieved by somatostatin (octreotide) given at 250 to 500 |g 3 times daily subcutaneously (Ippoliti et al, 1997). Individuals with the most severe form of GVHD are at high risk of developing sepsis due to loss of the mucosal barrier and immunosuppression, so prophylactic antibiotic use is

FIGURE 48-2. Endoscopic appearance of severe graft-versus-host disease in the duodenum. Histology was remarkable extensive surface erosion, inflamed granulation tissue, cryptitis, and crypt abscesses.

strongly advocated. Total parenteral nutrition (TPN) should also be initiated because of the tremendous protein and electrolyte losses sustained by these patients (Papadopoulou et al, 1996).

Infectious Diarrhea

Infectious diarrhea is a less frequent complication of SCT accounting for 13% of acute diarrheal episodes in one study (Cox et al, 1994). The most common enteric viral infections were astrovirus, adenovirus, cytomegalovirus (CMV), and rotavirus. CMV may cause colitis or gastritis, and generally occurs 4 to 5 months after transplantation in our experience, but all patients are at risk once they have engrafted. The presence of multinucleated giant cells or positive immunohistochemical stains of mucosal biopsies is diagnostic of CMV infection. On occasion the presence of CMV early antigen does not correlate with active GI involvement. Therapy for CMV is discussed in the chapter on infectious esophagitis (see Chapter 16, "Esophageal Infections"). Clostridium difficile is the most common cause of infectious diarrhea in the outpatient. Rare reports of parasitic infections occurring in the SCT patient also exist.

Chronic GVHD

Chronic GVHD affects 40 to 50% of SCT patients, occurring most often in those who have had acute GVHD, but can arise de novo. In contrast to acute GVHD, which is typified by mucosal injury in the gut, chronic GVHD in the gut is characterized by the presence of fibrosis and atrophy, leading to GI dysmotility syndromes such as gastropare-sis or constipation. Bacterial overgrowth may complicate small bowel dysmotility. Chronic GVHD usually does not induce inflammatory changes in the mucosa, making mucosal biopsies seldom useful in making the diagnosis. However, upper endoscopy or colonoscopy is sometimes performed to evaluate for other causes of gastric outlet obstruction, diarrhea, or new onset constipation.

Most commonly, even late diarrhea (occurring 100 days after SCT) is due to acute GVHD, particularly in patients who have had GI involvement in the past, and because acute GVHD and chronic GVHD are treated differently, making the correct diagnosis very important (Akpek et al, 2002). Therapy for chronic GVHD involves corticosteroids usually combined with cyclosporine A or tacrolimus. Salvage therapy is not standard and may involve such agents as mycophenolate mofetil, pentostatin, and rapamycin.

Constipation Prescription

Constipation Prescription

Did you ever think feeling angry and irritable could be a symptom of constipation? A horrible fullness and pressing sharp pains against the bladders can’t help but affect your mood. Sometimes you just want everyone to leave you alone and sleep to escape the pain. It is virtually impossible to be constipated and keep a sunny disposition. Follow the steps in this guide to alleviate constipation and lead a happier healthy life.

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