Diagnostic Images, Treatment Decisions: Young Man With Profuse Diarrhea, Nausea, and Fever

A 28-year-old man is admitted with a 3-day history of 10 to 15 episodes per day of profuse watery, nonbloody, explosive diarrhea with mucus. The diarrhea is associated with nausea, generalized crampy abdominal pain, and low-grade fever. History. The patient returned from a trip to his native village in Mexico about a week earlier and attended a wedding 4 days ago. He denies recurrent diarrhea, hematemesis, melena, cough, dyspnea, palpitation, rashes, adenopathy, weight loss, and tremors. He is taking levofloxacin and clindamycin for an acute exacerbation of chronic sinusitis. He does not use illicit drugs or alcohol, and he has a monogamous relationship with his wife. Examination. This well-built, well-nourished man appears ill. Heart rate is 92 beats per minute; temperature, 37.7°C (100°F); respiration rate, 24 breaths per minute; blood pressure lying down, 110/68 mm Hg; standing, 104/64 mm Hg. His hydration level is fair; the mucous membranes are dry. Examination of the head and neck reveals maxillary sinus tenderness but no evidence of erythema, candidal infection, or icterus. There is no palpable adenopathy or ankle edema, and the thyroid is not palpable. Abdominal examination reveals mild distention and generalized diffuse tenderness, but no organomegaly. Bowel sounds are hyperactive. Hernial orifices are clear. Findings from the rectal examination are normal; results of a guaiac stool test are positive. Other systemic examination results are normal. Laboratory studies. White blood cell (WBC) count, 26,000/μL, with 94% polymorphonuclear leukocytes and 6% lymphocytes. Hemoglobin level, 14 g/dL. Erythrocyte sedimentation rate, 60 mm/h. The results of 2 blood cultures are negative. Serum glucose level, 92 mg/dL; blood urea nitrogen, 30 mg/dL; creatinine, 1.1 mg/dL; serum sodium, 132 mEq/L; potassium, 3.4 mEq/L; chloride, 96 mEq/L; bicarbonate, 26 mEq/L. Thyroid function tests are normal. Urinalysis results are normal. Gram staining of a stool specimen shows numerous WBCs; culture results are negative for Salmonella, Shigella, and Campylobacter. The patient undergoes a colonoscopy.  What abnormalities are evident on this image and what do you suspect is the cause? A. Crohn disease B. Acute amebiasis C. Campylobacter-induced diarrhea D. Clostridium difficile colitis E. Giardia lamblia infection   Answer and Discussion on next page , WHAT’S WRONG: The colonoscopic examination reveals diffuse yellowish pseudomembranous plaques that suggest pseudomembranous colitis (PMC). In a patient with acute diarrhea who is taking clindamycin, these colonoscopic findings point to C difficile colitis, D. Hospital course. No ova or parasites are found on 3 successive stool examinations. The stool cytotoxin test is positive for C difficile toxins A and B.  The patient is rehydrated with intravenous fluids. Levofloxacin and clindamycin are discontinued, and metronidazole, 250 mg q6h, is begun. Within 72 hours, the patient’s diarrhea diminishes and the abdominal pain subsides. He is discharged with instructions to complete a 10-day course of metronidazole. At a follow-up appointment, he is doing well. CAUSE AND EPIDEMIOLOGY PMC is a toxin-mediated inflammatory disease of the colon caused by C difficile. Most cases of PMC during the past 3 decades have been associated with antibiotic therapy. Nearly all antimicrobial agents have been implicated, except for parenteral aminoglycosides, sulfonamides, and vancomycin. Clindamycin, cephalosporins, and ampicillin are the agents most frequently associated with C difficile diarrhea. In the United States, C difficile colitis occurs much more frequently in hospitalized patients than in community- dwelling persons. It is the fourth most common nosocomial disease reported to the CDC, with 1 to 10 cases per 1000 discharges. Outside the hospital, the incidence is less than 1 case per 10,000 antibiotic prescriptions. Other risk factors include advanced age, inflammatory bowel disease, uremia, burns, recent abdominal surgery, chemotherapy, immunosuppression, and cancer. PATHOPHYSIOLOGY PMC results from a disruption of the normal bacterial flora of the colon, colonization with C difficile, and release of toxins that cause mucosal damage and inflammation. Antibiotic therapy is the key factor that alters the colonic flora and allows C difficile to flourish. At least 2 toxins are involved in the disease process: toxin A (enterotoxin) and toxin B (cytotoxin). These toxins activate the release of cytokines from monocytes, which is instrumental in inducing the marked colonic inflammation seen in PMC. CLINICAL MANIFESTATIONS C difficile infection commonly presents as mild to moderate diarrhea sometimes accompanied by lower abdominal cramping. Symptoms usually begin during or shortly after a course of antibiotic therapy, but occasionally they do not appear for several weeks; thus, it is important to ask patients with diarrhea about recent antibiotic use. Severe colitis without pseudomembrane formation may present with profuse, debilitating diarrhea; diffuse abdominal pain; and distention. Common systemic manifestations include fever, nausea, anorexia, malaise, and dehydration. Peripheral leukocytosis and an increased number of fecal leukocytes are common. Occult colonic bleeding may occur. Sigmoidoscopy usually reveals diffuse or patchy colitis. The clinical picture of PMC—the most dramatic manifestation of C difficile infection—is similar to that of C difficile colitis without pseudomembranes except that diarrhea, abdominal tenderness, and systemic symptoms tend to be more pronounced. Diarrhea is profuse, watery or mucoid, green, and foul-smelling. Liquid stool may contain small amounts of blood. Diffuse abdominal pain with tenderness occurs in one third of cases. The temperature may reach 38.8°C to 39.4°C (102°F to 103°F) in 30% to 50% of patients. Marked leukocytosis (WBC count higher than 20,000/μL) occurs in 50% to 60% of patients. Sigmoidoscopic or colonoscopic examination reveals yellowish white plaques that vary in diameter from 2 to 10 mm; the underlying mucosa is reddened and edematous (Figure). The intervening mucosa generally appears normal or mildly erythematous. The rectum and sigmoid colon are typically involved, but in approximately 10% of cases pseudomembranes may be seen in the proximal colon. DIAGNOSIS Suspect PMC in a patient with profuse diarrhea who is taking or who has recently completed a course of antibiotic therapy.  Prompt endoscopic examination is recommended. Sigmoidoscopy is an option, but gastroenterologists prefer colonoscopy. Stool examination is critical. It should include: •Fecal leukocyte test. A positive result (more than 5 leukocytes per high-power field) excludes benign diarrhea. However, a negative result does not rule out PMC. •Stool Culture. This is performed to exclude other enteric pathogens, such as Salmonella, Shigella, and Campylobacter.  However, the presence of C difficile in stool culture does not establish the diagnosis of PMC, because the organism is found in the stool of 20% of patients taking antibiotics. •Stool cytotoxin test (tissue culture assay). This is the gold standard for diagnosis, with a sensitivity of 94% to 100% and a specificity of 99%. The test is expensive, however, and overnight incubation of samples is required. Several rapid immunoassays for detection of C difficile antigens and toxins are now commercially available. These include latex agglutination tests (sensitivity, 48% to 59%; specificity, 95% to 96%) and enzyme immunoassay (sensitivity, 69% to 87%; specificity, 99% to 100%). A complete blood cell count reveals leukocytosis; the WBC count ranges from 10,000/μL to 50,000/μL. In patients with severe disease, blood chemistry analysis demonstrates electrolyte abnormalities as well as hypoalbuminemia. TREATMENT Management includes supportive and specific measures. Offending antimicrobial therapy must be discontinued. Fluid electrolyte replacement with colloids and, in severe cases, parenteral nutrition are used to rest the bowel. Avoid antidiarrheal, antimotility, and narcotic agents because they may prolong or worsen the disease.  Specific therapy aimed at eradicating C difficile  is indicated if symptoms are severe or persistent. Metronidazole, 250 mg qid, is the drug of choice. Reserve vancomycin, 125 mg qid, for patients who cannot tolerate or do not respond to metronidazole. These agents are equally effective. Symptomatic improvement can be expected within 72 hours; diarrhea and colitis resolve completely in more than 95% of patients after 10 days of treatment. Patients who cannot tolerate oral medications because of ileus or recent abdominal surgery can be effectively treated with intravenous metronidazole; the drug is excreted in bile, and exudation from the inflamed colon results in bactericidal levels in feces. Intravenous vancomycin is not recommended because excretion of this agent into the GI lumen does not occur in adequate antimicrobial concentrations. Surgery is usually recommended for seriously ill patients; the preferred procedure is colectomy with a temporary diverting ileostomy. The principal indications for surgery are: • Failure to respond to medical management. • Progressive organ failure. • Toxic megacolon. • Signs of peritonitis. PROGNOSIS C difficile diarrhea recurs in up to 20% of cases. The typical clinical pattern is recurrence of diarrhea 3 to 10 days after treatment is discontinued. Subsequent relapses may occur in approximately 8% of patients after treatment of the initial relapse. Treatment of a relapse consists of a second course of antimicrobial therapy. Treatment of multiple relapses is controversial; it may include prolonged antibiotic therapy and administration of other agents, including cholestyramine, rifampin, lactobacilli, yeast, Saccharomyces boulardii,  or intravenous immunoglobulin.  Dr Manish Amin is an associate in the department of emergency medicine at Kern Medical Center in Bakersfield, Calif, where Dr Navin Amin is chairman of family medicine and pediatrics. Dr Navin Amin is also professor of family medicine at the University of California at Irvine, associate professor of medicine at the University of California at Los Angeles, and associate professor of family medicine at Stanford University School of Medicine in Stanford, Calif. FOR MORE INFORMATION: Bartlett JG. Clinical practice. Antibiotic associated diarrhea. N Engl J Med. 2002;346:334-339. Johnson S, Gerding DN. Clostridium difficile–associated diarrhea. Clin Infect Dis. 1998;26:1027-1036. Kelly CP, Pothoulakis C, Lamont T. Clostridium difficile colitis. N Engl J Med. 1994;330:257-262. Kyne L, Farrell RJ, Kelly CP. Clostridium difficile. Gastroenterol Clin North Am. 2001;30:753-758. Mylonakis E, Ryan ET, Calderwood SB. Clostridium difficile–associated diarrhea: a review. Arch Intern Med. 2001;161:525-533.