C. Mel Wilcox

Effect of Octreotide on Refractory AIDS-associated Diarrhea: A Prospective, Multicenter Clinical Trial

OBJECTIVE To determine the efficacy and safety of octreotide for treatment of refractory, profuse diarrhea in patients with the acquired immunodeficiency syndrome (AIDS). DESIGN A prospective, open-label study. SETTING Inpatient metabolic units of four university medical centers. PATIENTS Fifty-one patients infected with human immunodeficiency virus (HIV) who had uncontrolled diarrhea (greater than or equal to 500-mL liquid stool per day) despite treatment with maximally tolerable doses of antidiarrheal medications. INTERVENTION After initial baseline studies, patients received octreotide, 50 micrograms every 8 hours for 48 hours. If stool volume was not reduced to less than 250 mL/d, the dose of octreotide was increased stepwise to 100, 250, and 500 micrograms. MAIN RESULTS Fifty men and one woman (mean age, 36.3 +/- 1.1 years) entered and completed the 28-day protocol (14 days of inpatient therapy and 14 days of outpatient therapy). Stool frequency and volume decreased significantly (6.5 +/- 0.5 stools per day on day 0 compared with 3.8 +/- 0.3 stools per day on day 21 [P less than 0.001] and 1604 +/- 180 mL/d on day 0 compared with 1084 +/- 162 mL/d on day 14 [P less than 0.001], respectively). Twenty-one patients (41.2%) were considered to be partial or complete responders (reduction in daily stool volume by greater than or equal to 50% of initial collections or reduction to less than or equal to 250 mL/d). Of the 21 responders, 14 (67%) had no identifiable pathogens at initial screening compared with 9 of 30 (30%) nonresponders (P less than 0.01). CONCLUSION Patients with AIDS-associated refractory watery diarrhea, especially those without identifiable pathogens, may respond favorably to subcutaneously administered octreotide. This drug deserves further study in a randomized, placebo-controlled trial.

Atypical cytomegalovirus inclusions in gastrointestinal biopsy specimens from patients with the acquired immunodeficiency syndrome: Diagnostic role of in situ nucleic acid hybridization

Cytomegalovirus (CMV) infection of the gastrointestinal tract is a common cause of morbidity and mortality in the acquired immunodeficiency syndrome. The proper recognition of CMV-infected cells in gastrointestinal mucosal biopsies is critical so that effective therapy is not delayed, preventing further viral dissemination. Although the pathology criteria for classic CMV inclusions have been well described, the occurrence of morphologically atypical inclusions has been reported but the inclusions are not well characterized. This study prospectively examined the relative frequency of classic and atypical CMV inclusions in gastrointestinal mucosal biopsy specimens from 13 human immunodeficiency virus-positive symptomatic patients. The results demonstrated that classic inclusions were rarely found, including four esophageal, one gastric, and one colonic biopsy specimens in which none were seen. However, atypical CMV inclusions were identified from all biopsy specimens examined; these inclusions were much more numerous than classic inclusions and could be categorized into three morphologic types. The atypical inclusions were difficult to precisely identify as CMV-infected cells, but in situ DNA hybridization for CMV was valuable in establishing their viral origin, thus permitting the correct etiologic diagnosis.

Multicenter trial of octreotide in patients with refractory acquired immunodeficiency syndrome-associated diarrhea

BACKGROUND/AIMS Diarrhea is a significant problem in patients with acquired immunodeficiency syndrome (AIDS). The aim of this study was to determine octreotide effectiveness in refractory AIDS-associated diarrhea. METHODS In a 3-week protocol, 129 patients with a stool weight of > 500 g/day despite standard antidiarrheal therapy were randomized to receive octreotide or placebo (3:2 ratio). Octreotide dose was increased 100 micrograms weekly to a maximum of 300 micrograms three times a day based on weekly 72-hour stool collections. Subsequently, patients received open-label octreotide at doses of up to 500 micrograms three times a day. RESULTS A 30% decrease in stool weight defined response. After 3 weeks, 48% of octreotide- and 39% of placebo-treated patients had responded (P = 0.43). At 300 micrograms three times a day, 50% of octreotide- and 30.1% of placebo-treated patients responded (P = 0.12). At a baseline stool weight of 1000-2000 g/day, 57% of octreotide- and 25% of placebo-treated patients responded (P = 0.06). Response rates based on CD4 counts, diarrhea duration, body weight, human immunodeficiency virus risk factor, and presence or absence of pathogens showed no benefit of octreotide. Adverse events were more frequent in the octreotide-treated group. CONCLUSION In the doses studied, octreotide was not more effective than placebo in patients with refractory AIDS-associated diarrhea. This lack of effectiveness may be attributable to inadequate sample size, doses, and duration of study treatment.

Short‐Term In Vitro Culture and Molecular Analysis of the Microsporidian, Enterocytozoon bieneusi

ABSTRACT. The microsporidium, Enterocytozoon bieneusi, causes a severe, debilitating, chronic diarrhea in patients with the acquired immunodeficiency syndrome. Specific diagnosis of intestinal microsporidiosis, especially due to Enterocytozoon, is difficult and there is no known therapy that can completely eradicate this parasite. Preliminary studies indicate that a short term (about 6 months) in vitro culture of this parasite yielding low numbers of spores, may be established by inoculating human lung fibroblasts and/or monkey kidney cell cultures with duodenal aspirates and or biopsy from infected patients. The cultures may subsequently be used for the isolation and molecular analysis of parasite DNA.

Esophageal Disease in the Acquired Immunodeficiency Syndrome: Etiology, Diagnosis, and Management

Esophageal disease is a common complication and cause of morbidity in patients with human immunodeficiency virus (HIV) infection. Opportunistic esophageal diseases may occur in patients with long-standing infection or may be the initial manifestation of HIV disease. Although a variety of both opportunistic and nonopportunistic disorders result in esophageal disease in this population, candidal esophagitis is the most common cause of symptomatic disease. Ulcerative esophagitis resulting from cytomegalovirus and idiopathic esophageal ulceration constitute the next most important etiologies. In contrast to other immunocompromised hosts, herpes simplex virus esophagitis appears to be relatively uncommon. Multiple simultaneously discovered esophageal disorders have been documented in up to 50% of patients. Opportunistic neoplasms are an infrequent cause of symptomatic disease. Candidal esophagitis may present with either dysphagia or odynophagia, and oropharyngeal candidiasis is usually present at the time of diagnosis. In contrast, ulcerative esophagitis is usually first manifested by moderate to severe odynophagia. Barium esophagography and upper endoscopy are the most commonly employed diagnostic modalities for the evaluation of the symptomatic patient. Although barium esophagography may identify specific abnormalities, this procedure appears to be relatively insensitive for the detection of mild candidal disease as well as nondiagnostic for ulcerative lesions when compared with endoscopy. In the HIV-infected patient with new-onset esophageal symptoms, an empiric trial of a systemically acting oral antifungal agent should probably be the initial management strategy. If the patient does not respond to standard therapy within 1 to 2 weeks, an endoscopic evaluation appears to be the most cost-effective diagnostic test given the diversity of potential disorders, the possibility of one or more co-pathogens or diseases, the potential for an immediate diagnosis, and the availability of mucosal biopsy to make a definite diagnosis of ulcerative or mass lesions. Given the presently available therapy for these diverse processes, establishing a definitive diagnosis in the symptomatic patient not responsive to empiric antifungal therapy is warranted.

Localization of an obstructing esophageal lesion. Is the patient accurate

There are many opinions as to the accuracy of a patients subjective localization of an obstructing esophageal lesion. However, there are few studies specifically examining this issue. Over a 35-month period, all patients evaluated by our gastroenterology service undergoing endoscopy for dysphagia were prospectively identified. The patients subjective localization for the level of obstruction was evaluated by an investigator blinded to the results of prior barium esophagography and recorded on a schematic of the bony skeleton. At the time of endoscopy, the most proximal level of the obstructing lesion was documented. In all, 139 patients with dysphagia and an esophageal stricture were evaluated. Barium esophagograms were performed prior to endoscopy in all but nine patients (6.5%). The most common lesions causing dysphagia were carcinoma (34.5%), gastroesophageal reflux disease (22.3%), and a Schatzkis ring (15.8%). The level of obstruction was localized exactly in 30 patients (21.6%), within ±2 cm in 72 (52%), and within ±4 cm in 31 additional patients (74%). Eight patients (15%) with a distal esophageal lesion localized the obstruction to the proximal esophagus, whereas only two patients (5%) with a lesion in the proximal esophagus localized the level of obstruction to the distal esophagus. Overall, patients with distal obstructing lesions were more likely to have referral >6 cm proximally than proximal lesions with referral to the distal esophagus (P=0.003). There were no significant differences in accuracy based on the cause of dysphagia. In conclusion, a patients subjective localization of the level of an esophageal stricture is highly accurate. Patients appear to be most accurate in localizing proximal rather than distal lesions.There are many opinions as to the accuracy of a patients subjective localization of an obstructing esophageal lesion. However, there are few studies specifically examining this issue. Over a 35-month period, all patients evaluated by our gastroenterology service undergoing endoscopy for dysphagia were prospectively identified. The patients subjective localization for the level of obstruction was evaluated by an investigator blinded to the results of prior barium esophagography and recorded on a schematic of the bony skeleton. At the time of endoscopy, the most proximal level of the obstructing lesion was documented. In all, 139 patients with dysphagia and an esophageal stricture were evaluated. Barium esophagograms were performed prior to endoscopy in all but nine patients (6.5%). The most common lesions causing dysphagia were carcinoma (34.5%), gastroesophageal reflux disease (22.3%), and a Schatzkis ring (15.8%). The level of obstruction was localized exactly in 30 patients (21.6%), within ±2 cm in 72 (52%), and within ±4 cm in 31 additional patients (74%). Eight patients (15%) with a distal esophageal lesion localized the obstruction to the proximal esophagus, whereas only two patients (5%) with a lesion in the proximal esophagus localized the level of obstruction to the distal esophagus. Overall, patients with distal obstructing lesions were more likely to have referral >6 cm proximally than proximal lesions with referral to the distal esophagus (P=0.003). There were no significant differences in accuracy based on the cause of dysphagia. In conclusion, a patients subjective localization of the level of an esophageal stricture is highly accurate. Patients appear to be most accurate in localizing proximal rather than distal lesions.

A pilot study of oral corticosteroid therapy for idiopathic esophageal ulcerations associated with human immunodeficiency virus infection

PURPOSE To evaluate the efficacy and safety of oral prednisone therapy for idiopathic esophageal ulcerations (IEU) associated with human immunodeficiency virus (HIV) infection. PATIENTS AND METHODS Over a 14-month period, all HIV-infected patients with IEU as defined by clinical, endoscopic, and pathologic criteria were prospectively identified. Prednisone was initiated at a dose of 40 mg/d orally, tapering 10 mg/wk, for a total of 1 month of therapy. Patients were closely followed to determine the response to therapy as well as the occurrence of any side effects related to prednisone. All patients were requested to undergo endoscopy within 1 week of the completion of therapy. RESULTS Of 14 patients identified with IEU, 12 consented to prednisone therapy. The mean duration of esophageal symptoms was 2.9 weeks, and odynophagia was the most common presenting symptom. Ten of 12 patients had the acquired immunodeficiency syndrome. Eleven of the 12 patients (92%) had a complete symptomatic response, usually within the first week of therapy. In some patients, the response was dramatic such that oral intake could be rapidly resumed and discharge from the hospital possible. Two patients completed 2 and 3 weeks of therapy, respectively, prior to death, both with a complete symptomatic response. Endoscopic re-examination in seven patients demonstrated complete ulcer healing in all six symptomatic responders, but a persistent ulceration in the one nonresponder. The oral corticosteroid regimen was well tolerated. Mild asymptomatic Candida esophagitis was identified in three of seven patients undergoing follow-up endoscopy. One patient developed self-limited herpes zoster during therapy. No systemic opportunistic infections were documented during or within 1 month of the completion of therapy. CONCLUSIONS Oral corticosteroid therapy appears to be a highly efficacious and safe therapy for HIV-associated IEU. Further controlled studies will be necessary to conclusively establish efficacy, as well as determine the optimal dose and duration of therapy.

Cytomegalovirus esophagitis in AIDS: A prospective evaluation of clinical response to ganciclovir therapy, relapse rate, and long-term outcome

PURPOSE Although cytomegalovirus (CMV) esophagitis is an important complication of acquired immunodeficiency syndrome, there has been little study specifically addressing the response to currently available antiviral therapy, relapse rate without maintenance therapy, and long-term outcome. PATIENTS AND METHODS Over a 45-month period, 44 patients with CMV esophagitis established endoscopically and histopathologically were prospectively identified from among all human immunodeficiency virus (HIV)-infected patients undergoing endoscopy. Induction therapy consisted of intravenous ganciclovir at 10 mg/kg per day for approximately 14 days. Foscarnet was given at 60 mg/kg every 8 hours for nonresponders to ganciclovir. RESULTS Of these patients, 35 completed induction ganciclovir therapy, resulting in a complete response in 17 (49%) and a partial response in 10 (29%), yielding a 77% overall response rate. Seven of 8 nonresponders were subsequently treated with foscarnet, with a clinical response seen in 5 patients. In the 18 eventual complete responders to ganciclovir or foscarnet followed up without maintenance therapy, 7 (39%) relapsed at a median of 4 months (range 2 to 18 months). In all cases, relapse was manifested by recurrent odynophagia. Reinduction ganciclovir therapy yielded a complete response in 1 patient and a partial response in 2, and induction foscarnet treatment resulted in a complete response in the other treated patients. During long-term follow-up, 1 complete responder developed CMV colitis with concurrent retinitis, and 4 other patients developed retinitis. The median survival after diagnosis was 8.2 months, although survival for greater than 1 year was seen in 4 patients. No patient died as a direct result of esophageal disease, although ulcer-related bleeding may have contributed to death in 2 patients with end-stage liver diseases and hepatic encephalopathy. CONCLUSIONS CMV esophagitis has a favorable response to induction ganciclovir therapy, and a long-term remission may occur after induction therapy alone. Despite the favorable response to ganciclovir therapy, the long-term survival is poor, reflecting the severe immunodeficiency of these patients.

Etiology of esophageal disease in human immunodeficiency virus-infected patients who fail antifungal therapy

PURPOSE To determine the etiologies of esophageal symptoms in human immunodeficiency virus (HIV)-infected patients failing antifungal treatment. METHODS Between August 1, 1990 and December 31, 1994, all HIV-infected patients seen at a large inner-city hospital who had esophageal complaints despite being on antifungal therapy were prospectively evaluated for the cause of symptoms. Thus, the population studied included patients given empiric antifungal therapy for esophageal symptoms and patients who developed symptoms while on long-term antifungal therapy. Endoscopy was performed in all patients. The cause of symptoms was determined by the clinical, endoscopic, and pathologic findings, and follow-up after treatment. RESULTS Over the 53-month study period, 74 patients failing empiric antifungal therapy were identified. The majority (77%) of these patients had esophageal ulcers; 25 patients had idiopathic ulcers and 24 had cytomegalovirus. In 2 patients, Candida was present with other causes of ulcerative esophagitis. Candida esophagitis alone was diagnosed in only 3 patients. No endoscopic abnormalities were observed in 14 patients (19%). An additional 24 patients developed esophageal symptoms while receiving antifungal therapy; endoscopic findings in these patients included ulceration in 16 (67%), Candida esophagitis alone in 2, and normal in 6. Empirically treated patients in whom odynophagia was not the only symptom, those with dysphagia alone, and those with a CD4 count > 100/mm3 were less likely to have an endoscopic diagnosis. CONCLUSIONS Esophageal ulceration is the most common cause of esophageal symptoms in HIV-infected patients failing empiric antifungal therapy and those developing symptoms while receiving antifungal agents. Given these findings, endoscopy should be the test of choice for these nonresponders, rather than escalating the dose of antifungal agent, adding other empiric treatments, or performing barium esophagography.

Textbooks of Gastroenterology: A Broad View

The first major gastroenterology textbook was published in 1946 by Henry Bockus. During the ensuing four decades, this text blossomed to become a multiauthor, multivolume encyclopedia; the next edition will appear later this year. In 1970, a single-author work by Howard Spiro appeared; this was written specifically for the practicing gastroenterologist. Three years later, the first edition of Sleisenger and Fordtrans Textbook of Gastrointestinal Disease was published. In contrast to Spiros text, this multiauthor endeavor reviewed not only clinical gastroenterology but physiology and pathophysiology as well, and it quickly became the standard with which other texts have been compared. During the last decade, many gastroenterology texts have appeared, attempting to fill a perceived void, create a niche, or compete directly with Sleisenger and Fordtran. Thus, different types of books are now available to suit any need. My review contrasts and compares these texts in an effort to help physicians in different disciplines select the appropriate one. Gastrointestinal Disease: Pathophysiology, Diagnosis, and Management Fifth edition. M.H. Sleisenger, J.S. Fordtran, B.F. Scharschmidt, and M. Feldman; eds. Philadelphia: W.B. Saunders; 1993.