Interferon-gamma-mediated activation of enterocytes in immunological control of Encephalitozoon intestinalis infection.

The microsporidian Encephalitozoon intestinalis develops within intestinal epithelial cells (enterocytes) and is an important opportunistic diarrhoeal pathogen associated with AIDS. Little is known about the protective immune response against the parasite although in mice IFN-gamma is involved and is required to prevent dissemination of the infection to other organs. The present study was designed to establish a suitable short-term in vitro culture technique for E. intestinalis that would enable studies of the role of cytokines such as IFN-gamma in the effector phase of immunity. Encephalitozoon intestinalis reproduced considerably better in the murine enterocyte cell line CMT-93 than in the three human enterocyte cell lines Caco-2, HT29 and HCT-8. Treatment of CMT-93 cells with IFN-gamma significantly reduced parasite reproduction in a dose- and time-dependent manner. IFN-gamma also inhibited development of the parasite in Caco-2 cells. Neither production of NO nor Fe deprivation appeared to be involved in IFN-gamma-mediated parasite killing. However studies suggested that tryptophan catabolism by indoleamine 2,3-dioxygenase played an important part in inactivation of E. intestinalis.

Guidelines for capsule endoscopy: diagnoses will be missed.

BACKGROUND: Capsule endoscopy represents a significant advance in the investigation of intestinal disease. National Institute of Health and Clinical Excellence, European Society of Gastrointestinal Endoscopy and American Society for Gastrointestinal Endoscopy guidelines support capsule endoscopy in obscure GI bleeding, Crohn's disease and the evaluation of non-steroidal anti-inflammatory drug side-effects, polyposis syndromes and coeliac disease. AIM: To determine whether the application of guidelines leads to missed diagnoses that would have been made if less stringent indications were adopted. METHODS: Retrospective analysis of 100 consecutive unselected capsule endoscopy examinations at Homerton Hospital, from October 2003 to November 2005. All referrals accepted following traditional investigations. Indications and findings were recorded. Comparison made as to whether diagnoses would have been missed if guidelines had been followed and capsule endoscopy not performed. RESULTS: Among the subjects 37 patients were children and 55 were male. Indications included recurrent bleeding and anaemia, assessment of Crohn's disease, 'others', i.e. assessment of coeliac disease, Peutz-Jehgers syndrome, Blue Rubber Bleb syndrome or non-specific abdominal pain. In patients with coeliac disease, widespread enteropathy was confirmed, with additional diagnoses of delayed gastric emptying and colitis. For those with abdominal pain findings included angiodysplasia, lymphoid hyperplasia and distal small bowel ulcers. CONCLUSIONS: Capsule endoscopy in patients with non-conventional indications yielded abnormal pathology, such as ulcers and inflammation. If published guidelines had been followed such diagnoses would have been missed.

Treatment of intestinal microsporidiosis with albendazole in patients with AIDS.

OBJECTIVE: To determine the clinical and parasitological response to treatment of intestinal microsporidiosis with albendazole. DESIGN: Open prospective study. SETTING: Hospital-based HIV/genito-urinary medicine unit. PATIENTS, PARTICIPANTS: Six consecutive AIDS patients with small intestinal microsporidiosis as the only identified cause of diarrhoea after intensive gastrointestinal investigations. RESULTS: Diarrhoea resolved completely in all patients within 1 week of starting treatment, and body weight stabilized or increased. Four patients who relapsed at 19-31 days after the cessation of treatment responded to a second course of albendazole. Degenerative changes occurred in the parasites after treatment, which had not been seen either in pre-treatment biopsies or, in four patients, following therapy with other drugs. CONCLUSIONS: Albenazole is a useful palliative treatment for microsporidial diarrhoea.

Treatment of HIV-related cytomegalovirus disease of the gastrointestinal tract with foscarnet.

Gastrointestinal cytomegalovirus (CMV) disease occurs in a significant proportion of patients with AIDS. A series of 66 AIDS patients with first-episode gastrointestinal CMV disease diagnosed on the basis of clinical and histopathologic findings were treated with foscarnet as first-line therapy at our institution between January 1987 and January 1991. Primary sites of infection were the colon (28 patients) and the esophagus (22 patients). Foscarnet was administered as a continuous infusion of 200 mg/kg (prior to 1988) or as an intermittent infusion of 60 mg/kg t.i.d. or 90 mg/kg b.i.d., with saline hyperhydration accompanying each infusion. Patients were treated initially for 2 weeks, with an additional 1-2 weeks of treatment being given in those not having a complete response during initial treatment; maintenance therapy was given only in cases of concurrent CMV retinitis. Complete response to foscarnet therapy (resolution of symptoms and endoscopic findings) was observed in 17 esophagitis patients (77%) within 3 weeks, with only 4 patients relapsing (at 1-7 months) and none developing colitis or retinitis. Complete response was observed in 16 colitis patients (57%) within 3 weeks, with relapse occurring in 5. Asymptomatic hypocalcemia occurred in 19.7% of patients and penile ulceration occurred in 6.1%; increases in serum creatinine were observed in five patients (7.6%), but did not require discontinuation of treatment. These findings indicate that foscarnet is an effective first-line treatment for gastrointestinal CMV infection. They also suggest that maintenance therapy with foscarnet may not be required in all patients.

A placebo-controlled study to assess the effects of 7-day dosing with 10, 20 and 40 mg rabeprazole on 24-h intragastric acidity and plasma gastrin in healthy male subjects.

AIM: To compare the effects of rabeprazole 10, 20 and 40 mg o.d. on 24-h intragastric acidity and plasma gastrin concentration in a randomized, double-blind placebo-controlled trial. METHODS: Twenty-four healthy male volunteers were studied on the 7th day of morning dosing with either placebo or rabeprazole 10, 20 or 40 mg in a crossover fashion. On day 7, hourly intragastric acidity was measured for 24 h from 08.00 hours by gastric aspiration. Plasma gastrin concentrations were also measured hourly from 08.00 to 24.00 hours, and 2-hourly thereafter. RESULTS: Compared with placebo, rabeprazole 10, 20 and 40 mg produced significant dose-related decreases in intragastric acidity (median 24-h integrated acidity=697, 186, 129 and 82 mmol h/L, respectively). This was associated with significant elevation of plasma gastrin concentration (median 24-h integrated gastrin=141, 1184, 1484 and 1763 pmol.h/L, respectively). Rabeprazole 40 mg resulted in significantly decreased acidity compared with both 10 and 20 mg, and in longer times for which intragastric pH was maintained at > 3 (19. 2 h vs. 17.3 h and 17.5 h) and > 4 (17 h vs. 14.2 h and 15.2 h), but was accompanied by significantly increased plasma gastrin. There was a consistent trend for greater antisecretory activity for 20 mg compared with 10 mg, but these differences did not reach statistical significance. The interindividual variability in antisecretory response was greatest with 10 mg. CONCLUSIONS: Rabeprazole 10, 20 and 40 mg produce significant, profound dose-related inhibition of gastric acid secretion. Taking into account reciprocal increases in plasma gastrin and the interindividual variation in antisecretory response, 20 mg appears to be the preferred dose for routine clinical use.

Adenovirus infection of the large bowel in HIV positive patients.

AIMS: To describe the microscopic appearance of adenovirus infection in the large bowel of human immunodeficiency virus (HIV) positive patients with diarrhoea. METHODS: Large bowel biopsy specimens from 10 HIV positive patients, eight of whom were also infected with other gastrointestinal pathogens, with diarrhoea were examined, together with six small bowel biopsy specimens from the same group of patients. Eight of the patients had AIDS. The biopsy specimens were examined by light microscopy performed on haematoxylin and eosin stained and immunoperoxidase preparations, the latter using a commercially available antibody (Serotec MCA 489). Confirmation was obtained with electron microscopy. RESULTS: The morphological appearance of cells infected with adenovirus showed characteristic nuclear and cellular changes, although the inflammatory reaction was non-specific. Immunoperoxidase staining for adenovirus was sensitive and specific, and the presence of viral inclusions consistent with adenovirus was confirmed by electron microscopy. CONCLUSIONS: The light microscopic features of adenovirus infection are distinctive and immunocytochemistry with a commercially available antibody is a sensitive and specific means of confirming the diagnosis. Further studies of the role of adenovirus in causing diarrhoea in these patients are indicated.

Electron microscopic changes in Enterocytozoon bieneusi following treatment with albendazole.

AIM: To identify and describe electron microscopic changes occurring in Enterocytozoon bieneusi in patients treated with albendazole. METHODS: Eighteen HIV seropositive patients with E bieneusi infection of the small intestine were treated with albendazole 400 mg twice a day for one month. Duodenal biopsy specimens obtained before and at the end of treatment were examined electron microscopically by a pathologist who was unaware of the clinical response. A semiquantitative assessment of the parasite load and description of the parasite morphology was made. RESULTS: A complete resolution of diarrhoea occurred in nine patients and a further three had a greater than 50% reduction in baseline stool frequency or volume. Three of the non-responders were also infected with cryptosporidium. There was a reduction in parasite load in those responding to treatment and an increase in abnormal forms in both responders and non-responders. CONCLUSION: The clinical response to albendazole treatment seen in some patients with small intestine microsporidiosis may be due to damage to the developmental stages, causing a partial inhibition of parasite reproduction.

Histological diagnosis of intestinal microsporidiosis in patients with AIDS.

Fifty nine patients seropositive for human immunodeficiency virus (HIV) and diarrhoea and 20 with weight loss were investigated for microsporidiosis using light and electron microscopical examination of duodenal and jejunal biopsy specimens. Eight cases of microsporidiosis were found, in five of whom it was the sole pathogen. In all eight cases the organism was identified at light microscopy without prior knowledge of the electron microscopical findings. All stages of the life cycle are best seen in resin sections cut at 1 micron and stained with Giemsa, but spores could easily be identified in paraffin sections cut at 5 microns and stained with haematoxylin and eosin. In all cases the parasite was identified both in duodenal pinch and jejunal "Crosby" capsule biopsy specimens. All cases of microsporidiosis occurred in patients with diarrhoea. Both electron and light microscopical examination suggested that the pathogenic mechanism involves the shedding of infected enterocytes containing large numbers of spores. It is suggested that the optimal way to diagnose microsporidiosis is by light microscopical examination of duodenal pinch biopsy specimens.

Acute Budd-Chiari syndrome treated by liver transplantation in a woman homozygous for factor V Leiden.

We describe the first case of Budd-Chiari syndrome due to homozygosity for factor V Leiden resulting in resistance to activated protein C. This is now recognized as the most common procoagulant disorder, and may account for many cases of Budd-Chiari syndrome previously though to be idiopathic or due to a latent myeloproliferative disorder. A further unique feature of this case is that the patient required orthotopic liver transplantation following failure of portacaval shunting and progressive hepatic necrosis. We demonstrated that liver transplantation resulted in correction of the serum coagulation abnormality; however, it is unlikely to have cured the disorder as platelet factor V would still be of the Leiden phenotype.

Pilot studies of azithromycin, letrazuril and paromomycin in the treatment of cryptosporidiosis.

Pilot studies of the safety and efficacy of 3 drugs thought to have anticryptosporidial activity were carried out to determine whether any of them are suitable for large-scale clinical trials. Open studies of the use of azithromycin, letrazuril and paromomycin in patients with acquired immunodeficiency syndrome (AIDS) and confirmed cryptosporidial diarrhoea for at least a month. Azithromycin 500 mg daily was ineffective. Letrazuril 150-200 mg daily was associated with an improvement in symptoms in 40% of patients treated and cessation of excretion of cryptosporidial oocysts in the stool in 70%; however biopsies remained positive. Paromomycin therapy was associated with a complete resolution of diarrhoea in 60% of patients treated and some improvement in symptoms in a further 5% but it did not eliminate the infection. None of the drugs had any major toxicities. Dose escalation studies of azithromycin should be performed. Letrazuril should be further investigated for efficacy in double-blind placebo-controlled trials. Paromomycin appears to result in prolonged symptomatic remission of cryptosporidial diarrhoea, but has no effect on cryptosporidial cholangitis.

Gastrointestinal manifestations of HIV infection.

As patients with human immunodeficiency virus (HIV) infection become more immunocompromised, gastrointestinal symptoms become more common. Most symptoms result from opportunistic infections and can be diagnosed and treated by gastroenterologists, although medical microbiology and histopathology input is essential.

Natural history of AIDS related sclerosing cholangitis: a study of 20 cases.

A case control study of AIDS related sclerosing cholangitis indicates that it has no overall influence on prognosis, but is responsible for a striking reversal of the usual inverse correlation of age and survival in HIV infection. Pain, the principal symptom, was controlled in surviving patients with analgesics alone. Twenty consecutive patients with AIDS related sclerosing cholangitis, defined from at least two characteristic lesions at endoscopic retrograde cholangiopancreatography, were followed for a minimum of 10 months or until death. Median age was 33.5 years (range 27-50). All had abdominal pain; 11 had diarrhoea. Alkaline phosphatase was > 2X normal in 13, but the bilirubin was raised in only three. The median CD4 was 0.024 x 10(9)/l (0.005-0.341). Thirteen had cryptosporidiosis, six had active cytomegalovirus, five had no gastrointestinal pathogen. Three patients are alive without AIDS related sclerosing cholangitis symptoms at 10, 11, and 21 months. Seventeen have died at median 7 (1-23) months. Cytomegalovirus therapy had no apparent influence. The initial CD4 was < 0.11 in all those dying within six months, but correlation of CD4 with prognosis was otherwise poor. Controls, matched for age, CD4, and opportunistic infections had virtually identical overall outcome (median survival 7.5 months) and the expected worse prognosis with increasing age. Increasing age, however, appeared protective in AIDS related sclerosing cholangitis (r = +0.6; p < 0.05): this is not explained by disproportionate degrees of immunosuppression, nor by opportunistic infections.

Natural history and prognosis of diarrhoea of unknown cause in patients with acquired immunodeficiency syndrome (AIDS).

This paper is a prospective study of patients with advanced human immunodeficiency virus infection and chronic diarrhoea for which no cause could be found after extensive investigations, including examination of multiple stool specimens for all known faecal pathogens and the histological examination of small and large bowel biopsy specimens. Of 39 such patients recruited from 155 prospectively investigated patients, eight had a possible cause of diarrhoea identified on follow up investigations, including small bowel neoplasms in three and cytomegalovirus in two. In 17 of the remaining 31 the diarrhoea resolved completely in a mean of seven months from its onset. Eleven had continuing mild or intermittent diarrhoea and three had more than 1 litre of diarrhoea daily for which no cause could be found. The median survival for patients with 'pathogen negative' diarrhoea was 48.7 months, which is similar to that of control patients with no diarrhoea and significantly longer than that of matched patients with a gastrointestinal pathogen (9.6 months).

Investigation of chronic diarrhoea in acquired immunodeficiency syndrome. A prospective study of 155 patients.

BACKGROUND AND AIMS: The optimum diagnostic investigation for patients with acquired immunodeficiency syndrome (AIDS) and diarrhoea is not known. Often no pathogen is detected and it is unclear whether this is because pathogens are absent in some patients or the investigations used fail to detect them. The hypothesis that AIDS related diarrhoea is usually due to an infection, which can be identified by a simple diagnostic strategy based on the results of intensive investigation of a cohort of such patients, was investigated. METHODS: 155 patients with AIDS and chronic diarrhoea underwent contemporaneous examination of stools, duodenal, jejunal, and rectal biopsy specimens and duodenal aspirate for bacterial, protozoal, and viral pathogens. A decision tree analysis was used to determine the best sequential diagnostic strategy for clinicians. RESULTS: 128 of 155 patients investigated (83%) had at least one potential pathogen. The presenting clinical features could not predict the presence or site of the pathogens. Stool analysis identified the most pathogens (93 of 199, 47%). Rectal biopsy was essential for the diagnosis of cytomegalovirus and adenovirus. Duodenal biopsy was as helpful as jejunal biopsy and detected some treatable pathogens missed by other methods. Electron microscopy, impression smears, and duodenal aspirate yielded little extra information. If gut biopsy was reserved for patients without a stool pathogen, some treatable pathogens would have been missed. CONCLUSION: Most patients with AIDS and chronic diarrhoea have at least one gut pathogen, which can be identified by stool analysis and light microscopic examination of duodenal and rectal biopsies. Some pathogens will be missed unless all these investigations are done on all such patients.

Ventricular fibrillation due to lithium withdrawal--an interaction with chlorpromazine?

We report a case of primary ventricular fibrillation following withdrawal of lithium in a patient concurrently taking chlorpromazine. A potentially important drug interaction is discussed.