Is There a Role for the Enteral Administration of Serum-Derived Immunoglobulins in Human Gastrointestinal Disease and Pediatric Critical Care Nutrition?

Twenty years ago, there was profound, international interest in developing oral human, bovine, or chicken egg-derived immunoglobulin (Ig) for the prevention and nutritional treatment of childhood malnutrition and gastrointestinal disease, including acute diarrhea and necrotizing enterocolitis. Although such Ig products were shown to be effective, with both nutritional and antidiarrheal benefits, interest waned because of their cost and because of the perceived risk of bovine serum encephalitis (BSE). BSE is no longer considered a barrier to use of oral Ig, because the WHO has declared the United States to be BSE-free since the early 2000s. Low-cost bovine-derived products with high Ig content have been developed and are regulated as medical foods. These new products, called serum bovine Igs (SBIs), facilitate the management of chronic or severe gastrointestinal disturbances in both children and adults and are regulated by the US Food and Drug Administration. Well-established applications for use of SBIs include human immunodeficiency virus (HIV)-associated enteropathy and diarrhea-predominant irritable bowel syndrome. However, SBIs and other similar products could potentially become important components of the treatment regimen for other conditions, such as inflammatory bowel disease, by aiding in disease control without immunosuppressive side effects. In addition, SBIs may be helpful in conditions associated with the depletion of circulating and luminal Igs and could potentially play an important role in critical care nutrition. The rationale for their use is to facilitate intraluminal microbial antibody coating, an essential process in immune recognition in the gut which is disturbed in these conditions, thereby leading to intestinal inflammation. Thus, oral Ig may emerge as an important "add-on" therapy for a variety of gastrointestinal and nutritional problems during the next decade.

Human Immunodeficiency Virus-Associated Diarrhea: Still an Issue in the Era of Antiretroviral Therapy.

Over half of patients with human immunodeficiency virus (HIV) experience diarrhea that contributes negatively to quality of life and adherence to antiretroviral therapy (ART). Opportunistic infectious agents that cause diarrhea in patients with HIV span the array of protozoa, fungi, viruses, and bacteria. With global use of ART, the incidence of diarrhea because of opportunistic infections has decreased; however, the incidence of noninfectious diarrhea has increased. The etiology of noninfectious diarrhea in patients with HIV is multifactorial and includes ART-associated diarrhea and gastrointestinal damage related to HIV infection (i.e., HIV enteropathy). A basic algorithm for the diagnosis of diarrhea in patients with HIV includes physical examination, a review of medical history, assessment of HIV viral load and CD4+ T cell count, stool microbiologic assessment, and endoscopic evaluation, if needed. For patients with negative diagnostic results, the diagnosis of noninfectious diarrhea may be considered. Pharmacologic options for the treatment of noninfectious diarrhea are primarily supportive; however, the use of many unapproved agents is based on unstudied and anecdotal information. In addition, these agents can be associated with treatment-limiting adverse events (AEs), such as drug-drug interactions with ART regimens, abuse liability, and additional gastrointestinal AEs. Currently, crofelemer, an antisecretory agent, is the only therapy approved in the USA for the symptomatic relief of noninfectious diarrhea in patients with HIV on ART.

HIV enteropathy: HAART reduces HIV-induced stem cell hyperproliferation and crypt hypertrophy to normal in jejunal mucosa.

OBJECTIVE: To analyse the structural and kinetic response of small intestinal crypt epithelial cells including stem cells to highly active antiretroviral therapy (HAART). DESIGN: Crypt size and proliferative activity of transit and stem cells in jejunal mucosa were quantified using morphometric techniques. METHODS: Crypt length was measured by counting the number of enterocytes along one side of a number of crypts in each biopsy specimen and the mean crypt length was calculated. Proliferating crypt cells were identified with MIB-1 monoclonal antibody, and the percentage of crypt cells in proliferation was calculated at each cell position along the length of the crypt (proliferation index). Data were obtained from 9 HIV-positive test patients co-infected with microsporidia, 34 HIV-positive patients receiving HAART and 13 control cases. RESULTS: Crypt length was significantly greater in test patients than in controls, but crypt length in patients receiving HAART was normal. The proliferation index was greater in test subjects than in controls in stem and transit cell compartments, and was decreased in patients treated with HAART only in the stem cell region of the crypt. CONCLUSIONS: Villous atrophy in HIV enteropathy is attributed to crypt hypertrophy and encroachment of crypt cells onto villi. HAART restores normal crypt structure by inhibition of HIV-driven stem cell hyperproliferation at the crypt bases.

Crofelemer, a novel agent for treatment of non-infectious diarrhea in HIV-infected persons.

Crofelemer is the first US FDA-approved drug for symptomatic relief in HIV-infected persons on antiretroviral therapy (ART) who have non-infectious diarrhea. With the availability of ART, there is increased survival and decrease in gastrointestinal opportunistic infections. However, diarrhea secondary to ART and HIV enteropathy is common in HIV-infected persons. Crofelemer is manufactured from the red latex sap of the Croton lechleri tree in South America. It has a unique mechanism leading to inhibition of chloride ion secretion by blocking chloride channels in the gastrointestinal lumen. This reduces efflux of sodium and water, which in turn reduces the frequency and consistency of diarrhea. Crofelemer is well tolerated due to minimal systemic absorption and has a good safety profile. The availability of crofelemer will likely have a positive impact on the quality of life in HIV-infected persons and also increase compliance to ART.

Systemic antibody responses to gut commensal bacteria during chronic HIV-1 infection.

BACKGROUND: Human systemic antibody responses to commensal microbiota are not well characterised during health and disease. Of particular interest is the analysis of their potential modulation caused by chronic HIV-1 infection which is associated with sustained enteropathy and systemic B cell disturbances reflected by impaired B cell responses and chronic B cell hyperactivity. The mechanisms underlying B cell hyperactivation and the specificities of the resulting hypergammaglobulinaemia are only poorly understood. METHODS: By a technique referred to as live bacterial FACS (fluorescence-activated cell sorting), the present study investigated systemic antibody responses to several gut and skin commensal bacteria as well as Candida albicans in longitudinal plasma and serum samples from healthy donors, chronic HIV-1-infected individuals with or without diarrhoea and patients with inflammatory bowel disease (IBD). RESULTS: The data show that systemic antibody responses to the commensal microbiota were abundantly present in humans and remained remarkably stable over years. Overall systemic antibody responses to gut commensal bacteria were not affected during chronic HIV-1 infection, with titres decreasing when normalised to elevated plasma immunoglobulin G (IgG) levels found in patients with HIV. In contrast, increases in the titres of high affinity antimicrobiota antibodies were detected in patients with IBD, demonstrating that conditions with known increased intestinal permeability and aberrant mutualism can induce changes in antibody titres observed in these assays. CONCLUSION: Neither HIV-associated enteropathy nor B cell dysfunction impact on the high-affinity systemic antibody responses to gut commensal bacteria. HIV-associated hypergammaglobulinaemia is therefore unlikely to be driven by induction of antimicrobiota antibodies.

Altered host-microbe interaction in HIV: a target for intervention with pro- and prebiotics.

The intestinal immune system is severely affected by HIV and circulating microbial products from the intestinal tract that provide an ongoing source of systemic inflammation and concomitant viral replication. In addition, HIV-infected individuals can have a deregulated immune response that may hamper the anti-viral capacity of the host. Various probiotic organisms and prebiotic agents have been shown to enhance intestinal epithelial barrier functions, reduce inflammation, and support effective Th-1 responses. As these characteristics may benefit HIV patients, this review aims to provide a theoretical framework for the development of probiotic and prebiotic interventions specifically for this population.

Gastric and intestinal barrier impairment in tropical enteropathy and HIV: limited impact of micronutrient supplementation during a randomised controlled trial.

BACKGROUND: Although micronutrient supplementation can reduce morbidity and mortality due to diarrhoea, nutritional influences on intestinal host defence are poorly understood. We tested the hypothesis that micronutrient supplementation can enhance barrier function of the gut. METHODS: We carried out two sub-studies nested within a randomised, double-blind placebo-controlled trial of daily micronutrient supplementation in an urban community in Lusaka, Zambia. In the first sub-study, gastric pH was measured in 203 participants. In the second sub-study, mucosal permeability, lipopolysaccharide (LPS) and anti-LPS antibodies, and serum soluble tumour necrosis factor receptor p55 (sTNFR55) concentrations were measured in 87 participants. Up to three stool samples were also analysed microbiologically for detection of asymptomatic intestinal infection. Gastric histology was subsequently analysed in a third subset (n = 37) to assist in interpretation of the pH data. Informed consent was obtained from all participants after a three-stage information and consent process. RESULTS: Hypochlorhydria (fasting gastric pH > 4.0) was present in 75 (37%) of participants. In multivariate analysis, HIV infection (OR 4.1; 95%CI 2.2-7.8; P < 0.001) was associated with hypochlorhydria, but taking anti-retroviral treatment (OR 0.16; 0.04-0.67; P = 0.01) and allocation to micronutrient supplementation (OR 0.53; 0.28-0.99; P < 0.05) were protective. Hypochlorhydria was associated with increased risk of salmonellosis. Mild (grade 1) gastric atrophy was found in 5 participants, irrespective of Helicobacter pylori or HIV status. Intestinal permeability, LPS concentrations in serum, anti-LPS IgG, and sTNFR55 concentrations did not differ significantly between micronutrient and placebo groups. Anti-LPS IgM was reduced in the micronutrient recipients (P <0.05). CONCLUSIONS: We found evidence of a specific effect of HIV on gastric pH which was readily reversed by anti-retroviral therapy and not mediated by gastric atrophy. Micronutrients had a modest impact on gastric pH and one marker of bacterial translocation. TRIAL REGISTRATION: Current Controlled Trials ISRCTN31173864.

Idiopathic AIDS enteropathy and treatment of gastrointestinal opportunistic pathogens.

Diarrhea in patients with acquired immune deficiency syndrome (AIDS) has proven to be both a diagnostic and treatment challenge since the discovery of the human immunodeficiency virus (HIV) virus more than 30 years ago. Among the main etiologies of diarrhea in this group of patients are infectious agents that span the array of viruses, bacteria, protozoa, parasites, and fungal organisms. In many instances, highly active antiretroviral therapy remains the cornerstone of therapy for both AIDS and AIDS-related diarrhea, but other targeted therapies have been developed as new pathogens are identified; however, some infections remain treatment challenges. Once identifiable infections as well as other causes of diarrhea are investigated and excluded, a unique entity known as AIDS enteropathy can be diagnosed. Known as an idiopathic, pathogen-negative diarrhea, this disease has been investigated extensively. Atypical viral pathogens, including HIV itself, as well as inflammatory and immunologic responses are potential leading causes of it. Although AIDS enteropathy can pose a diagnostic challenge so too does the treatment of it. Highly active antiretroviral therapy, nutritional supplementation, electrolyte replacements, targeted therapy for infection if indicated, and medications for symptom control all are key elements in the treatment regimen. Importantly, a multidisciplinary approach among the gastroenterologist, infectious disease physician, HIV specialists, oncology, and surgery is necessary for many patients.

Treatment of HIV-associated diarrhea with curcumin.

Curcumin is the organic extract of turmeric and possesses known anti-inflammatory properties. Our aim was to explore the utility of curcumin in patients with HIV-associated diarrhea. Eight patients with HIV-associated diarrhea were given a mean daily dose of 1,862 mg of curcumin and followed for a mean of 41 weeks. All had resolution of diarrhea and normalization of stool quality in a mean time of 13 +/- 9.3 days. Mean number of bowel movements per day dropped from 7 +/- 3.6 to 1.7 +/- 0.5. Seven of eight patients had considerable weight gain on curcumin (10.8 +/- 8.9 lbs). Five of six patients had resolution of bloating and abdominal pain. Patients on anti-retroviral therapy experienced no discernible drug interactions, changes in CD(4) count, or changes in HIV viral load while taking curcumin. Curcumin therapy was associated with rapid and complete resolution of diarrhea, substantial weight gain, improvement in the reduction of bloating and abdominal pain.

[Gastrointestinal manifestations of HIV infection]. / Gastrointestinale Manifestationen der HIV-Infektion.

BACKGROUND: HIV-related immunodeficiency particularly affects the mucosal immune system. Therefore, the gastrointestinal tract is target to numerous HIV-associated diseases. Since the introduction of highly active antiretroviral therapy (HAART) the prevalence of HIV-related secondary diseases has significantly declined. Their clinical appearance, however, remained unchanged. RESULTS: This review summarizes the most important gastrointestinal complications of HIV disease and their treatment focusing on key symptoms and signs. In addition, appropriate diagnostic strategies are proposed. CONCLUSIONS: Given the high number of secondary gastrointestinal diseases and their potential impact on prognosis and quality of life of HIV-infected patients, it is important to employ an effective diagnostic and therapeutic approach to these patients. Control of HIV replication and immune deficiency by HAART offers new therapeutic options in cryptosporidiosis and microsporidiosis and is crucial for the long-term prevention of opportunistic enteric infections or HIV-related malignancies.

Pharmacokinetic and other drug interactions in patients with AIDS.

A variety of medications are used in treating patients infected with the human immunodeficiency virus (HIV). These medications are used to control viremia and to prevent and treat opportunistic infections. An individual is often required to take numerous drugs at the same time and thus clinicians are confronted with potential drug interactions, some of which are significant. Three different groups of anti-HIV drugs are used to treat patients. These groups include nucleoside reverse transcription inhibitors, non-nucleoside reverse transcription inhibitors, and protease inhibitors. This article reviews the most relevant drug interactions that occur during the treatment of HIV-infected patients with traditional and also alternative drugs. The role of therapeutic drug monitoring in the routine management of HIV-infected patients is discussed.

Management of protozoal diarrhoea in HIV disease.

Since the first reported case of HIV infection in 1981, many HIV-seropositive patients have died as a result of diarrhoea induced by opportunistic protozoal infections: pathogens that would normally cause only a transient illness in immunocompetent individuals. The introduction of highly active antiretroviral therapy (HAART) in 1996 has been associated with a significant decline in incidence and mortality arising from infections such as cryptosporidia and microsporidia. Previously, there were no chemotherapeutic agents known to be effective in eradicating these parasites, but since the availability of HAART, the memory of the emaciated terminally ill patient with advanced AIDS suffering from refractory diarrhoea will hopefully be a thing of the past. Significant advances in the knowledge of the pathogenesis of HIV disease, earlier detection and thus treatment of the virus, and availability of improved diagnostic techniques and HAART have transformed the way HIV-associated diarrhoea is managed. In this review, we look specifically at the management of protozoa-induced diarrhoea.

Impact of protease inhibitors on the outcome of human immunodeficiency virus-infected patients with chronic diarrhea.

OBJECTIVE: The effect of protease inhibitors on the outcome of chronic HIV-related diarrhea is unknown. The aim of this study was to compare the response to treatment of chronic HIV-related diarrhea, recurrence of diarrhea, and survival in a large cohort of individuals taking protease inhibitors to the outcome in similar patients not receiving protease inhibitors. METHODS: We reviewed the medical records of all patients referred between October 1993 and October 1996 at Bellevue Hospital for endoscopic evaluation of chronic HIV-related diarrhea after negative stool examination. Only patients presenting after December 1995 received protease inhibitor therapy. Follow-up data were obtained from chart review and direct telephone contact. The success of antidiarrheal therapy was compared between protease inhibitor and nonprotease inhibitor groups for patients receiving pathogen-specific therapy and for those with no pathogens found on endoscopy. RESULTS: Two hundred eighty-two of 307 patients evaluated for chronic diarrhea were followed for a mean of 69.9+/-34.1 weeks. Patients receiving protease inhibitors had a significantly higher rate of successful response to antidiarrheal therapy (62.0% vs 33.5%, p < 0.001). Protease inhibitors were associated with a significant decrease in stool frequency (4.8+/-4.5 vs 3.4+/-4.6 bowel movements per day, p = 0.01), an increase in weight (2.4+/-5.9 vs -1.6+/-6.2 kg, p < 0.001), a decrease in recurrence of diarrhea (34.8% vs 15.3%, p = 0.02), and a longer mean survival (148 vs 118 weeks, p = 0.002). CONCLUSIONS: Protease inhibitors significantly improve the outcome of antidiarrheal therapy and survival in patients with chronic HIV-associated diarrhea.

Palliative care and AIDS: 2--Gastrointestinal symptoms.

With the use of more intensive antiretroviral therapies (highly-active antiretroviral therapy, HAART) particularly in first world countries, reductions in the mortality and morbidity of HIV infection are being seen. However, though the prevalence of symptoms may change, symptom control does continue to be a problem for many people with HIV, particularly as their disease progresses. This is the second of 2 CME articles about palliative care and HIV infection. The first gave a background to palliative care, and covered symptom control of pain. This article gives suggestions for the treatment of common gastrointestinal symptoms in HIV infection; nausea and vomiting, cachexia and anorexia and chronic diarrhoea.

Prevalence of intestinal pathogens in HIV patients with diarrhea: implications for treatment.

Patients infected with the human immunodeficiency virus (HIV) commonly experience diarrhea at some time during their illness. A variety of enteric pathogens are identified in 50-80% of these patients, depending on the intensity of the diagnostic work-up that is done. In addition to the common enteric pathogens, several unusual enteric pathogens are recognized to cause diarrhea especially in HIV patients. These include protozoan parasites such as Cryptosporidia, Isospora belli, Cyclospora cayatenensis and Microsporidium species bacteria such as enteropathogenic Escherichia coli and Mycobacterium avium-intracellulare, fungi including Candida albicans and Histoplasma capsulatum, and viruses such as astroviruses and caliciviruses. Diagnosis of these infections sometimes involves special procedures not readily available every where, and empiric therapy based on knowledge of the likely pathogens has been advocated for developing countries. This article reviews the currently available data on geographic variation of enteric pathogens in HIV patients with diarrhea and outlines a rational strategy for empiric therapy of these patients.

Managing and treating. AIDS-related diarrhea.

Diarrhea is a significant problem for most people with AIDS. Its causes are multifactorial, ranging from infectious organisms to malignancies and functional problems. A thorough evaluation will usually determine the etiology and guide treatment. With HAART, dramatic improvements in immune status have caused a decline in opportunistic infections, including those that cause diarrhea. It is a sign of hope for all patients with HIV.