Altered Virome and Bacterial Microbiome in Human Immunodeficiency Virus-Associated Acquired Immunodeficiency Syndrome.

Human immunodeficiency virus (HIV) infection is associated with increased intestinal translocation of microbial products and enteropathy as well as alterations in gut bacterial communities. However, whether the enteric virome contributes to this infection and resulting immunodeficiency remains unknown. We characterized the enteric virome and bacterial microbiome in a cohort of Ugandan patients, including HIV-uninfected or HIV-infected subjects and those either treated with anti-retroviral therapy (ART) or untreated. Low peripheral CD4 T cell counts were associated with an expansion of enteric adenovirus sequences and this increase was independent of ART treatment. Additionally, the enteric bacterial microbiome of patients with lower CD4 T counts exhibited reduced phylogenetic diversity and richness with specific bacteria showing differential abundance, including increases in Enterobacteriaceae, which have been associated with inflammation. Thus, immunodeficiency in progressive HIV infection is associated with alterations in the enteric virome and bacterial microbiome, which may contribute to AIDS-associated enteropathy and disease progression.

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.

Chronic diarrhea and AIDS: insights into studies with non-human primates.

Diarrhea is the pathophysiological reaction of host's gastrointestinal tract to a variety of external stimuli. Classified as a clinical syndrome, diarrhea is the leading cause of mortality and morbidity worldwide. Clinical manifestations can occur in two major forms: A) acute, which usually resolves in less than three weeks and B) chronic, which can last for months. Because of its impact on the host immune system, acquired immune deficiency syndrome (AIDS) is currently the major cause of chronic diarrhea in many parts of the world. It is estimated that up to 90% of HIV-infected individuals with symptoms of AIDS exhibit clinical diarrhea [9, 74, 55]. In SIV-infected rhesus macaques, intense infiltration of intestinal lamina propria with virus-containing lymphocytes and macrophages can be found within days after experimental virus inoculation [25, 57]. In addition to acute enteropathy syndrome, viral infection ultimately leads to other alterations of the gastrointestinal tract including persistent and/or chronic diarrhea, a condition similar to untreated AIDS of human patients. In this short review, the chronic diarrhea is presented from the perspective of the non-human primate or simian model of AIDS (SAIDS), and its most common opportunistic and pathogenic co-infections.

The virotoxin model of HIV-1 enteropathy: involvement of GPR15/Bob and galactosylceramide in the cytopathic effects induced by HIV-1 gp120 in the HT-29-D4 intestinal cell line.

BACKGROUND: Malabsorption and diarrhea are common, serious problems in AIDS patients, and are in part due to the incompletely understood entity HIV enteropathy. Our prior in vitro work has shown that increased transepithelial permeability and glucose malabsorption, similar to HIV enteropathy, are caused by HIV surface protein gp120, although the mechanism remains unclear. RESULTS: We studied the effects of HIV surface protein gp120 on the differentiated intestinal cell line HT-29-D4, specifically the effects on microtubules, transepithelial resistance, and sodium glucose cotransport. gp120 induced extensive microtubule depolymerization, an 80% decrease in transepithelial resistance, and a 70% decrease in sodium-dependent glucose transport, changes closely paralleling those of HIV enteropathy. The effects on transepithelial resistance were used to study potential inhibitors. Neutralizing antibodies to GPR15/Bob but not to CXCR4 (the coreceptor allowing infection with these HIV strains) inhibited these effects. Antibodies to galactosylceramide (GalCer) and a synthetic analog of GalCer also inhibited the gp120-induced changes, suggesting the involvement of GalCer-enriched lipid rafts in gp120 binding to intestinal epithelial cells. CONCLUSION: We conclude that direct HIV infection and gp120-induced cytopathic effects are distinct phenomena. While in vivo confirmation is needed to prove this, gp120 could be a virotoxin significantly contributing to HIV enteropathy.

[Chronic diarrhea: value of microbiology in diagnosis]. / Chronische Diarrhoe: Stellenwert der Mikrobiologie in der Diagnostik.

Chronic diarrhoea of the adult is defined as diarrhea during 30 days or longer. Frequent causes of chronic diarrhea in the immunocompetent adult without recent travel to developing countries are noninfectious processes, including laxatives misuse, diseases causing chronic maldigestion, osmotically active artificial sweeteners (i.e. sorbitol), hormonal disorders or drugs with intestinal side effects. Infectious agents as the cause of chronic diarrhea are important in two populations, namely in travelers returning from tropical countries bearing a significant risk of intestinal parasitic infections and in immunocompromised patients, especially AIDS patients with CD4 cell counts below 50 per microliter. Intestinal parasites and C. difficile, Y. enterocolitica, Shigellae and Cytomegalovirus are the most important causative agents of chronic diarrhea. Intestinal pathogens were identified in 46% of chronic, but only in 16.5% of acute diarrhea episodes of HIV-infected patients. An extensive medical history including recent travel as well as the detailed characteristics of onset of symptoms and of their time course is essential for the diagnosis. All patients should have a complete differential blood count, ESR, determination of electrolytes, liver enzymes, creatinine, blood glucose, and serum albumin. Tests to exclude hyperthyriodism, or pancreatic insufficiency as well as a d-xylose absorption test can be included, if appropriate. Microbiological-parasitological investigations are obligatory in patients with chronic diarrhea returning from countries with increased risk of traveler diarrhea, in cases of suspected immunodeficiency, if sudden onset of symptoms with fever is reported, after antibiotic treatment, and in children below six years of age. As a rule, stool specimens are appropriate, for the detection of cytomegalovirus colonic biopsies are necessary. In the latter case colonosigmoidoscopy has no diagnostic advantage. One single stool specimen is sufficient for the detection of bacteria or toxins, in contrast to parasitological investigations, where only three consecutive specimens provide sufficient diagnostic sensitivity.

The changing etiology of chronic diarrhea in HIV-infected patients with CD4 cell counts less than 200 cells/mm3.

PURPOSE: The purpose of this study was to evaluate the incidence and causes of chronic diarrhea in patients with AIDS over a period of time that included the pre-HAART (highly active antiretroviral therapy) era and the introduction of HAART. METHODS: The study cohort was comprised of patients receiving primary care at a university-associated outpatient HIV clinic from January 1, 1995 to December 31, 1997. Patients were identified retrospectively through a clinical database and were included in the study if their diarrhea had persisted for longer than two weeks and their CD4 cell count at time of symptoms was <200 cells/mm3. Further data were obtained by chart review. RESULTS: Over the 36-month period, the occurrence of chronic diarrhea did not change significantly, ranging from 8 to 10.5% per year in patients with CD4 cell counts <200 cells/mm3. The percentage of patients diagnosed with opportunistic infectious etiologies decreased over the three-year period from 53% (1995) to 13% (1997). The percentage of patients diagnosed with noninfectious causes increased from 32% to 70% over this same time period. CONCLUSIONS: Over the three years of the study, the incidence of chronic diarrhea in AIDS patients in our clinic did not change. The etiologies of diarrhea did change significantly, with an increased incidence of noninfectious causes and a decreased incidence of opportunistic infectious causes. This shift in etiologies coincides with the introduction and increased use of HAART in our clinic population (1996).

The diagnostic value of electron microscopy in human immunodeficiency virus-positive patients with gastrointestinal disease.

BACKGROUND: Our aim was to determine the diagnostic value of electron microscopy in evaluating the etiology of gastrointestinal disease in patients infected with the human immunodeficiency virus (HIV). METHODS: A retrospective review of electron microscopic and light microscopic results of all HIV-positive patients with gastrointestinal and liver diseases was made during a 3-year period from June 1995 to June 1998. RESULTS: A total of 145 HIV-positive patients had their electron microscopy specimens reviewed. Of these, 136 were investigated for diarrhea, and the other 9 for increased liver enzymes. Twenty-seven of the 145 (18.6%) HIV-positive patients had a pathogen identified by electron microscopy, compared with only 13 of 145 (9%) identified by light microscopy (P < 0.005). The sensitivity of light microscopy for detecting opportunistic pathogens was 68%. Twenty-one of the 27 (77.8%) patients diagnosed by electron microscopy had microsporidiosis, and the most commonly diagnosed species was Enterocytozoon bieneusi. Light microscopy failed to identify 12 cases of microsporidiosis and 2 cases of leishmaniasis. CONCLUSIONS: Electron microscopy contributes substantially to the identification of pathogens in HIV-positive patients. Light microscopy failed to identify one of every two pathogens diagnosed by electron microscopy.

Comparison of duodenal with jejunal biopsy and aspirate in chronic human immunodeficiency virus-related diarrhea.

OBJECTIVES: In human immunodeficiency virus (HIV)-infected patients with chronic unexplained diarrhea, upper endoscopy with small bowel biopsy and aspirate is often performed to identify treatable pathogens. The purpose of this study was to compare the diagnostic yield of duodenal with jejunal biopsy and aspirate. METHODS: All HIV-infected patients with chronic unexplained diarrhea who were evaluated by upper endoscopy at Bellevue Hospital Center between January 1992 and January 1997 were identified. Data were collected by reviewing patient charts, endoscopy reports, and pathology records. RESULTS: During the 5-yr study period, 442 patients underwent upper endoscopy with sampling of the duodenum (N=173) or jejunum (N=269). A pathogen was identified in 123 patients (27.8%). Microsporidia was the most common organism detected (12.2%). The diagnostic yield of jejunal biopsy and aspirate was significantly higher than that obtained from the duodenum (32.3% vs 20.8%, p=0.009). Small bowel aspirates detected a pathogen in only 1.8% of patients evaluated, and there was no difference in the yield of duodenal and jejunal aspirates (1.3% vs 2.1%, p=0.7). Patients with a CD4 count of < 100 cells/mm3 were significantly more likely to have a pathogen identified than those with higher CD4 counts (38.8% vs 7.1%,p < 0.0001). CONCLUSIONS: Upper endoscopy with small bowel biopsy and aspirate identifies a pathogen in 27.8% of individuals with HIV-related chronic unexplained diarrhea. In this patient population, jejunal biopsies acquired by enteroscopy are superior to those obtained from the duodenum. Small bowel aspirates are of little value in the workup of chronic HIV-related diarrhea.

Correlation of intestinal structure and function in HIV infection.

The gastrointestinal tract has great importance in HIV infection because of its role as a primary barrier to the external environment and consequent need for effective immune function. Many factors promote the development of diarrhea in HIV-infected individuals. Understanding the genesis of the symptom is key to formulating effective therapy. Ultimate control of the problem depends on preventing HIV replication and immune depletion, as well as avoiding the development of opportunistic enteric infections in patients with severe immune deficiency.

A 3-year follow-up of a brazilian AIDS patient with protracted diarrhea caused by Enterocytozoon bieneusi

Enterocytozoon bieneusi e o mais comum microsporidio agente de infeccoes gastrointestinais que ocorre predominantemente em pessoas com AIDS. Em todo o mundo os microsporidios sao reconhecidos como importantes patogenos oportunistas, entretanto poucos casos ja foram diagnosticados no Brasil, provavelmente devido ao pouco conhecimento do quadro clinico que os agentes produzem ou a dificuldades no diagnostico laboratorial. No presente trabalho relatamos o caso de um paciente brasileiro HIV-positivo acompanhado durante 3 anos, em que foram detectados esporos de microsporidios nas fezes, identificados como Enterocytozoon bieneusi por microscopia eletronica e PCR. O paciente apresentava diarreia cronica, contagem de linfocitos CD4 abaixo de 100/mm3 e fez uso de albendazol em diferentes ocasioes com melhora transitoria da diarreia, que reaparecia logo que a droga era suspensa...

[Intestinal diseases in HIV infection]. / Darmerkrankungen bei HIV-Infektion.

The gastrointestinal tract is very frequently affected by the manifestations of the acquired immunodeficiency syndrome (AIDS). A variety of opportunistic viral, fungal, bacterial, protozoal and helmintic infections and different unusual malignancies such as Kaposi's sarcoma, non-Hodgkin's lymphoma and papilloma-virus associated anal cancer are responsible for much of the morbidity and mortality in AIDS. Because specific therapy is not always available, in particular diagnosis of potentially infections should be attempted.

Presencia de parásitos intestinales en pacientes HIV seropositivos: primer informe de microsporosis humana en Costa Rica / Intestinal parasites in HIV seropositive patients: first report of human microsporosis in Costa Rica

Se estudiaron los parásitos intestinales en pacientes HIV positivos que presentaban diarrea crónica. Un total de 27,8 por ciento de los pacientes fueron positivos por protozoarios patógenos, un 24,1 por ciento presentaron infección por protozoarios no patógenos y en 7,4 por ciento se diagnosticaron helmintiasis. Se informa además de los primeros cinco casos de microsporosis diagnosticados en Costa Rica utilizando la técnica tricrómica modificada de Weber

Diagnostic yield of duodenal biopsy and aspirate in AIDS-associated diarrhea.

OBJECTIVES: To evaluate the diagnostic yield of performing duodenal biopsies and aspirates in AIDS patients with chronic diarrhea. METHODS: Retrospective review of esophagogastroduodenoscopy (EGD) records from January 1993 to March 1995 to identify those patients who underwent EGD for evaluation of AIDS associated diarrhea and had a duodenal biopsy and/or aspirate. Biopsies were examined for pathogens using routine histology and special stains, viral culture, and electron microscopy. Duodenal aspirates were evaluated for ova and parasites. All patients had previous negative stool studies. Pathology laboratory charges (hospital and professional fees) for each test and charges per positive test were determined. RESULTS: Of the 57 patients included in this study, 56 had a duodenal biopsy and 42 had a duodenal aspirate. An established pathogen was identified in only 15 (26%) patients. One patient had both Mycobacterium avium complex and microsporidia. Pathogens were identified in seven patients by hematoxylin and eosin stain, in three patients by acid-fast bacillus stain, and in six patients by electron microscopy. No pathogens were identified with Gomori's methenamine silver stain (44 patients), duodenal aspirate for ova and parasites (46 patients), immunoperoxidase stains (4 patients), or viral culture (4 patients). Cryptosporidia were identified in six, microsporidia in five, Mycobacterium avium complex in three, and Giardia lamblia and adenovirus each in one patient. CONCLUSIONS: In this series, the diagnostic yield of EGD with duodenal biopsy and aspirate in AIDS associated diarrhea was low. Pathogens were identified in 26% of patients; predominantly Cryptosporidium organisms and microsporidia. The routine performance of aspiration of duodenal contents for parasite examination and staining of duodenal tissue with Gomori's methenamine silver stain for fungal identification are not recommended. One should consider obtaining tissue for electron microscopy whenever duodenal biopsies are performed. The utility of EGD in AIDS associated diarrhea may improve as more effective therapies become available.

Causes of chronic diarrhea in patients with AIDS in Thailand: a prospective clinical and microbiological study.

A prospective study was designed to investigate the causes of chronic diarrhea in AIDS patients in Thailand. Forty-five patients from Bamrasnaradura Infectious Diseases Hospital were enrolled. Extensive investigations included multiple stool examinations for ova and parasites, using the stool formalin-ether concentration method, stool culture, stool acid-fast bacilli (AFB) stain, stool modified AFB stain, esophagogastroduoscopy with duodenal aspirate and biopsy, and colonoscopy with biopsy. Biopsied specimens were examined with H&E, Giemsa, Gram, Periodic acid Schiff, and AFB stains. Definitive causes were found in 29 patients (64.4%). Of these 29, 7 patients were found to habor more than 1 pathogen (15.5%). The most commonly found enteric pathogen was Cryptosporidium parvum (20.0%). Less frequently found pathogens were Mycobacterium tuberculosis (17.8%), Salmonella spp. (15.5%), Cytomegalovirus (11.1%), Mycobacterium avium intracellulare (6.6%), Strongyloides stercoralis (4.4%), Giardia lamblia (4.4%), Cryptococcus neoformans (2.2%), Histoplasma capsulatum (2.2%), Campylobacter jejun (2.2%), and Cyclospora cayetanensis (2.2%). Salmonella spp., Mycobacterium tuberculosis, and Mycobacterium avium intracellulare infections were shown to be more common in Thailand than in African countries.

Enfoque diagnóstico y terapéutico de la diarrea crónica en pacientes con SIDA / Diagnosis and therapeutics approach to the chronic diarrhea in AIDSns patients

Estudia las infecciones intestinales en pacientes con SIDA, las que les provocan diarrea con compromiso del intestino delgado y/o del colon. Se identifican los principales agentes patógenos y las manifestaciones clínicas de las infecciones que producen enfermedad primaria intestinal (Cryptosporidium, Enterocytozoon bieneusi, Isospora belli, Giardia lamblia, Salmonella, Shigella, Campylobacer, Clostridium difficile, Virus Herpes Simplex) y que producen compromiso intestinal secundario a infecciones sistémicas (Cytomegalovirus, Mycobacterium avium intracelular, Histoplasma capsulatum) y otros patógenos (Blastocystis hominis, Entamoeba hystolitica y otras). Se discuten las hallazgos relacionados con la enteropatía idiopática asociada al SIDA y a los neoplasmas intestinales (Sarcoma de Kaposi y linfomas). Se exponen algunos estudios realizados sobre tratamiento de estas infecciones (drogas empleadas, respuesta a las mismas y efectos adversos observados)