Infectious Diseases

Alimentary Tract Disease in the HIV Patient: Diarrheal Diseases

OVERVIEW: What every practitioner needs to know

Are you sure your patient has diarrheal alimentary tract disease? What should you expect to find?

Introduction

There is considerable heterogeneity in the clinical presentation of HIV-infected patients with diarrhea. Understanding the specific categories of patients as well as the similarities and differences between HIV-infected and non-infected patients narrows the range of possible diseases and helps direct the inquiry. The diagnosis of HIV/AIDS in any patient presenting with diarrhea may be unknown, so that HIV infection must be in the differential diagnosis of almost anyone with diarrhea. Patients may be aware of a HIV diagnosis, and may suffer from a range of immune depletion, from mild to severe, but not be receiving antiviral treatment.

Gastrointestinal (GI) disease in general and diarrheal disease in particular may be influenced by co-existing HIV infection. Importantly, many studies have documented that multiple pathogens may coexist in HIV/AIDS patients, in contradistinction to "Occam's razor", or the law of parsimony. Both susceptibility and the host response to pathogens may be affected, the latter more important in the presence of severe immune depletion. For this reason, opportunistic infections tend to be chronic and suppressible, though not curable, in the absence of immune reconstitution.

Different spectra of etiologies may be found as immune depletion progresses, including HIV-specific, as well as more usual pathogens. In general, high grade pathogens may occur at any time during the disease course, while low-grade pathogens are seen only in the case of severe immune depletion. The HIV virus itself or the host response to the virus may produce GI symptoms, especially in patients without severe immune depletion.

While clinical presentation or radiologic studies may suggest a specific diagnosis, mucosal biopsy often is required for definitive diagnosis.

Diarrhea may occur in HIV/AIDS via one of several pathogenic mechanisms, namely decreased mucosal surface area, ileal dysfunction, exudative enteropathy, inflammatory disease, and 'HIV enteropathy'. Historical clues are important in focusing the diagnostic work-up. The major initial task in the diagnostic evaluation, especially in a seriously ill patient, is the localization of the pathologic process, especially the distinction between small intestinal, or malabsorptive disease, and large intestinal disease, or colitis. There are several historical clues (Table I).

Table I.

Differentiation Between Malabsorption and Colitis
Malabsorption Colitis
Frequency 5-8/day 5-30/day
Volume Variable, large Small
Intervals Variable Regular
Formed stools? Rarely Never
Fecal leukocytes No Yes
Blood in stool No Yes, occult
Urgency Yes No
Tenesmus No Sometimes
Malodorous stools/gas Frequently No
Fever, systemic symptoms No Yes

The most important historical clue is the volume of diarrhea. Malabsorptive diarrhea typically leads to greater stool volumes and increased risk for dehydration. Bowel habits in a patient with malabsorption are characterized by variability in volume, frequency and intervals between bowel movements, including the chance of passing a formed stool, and are much more uniform in patients with colitis, including waking a patient from sleep for a bowel movement, which is much less common in patients with malabsorption.

Patients with malabsorption often complain of urgency prior to having a bowel movement, which improves after the bowel movement. In contrast, patients with colitis, especially those with proctitis, may suffer from urgency, but symptoms are not relieved by the bowel movement, and the patient may suffer from tenesmus, or involuntary contractions. Importantly, patients with protozoal disease do not have systemic symptoms, such as fever, and weight loss tends to be slow and may stabilize at a subnormal level. If a patient is strongly suspected or diagnosed as having malabsorption and also has systemic symptoms, one must consider the presence of mycobacterial disease, or a systemic infection co-existing with a malabsorptive disorder.

Clinical differentiation between malabsorption and colitis

Specificity

There are relatively few physical findings that provide specificity for the diagnosis of a specific enteric pathogen. Abdominal findings are few in patients with protozoal or enteroadherent bacterial infections. Patients with mycobacterial infections, C. difficile colitis, or bacterial enterocolitis may be febrile and have abdominal tenderness, corresponding to enlarged mesenteric nodes. Patients with mycobacterial disease also may have organomegaly and lymphadenopathy.

If an AIDS patient with diarrhea develops free air in the abdomen, one must consider the possibility of CMV infection with transmural infarction and perforation, a condition that most often involves the ileum.

How did the patient develop diarrheal alimentary tract disease? What was the primary source from which the infection spread?

People with HIV/AIDS may develop diarrheal disorders from a variety of sources. As with any patient, common source contamination may occur after contact with contaminated food and water, so that recent travel, eating at restaurants or from street food vendors are important historical details.

The possibility of increased vulnerability to enteric infections in patients with low CD4 counts raises the issue of food safety. The cause for the increased vulnerability is uncertain but may include disease or treatment-associated achlorhydria, which diminishes an innate defense against infection, namely gastric acidity.

Sexual activity, particularly oral-anal contact, has been shown to be a risk factor for enteric bacterial and parasitic infections. These sexual behaviors are not limited to men having sex with men.

Enteric viral infections, particularly from herpes viruses, are reactivation from prior infection and not primary. The risk factors and mode of spread of cytomegalovirus (CMV) are the same as for any patient. While not well studied, it appears that patients who acquire CMV at the same time as HIV have a particularly poor immune response to CMV, even in the presence of immune reconstitution.

The major epidemiologic factors differ, depending on the particular infection. Protozoal diseases are passed via food or water, and may be sexually transmitted as well through oral-anal contact. Adherent enteric bacterial infections have the same epidemiologic features. For this reason, questions about recent travel and food ingestion are important. Both travel to endemic areas or ingestion of foods, particularly fruits, that have been imported from those areas may be found.

For patients with low CD4 counts, food safety, including food preparation equipment become potential sources of severe enteric infections. Patients with mycobacterial disease associated with severe immune depletion have no specific epidemiologic characteristics, as the organism is ubiquitous in nature. Herpes virus infections, especially cytomegalovirus, typically are acquired prior to contracting HIV infection, and may be acquired in childhood, though sexual acquisition also is common, especially for herpes simplex virus.

Which individuals are of greater risk of developing diarrheal alimentary tract disease?

The different infections that cause chronic diarrhea can be organized based on the CD4 count. However, the level of CD4 depletion is an imperfect tool for differential diagnosis: Although abdominal tuberculosis may occur with relatively conserved CD4 cells, it is actually more frequent with CD4 counts below 50. With this caveat in mind:

  • Tuberculosis and histoplasmosis may occur with CD4 counts between 0 and greater than 300

  • Acute shigellosis and salmonellosis are not linked to immunosuppression. However, chronic forms with persistent diarrhea and bacteremia typically occur only in patients with CD4 counts below 100

  • Protozoal infections (cryptosporidiosis, microsporidiosis etc.), CMV colitis and disseminated MOTT (mycobacteria other than tuberculosis) infections: Rare exceptions notwithstanding, CD4 counts are usually below 50.

Beware: there are other diseases that can mimic diarrheal alimentary tract disease:

  • Several protozoal agents may affect the small bowel epithelium and cause a tropical sprue-like picture with accompanying malabsorption. These include Cryptosporidium parvum, the microsporidia Enterocytozoan bieneusi, and Encephaloitozoon intestinalis, Isospora belli, Cyclospora catayenses, and Giardia lamblia. Rarely, enteric adenovirus or other viral infections may produce a tropical sprue-like picture. Ileal and right colon disease may be due to enteroadherent E. coli, though M tuberculosis and H capsulatum may present with diarrhea and findings in the right colon and ileum. Exudative enteropathy is most often due to Mycobacterium avium complex, though Rhodococcus sp. and other organisms or conditions such as Kaposi's sarcoma or Castleman's disease may produce lymphatic blockade and present with diarrhea. CMV infection may present with an inflammatory diarrhea, as can Clostridium difficile infection or chlamydial proctitis (LGV) and, less commonly, amebiasis or cryptosporidial colitis. Chronic diarrhea also may be caused by intestinal spirochetosis, though the pathogenic mechanism is uncertain.

  • Diarrheal in a treated patient may occur as a consequence of antiretroviral or another therapy. Among the antiviral agents, the protease inhibitors are most commonly implicated. Nelfinavir is well known to cause diarrhea while diarrhea may occur with any protease inhibitor regimen, especially one boosted by ritonavir.

  • The differential diagnosis of diarrheal diseases in HIV-infected individuals also includes diarrheal diseases that can occur in anyone, both infectious and non-infectious. Some of these diseases, such as celiac disease, lactose intolerance, irritable bowel syndrome, inflammatory bowel disease, and others may have predated the acquisition of HIV infection, which is an important historical clue.

What laboratory studies should you order and what should you expect to find?

Results consistent with the diagnosis

  • Routine laboratory studies usually are of little value in the differential diagnosis of diarrheal illnesses. Stool examinations are helpful in the detection of protozoal infections, but results vary widely between laboratories and false negative results are common. Serologic testing for viral or chlamydial infection may provide clues in some circumstances but tissue diagnosis is needed in most cases. Culture techniques to detect adherent bacteria are not routinely available.

Results that confirm the diagnosis

  • While endoscopic features may be suggestive of specific diagnoses, histologic confirmation is imperative, and all diagnostic endoscopies should include biopsies for histopathologic interpretation. The yield of routine histologic staining of intestinal biopsies varies with the expertise of the pathologist. Special stains are available to assist in the detection of protozoa, while immunohistochemical tests may increase the sensitivity and provide specificity for the diagnosis of specific viral infections, such as cytomegalovirus. Electron microscopy has proved to be valuable in the detection of protozoal infection. While electron microscopy can be performed on paraffin-embedded tissue, it is better to obtain tissues fixed in glutaraldehyde, or another fixative designed for electron microscopy. Culture of tissue specimens is rarely performed clinically.

What imaging studies will be helpful in making or excluding the diagnosis of diarrheal alimentary tract disease?

  • Imaging studies are not often helpful in the evaluation of patients with diarrhea. Protozoal and adherent bacterial infections do not produce specific radiologic changes, though small bowel series or CT may suggest a small intestinal cause for diarrhea. Radiologic studies also may suggest colitis, but provide no distinguishing characteristics to allow for a specific diagnosis. The only major type of diarrheal associated with radiologic changes is exudative enteropathy, and the associated findings, intestinal wall thickening, mesenteric node enlargement, and hepatosplenomegaly also are non-specific.

What consult service or services would be helpful for making the diagnosis and assisting with treatment?

If you decide the patient has diarrheal alimentary tract disease, what therapies should you initiate immediately?

There are three important considerations in the management of patients with diarrheal disorders; the etiologic cause and its effects of nutritional and hydration status. Most of the infections typically associated with AIDS patients occur in patients with severe CD4 depletion. For this reason, initiation of HAART therapy is an important part of the therapeutic regimen. HAART therapy is more efficacious than most anti-infective therapies. There is no concern about the development of an immune reconstitution syndrome specifically targeting the GI tract.

Patients with diarrheal disorders are at increased risk for the development of malnutrition and dehydration. Small bowel diseases due to protozoal infections produce a sprue-like syndrome with malabsorption of all classes of macro and micronutrients. Patients with malabsorption due to exudative enteropathy may suffer disproportionate depletion of fat soluble vitamins and may also lose proteins, e.g. albumin, due to extravasation into the gut lumen. Patients with inflammatory diseases often undergo rapid weight loss and depletion of lean mass due to the local and systemic inflammatory response.

Dehydration may occur in anyone with diarrhea due either to excess fecal losses or to debilitation and insufficient fluid intake. Patients with small intestinal disease and malabsorption are particularly vulnerable to the development of dehydration. In addition, the patients may develop multiple electrolyte abnormalities, including hypokalemia, hyperchloridemia, and acidosis with a normal anion gradient.

If I am not sure what pathogen is causing the infection what anti-infective should I order?

Empiric therapy is not generally recommended for the management of diarrhea in patients with HIV/AIDS. One possible exception is the use of a quinolone or similar agents for suspected adherent E. coli infection, after a work-up reveals no other pathogens. In addition, presumptive therapy for C. difficile toxin-associated diarrhea may be considered in patients felt to have severe or severe and complicated infection, after sending appropriate stool studies (Table II).

Table II.

Treatment of Diarrheal Diseases

How do these pathogens cause diarrheal alimentary tract disease?

The different types of enteric pathogens promote characteristic and distinctive pathologic lesions and clinical presentations. Protozoal diseases typically are localized to intestinal epithelial cells, and affected intestines demonstrate partial villous atrophy and crypt hyperplasia, resembling the histologic picture of tropical sprue.

Clinical studies have demonstrated the specificity of protozoal infection for the sprue-like lesion. Villous and crypt heights and cell counts were markedly abnormal and disaccharidase enzyme specific activities were markedly depressed in patients with cryptosporidial or microsporidial infections compared to healthy control patients. However, AIDS patients at a similar level of immune depletion but without protozoal infection by electron microscopy have results similar to the healthy controls. These results indicate that it was the protozoal infection, not the level of immune depletion that produced the alteration in small bowel structure and function. However, since patients with acute diarrhea, untreated HIV infection in the absence of severe immune depletion, or other small bowel pathogens including mycobacterium avium-intracellulare (MAC) were not studied, the presence of small bowel disease is not entirely specific for protozoal infection.

Clinical evidence of ileal dysfunction was seen in HIV/AIDS patients in the pre-HAART era and was associated with enteric infection with enteroadherent E. coli, as demonstrated both by ultrastructural studies and by specific culture techniques to detect adherent organisms. Diarrhea is presumed due to bile salt malabsorption as a result of ileal infestation with these organisms.

Exudative enteropathy has been documented mainly with MAC infection, but also with other organisms, such as Rhodococcus sp. The key pathogenic characteristic is the accumulation of infected macrophages in the intestinal lamina propria and lymphatics. The infiltration of the intestinal mucosa and the lymphatic blockage combine to produce a block to the uptake of luminal nutrients and, in severe cases, to direct loss of intestinal lymph, containing chylomicrons and other materials, into the intestinal lumen.

Inflammatory diseases of the intestine are seen mainly with CMV infection, though Clostridium difficile, bacterial colitides, tuberculosis, and histoplasmosis can produce diarrhea through the same mechanisms, namely cytokine-mediated inflammation and intestinal secretion, mucosal destruction, stimulation of propulsion via the enteric nerves, and others.

Several pathogens produce non-specific diarrhea and other GI symptoms. Mucosal HIV infection is believed to directly affect mucosal function and promote the so-called "HIV enteropathy". The precise mechanisms promoting intestinal fluid secretion or decreasing absorption have not been clarified. Certain infestations, such as from intestinal spirochetes, certain amebae such as Blastocystis hominis and Dientamoeba fragilis, among others, may be found in patients with diarrhea and other symptoms, with or without HIV infection. The specificity of these organisms for producing diarrhea and the pathogenic mechanisms underlying the diarrhea are unclear.

How can diarrheal alimentary tract disease be prevented?

Primary prophylaxis is not recommended, other than routine sanitary habits. Secondary prophylaxis is recommended in patients with low CD4 counts, who have contracted isosporiasis or cyclosporiasis and, who are unable to access HAART therapy. In addition to routine prevention measures related to using safe food and water, trimethoprim sulfamethoxazole (160mg/800mg) TIW-daily or ciprofloxacin 500mg TIW is prescribed.

WHAT'S THE EVIDENCE for specific management and treatment recommendations?

Cronin, WJ, Reka, S, Torlakovic, E, Sigal, S, Kotler, DP. "Rectal mucosal histopathology in HIV infection varies with disease stage and HIV protein content". Gastroenterology. vol. 103. 1992. pp. 919-33.

(This study demonstrates the mucosal changes that occur in patients without enteric pathogens i.e. HIV-associated enteropathy.)

Didier, ES, Weiss, LM. "Microsporidiosis: current status". Curr Opin Infect Dis.. vol. 19. 2006. pp. 485-92.

(A comprehensive review of microsporidial infections.)

Kaplan, JE, Benson, C, Holmes, KH. "Guidelines for prevention and treatment of opportunistic infections in HIV-infected adults and adolescents: recommendations from CDC, the National Institutes of Health, and the HIV Medicine Association of the Infectious Diseases Society of America". MMWR Recomm Rep.. vol. 58. 2009. pp. 1-207.

(Recent treatment guidelines.)

Kotler, DP, Reka, S, Chow, K, Orenstein, JM. "Effects of enteric parasitoses and HIV infection upon small intestinal structure and function in patients with AIDS". J Clin Gastro.. vol. 16. 1993. pp. 10-5.

(A study correlating intestinal protozoal infections with mucosal histopathology.)

Monkemuller, KE, Call, SA, Lazenby, AJ, Wilcox, CM. "Declining prevalence of opportunistic gastrointestinal disease in the era of combination antiretroviral therapy". Am J Gastroenterol. vol. 95. 2000. pp. 457-62.

(Demonstration of the benefit of HAART in reducing GI opportunistic infections.)

Carr, A, Marriott, D, Field, A. "Treatment of HIV-1-associated microsporidiosis and cryptosporidiosis with combination antiretroviral therapy". Lancet. vol. 351. 1998. pp. 256-61.

(Demonstration of the ability of HAART therapy and immune reconstitution to eradicate protozoal infections in AIDS patients.)

Field, AS, Milner, DA. "Intestinal microsporidiosis". Clin Lab Med.. vol. 35. 2015 Jun. pp. 445-59.

(Complements the paper by Didier and Weiss with new information regarding sequencing techniques used in diagnosis.)

Dikman, AE, Schonfeld, E, Srisarajivakul, NC, Poles, MA.. "Human Immunodeficiency Virus-Associated Diarrhea: Still an Issue in the Era of Antiretroviral Therapy". Dig Dis Sci.. vol. 60. 2015 Aug. pp. 2236-45.

(Review with a particular focus on non-infectious diarrhea which has become relatively more important in patients treated with HAART.)
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