Bacterial Infections

Patients with HIV have risks of developing diarrhea due to bacteria similar to those of immunocompetent patients, although for HUV patients these infections result in greater systemic compromise. ^2,8 Campylobacter infections occur with diarrhea, abdominal pain, fever and even bacteremia. ⁹ The diagnosis is made with a stool culture. Infection with non-typhoid Salmonella causes gastroenteritis, bacteremia, and local or disseminated infections in patients with HIV. ¹⁰ The diagnosis can be made by stool or blood cultures.

Management of these infections is based on ciprofloxacin which is recommended for 14 days. In patients with proctocolitis and HIV, chlamydia trachomatis infections should be suspected. The diagnosis is made with a stool culture and a blood culture given the high prevalence of bacteremia in immunosuppressed patients. ¹¹ Treatment with 100 mg doxycycline every 12 hours for 7 days or with a single 1g dose of azithromycin is recommended.

Although mycobacterial infections occur infrequently, they can compromise the digestive system. The mycobacterium avium complex (MAC) is the most common. ^12,13 The disease disseminated by MAC was the most common opportunistic bacterial infection in patients with AIDS. With the advent of ART, its incidence has declined, but it still occurs in patients with poor immunovirological responses. Its clinical presentation varies and can include fever, weight loss, nocturnal diaphoresis, watery diarrhea, malabsorption, lymphadenopathy and unusual enlargement of organs. ¹⁴ Usually, it compromises the duodenum and should be suspected when mucous nodules or yellowish patches can be seen in esophagogastroduodenoscopy. ¹⁵ In a biopsy, the infection is indicated by macrophages with acid-fast bacilli inclusions similar to those presented in Whipple’s disease. It can also be diagnosed in blood cultures and stool cultures. ¹⁴ Management with oral administration of 500 mg of clarithromycin every 12 hours and 15 mg/kg of ethambutol once a day VO with or without 300 mg of rifabutin daily is suggested. ¹⁶

Clostridium difficile bacteria can also be associated with diarrhea in patients with HIV. The diagnosis can be established by immunoassay techniques that detect toxins A and B. Their sensitivity is between 70% and 78%. Testing for the common antigen provides greater sensitivity, but it does not discriminate between pathogenic and non-pathogenic strains. ⁽¹⁷

Polymerase chain reactions (PCR) amplify genes for toxins A and B and offer greater sensitivity and specificity than do other techniques, ¹⁸ but the gold standard of diagnostic testing is culturing, but it has the limitation that it can take up to 72 hours. Standard management consists of oral administration of 500 mg of metronidazole every 8 hours for 10 to 14 days or oral administration of 125-250 mg of vancomycin every 6 hours for 10 to 14 days.

For severe infections by virulent strains and for patients with HIV, vancomycin seems to be superior to metronidazole. Another alternative is 200 mg of fidaxomicin every 12 hours for 10 days.

Fidaxomicin is an antibiotic that is not absorbed in the gastrointestinal tract whose efficacy is close to that of vancomycin. ¹⁹

Viral Infections

Cytomegalovirus (CMV) generates high rates of morbidity and mortality in HIV patients. It can affect any part of the gastrointestinal tract and manifests with fever, weight loss, anorexia, abdominal pain and bloody diarrhea. A colonoscopy, the diagnostic method of choice, will show evidence of patchy erythema mucosa, erosions and ulcers. ^20,21

The most effective antiviral treatment is intravenous administration of 5 mg/kg of ganciclovir every 12 hours for at least 3 weeks. Alternatively, 900 mg of valganciclovir can be administered orally every 12 hours for at least 3 weeks, or 90 mg of foscarnet can be administered intravenously every 12 hours for 3 to 6 weeks.

Parasitical Infections

Parasites that cause diarrhea in patients with HIV include those that can also generate infections in immunocompetent people as well as opportunistic parasites that do not generate diseases in the healthy population. The first group includes giardia lamblia, entamoeba histolytica and strongyloides stercoralis.

Cryptosporidium infections compromises the small intestine which causes severe diarrhea in patients with HIV. It also has the ability to infect the epithelium of the respiratory tract and the bile duct.^22,23. With the advent of ART, the morbidity attributed to cryptosporidium has decreased.^24,25 Diagnosis is made by modified Ziehl-Neelsen stains of fecal matter, or by identification of oocytes through PCR of biopsies of the small intestine or rectum. ⁸ Treatment is administration of ART to increase the CD4 T lymphocyte count. ²³ There is some evidence that suggests management with 500 mg of nitazoxanide every 12 hours until the symptoms are resolved and eradication in fecal matter is achieved. ^8,24

Isospora belli can cause diarrhea, vomiting, abdominal pain and weight loss. ²⁵ Therapeutic options in this case are trimethoprim/sulfamethoxazole (160 mg/800 mg) every 6 hours for 10 days or 500 mg of ciprofloxacin every 12 hours for 7 days in cases of allergies to sulfas. ⁸

The spectrum of symptoms of strongyloides stercoralis infections in patients with HIV varies from chronic diarrhea and anemia, to digestive bleeding, intestinal obstruction and even hyperinfection syndrome. ^26,27

Hyperinfection syndrome occurs most frequently in adult male patients and is characterized by uncontrolled larval multiplication including significant increases of the number of infective larvae outside the digestive system through the vascular and alveolar spaces. This causes pulmonary edema, pneumonia and alveolar hemorrhaging which can continue until respiratory failure and multiorgan failure with a mortality rate as high as 80%. The diagnosis is made by observing the larvae in the lungs.

Another system involved in hyperinfection is the central nervous system (CNS) where it can affect patients with meningitis with various cutaneous lesions ranging from Larva currens to periumbilical maculopapular eruptions, purpura and petechiae. The liver can also be affected through biliary obstructions and granulomatous portal inflammation. Less commonly, the heart, thyroid, pancreas and bladder can be affected.^26,27

The diagnosis is usually made by direct study of fecal matter, although the most sensitive method is a duodenal biopsy. Recommended treatment is oral administration of 200 μg/kg of ivermectin once a day for one or two days. If necessary, the treatment can be repeated two to three weeks after the first dose. ²⁷ In cases of hyperinfection syndrome, ivermectin should be administered daily until the symptoms resolve and fecal tests are negative for two weeks. ²⁷

Fungal Infections

Gastrointestinal histoplasmosis due to histoplasma capsulatum occurs infrequently, usually in patients with low CD4 levels and usually in the ileocecal region. Diagnosis can be made with cultures of fecal material, blood cultures, identification of urinary antigens and analysis of biopsy specimens.^28,29 It should be treated with amphotericin B for one to two weeks followed by itraconazole for 12 months. Patients with HIV and a CD4 count of less than 150 cells/mm³ who live in endemic areas should receive prophylaxis with 200 mg/day of itraconazole. ²⁹

Manifestations of microsporidial infections include non-inflammatory chronic diarrhea, weight loss, abdominal pain, nausea, vomiting and fever. (30 Diagnosis is a challenge given the germ’s small size of 1 to 2 μm. The gold standard for diagnosis remains modified Ziehl-Neelsen staining, but, there are other methods such as PCR and enzyme-linked immunosorbent assays (ELISA). ³⁰ Treatment is based on 400 mg of albendazole every 12 hours for three weeks, but ART with an increase in CD4 tends to resolve this infection. ¹¹

First stage: evaluation of infections by germs³⁴

The first step is to take a complete medical history that focuses on the evolution of the HIV infection, treatment received, adherence to treatment and risk factors for infections such as travel to endemic areas (important for amebae and giardia), anal sex (C. trachomatis or herpes), and recent use of antibiotics (C. difficile). Whether diarrhea is acute or chronic must be defined, and it should be categorized into one of four grades. ³⁵

This classification allows establishment of whether the patient should be hospitalized or an outpatient, priority of tests, probability of diagnosing opportunist infections, and whether empirical treatment should be initiated.

In the physical examination, the patient’s nutritional profile and signs of dehydration should be evaluated. If there are eye symptoms, the fundus of the eye should be checked for CMV retinitis or microsporidium retinitis. Whether or not hepatosplenomegaly is present must be determined. If the patient reports perianal pain, it is necessary to perform a digital rectal examination to rule out sexually transmitted infections (Figure 1).

Figure 1 Sigmoidoscopy of a patient with HIV. Multiple verrucous lesions in the rectum that extend into the anal canal are suggestive of perianal condylomata. 

To improve detection of germs, at least three coloproctological samples should be taken in a period of 10 days. ³⁶ Whenever there is a risk for infection by microsporidium, cryptosporidium or Isospora, modified Ziehl-Neelsen staining should be performed. If there is suspicion of CMV infection, a blood test should be performed to measure the antigen or immunoglobulin M (IgM) and, if the suspicion persists, direct methods such as PCR of blood and fecal matter should be used. The samples of Shigella and Salmonella for culturing must be transported immediately to the laboratory since any change of pH without refrigeration alters performance. For initial detection of C. difficile, test for toxin A and B in fecal matter. The probability of culturing mycobacteria from fecal matter is low, so it is not recommended. Determining the level of CD4 is essential for finding causes of diarrhea in patients with HIV (Table 1, Figure 2). ^1,3

Table 1 CD4 level and risk of infection by germs associated with diarrhea in HIV 

Figure 2 Flow diagram of approach to diarrhea in patients with HIV. EVDA: upper digestive tract endoscopy; NMR: nuclear magnetic resonance; CT scan: computerized axial tomography. 

Second Stage: Gastrointestinal Tract Examination³⁴

If a pathogen is not diagnosed in the first phase, and diarrhea persists and is severe, endoscopic or radiological studies should be performed.^34,37 The guidelines for endoscopic study of diarrhea from ​​the American Society for Gastrointestinal Endoscopy (ASGE) ³⁷ recommend initially performance of sigmoidoscopy in patients with HIV, but they clarify that if the sigmoidoscopy is not positive and the probability of opportunistic infection is high, a colonoscopy should be performed with ileum and colon biopsies, and an esophagogastroduodenoscopy should be performed with duodenal biopsies (Figure 3).

Figure 3 Colonoscopy of a patient with HIV and anal intercourse. Large rectal ulcer due to herpes virus. 

Several studies have demonstrated the usefulness of endoscopic procedures, but it should be clarified that there is no typical endoscopic pattern of opportunist infection, so biopsies should always be taken. It has been suggested that Salmonella infections predominates in the right colon and ranges from erythema to ulcerations. Amoeba infections usually affect the cecum and rectosigmoid with ulcerations and areas of necrosis (Figure 4). CMV can generate ulcerations that predominate in the left colon (Figure 5). The yield of colonoscopy ranges from 27% to 39%, and CMV is the most common germ found. ³⁸

Figure 4 Colonoscopy in a patient with HIV and bloody diarrhea. There are multiple, poorly defined ulcerations with necrotic material on the surface and an active inflammatory background in the cecum and right colon. Structural alterations with hemophagocytosis and trophozoites of E. histolytica were observed in biopsies. 

Figure 5 Sigmoidoscopy in a patient with HIV and bloody diarrhea. Multiple patchy round erosions can be seen. Immunohistochemistry (IHC) suggests a CMV infection. 

One study that compared microbiological examinations of fecal matter with endoscopic biopsies has found that the latter have better diagnostic yields in patients with CD4 <200 cells/mm³. ³⁹ Another study diagnosed opportunistic infections by endoscopic methods in 21/48 patients (44%; 95% confidence interval: 30% to 58%). Colonoscopy found the diagnosis in 13 patients, including nine cases of CMV. In the majority of patients, the diagnosis was made by biopsies of the rectosigmoid. Esophagogastroduodenoscopy diagnosed seven cases of microsporidium infections and two cases of cryptosporidium infections. ⁴⁰

Another prospective study of 79 patients found diagnoses in 22 cases with biopsies from the left colon contributed the most diagnoses (17/22 patients with sensitivity of 77%) including all 15 patients diagnosed with CMV infections (sensitivity of 100%). The combination of left and right colon biopsies had a sensitivity of 82%. Duodenal biopsies taken during esophagogastroduodenoscopy did not contribute to diagnosis unlike those taken during colonoscopy. ⁴¹ A study of 40 patients found diagnoses by colonoscopy in 65% of the patients. Amoebic colitis and CMV were the main causes. ⁴²

Whenever endoscopic procedures are performed, regardless of the findings, biopsies of both the colon and small intestine should be taken. Although the diagnostic yield of healthy mucosal biopsies is lower, opportunistic infections can sometimes be diagnosed ^43). Diagnoses of isolated CMV infections in the right colon occur in as many as 29% to 39% of patients, so a total colonoscopy is preferable to a sigmoidoscopy. ^38,44 If the suspicion is high, testing by immunohistochemistry and PCR should be performed on biopsies. Whenever biopsies are taken for microbiological study, they should be sent in a dry tube or saline solution, never in formaldehyde.

When an esophagogastroduodenoscopy is performed, duodenal biopsies should be taken as distal as possible, from the third or fourth duodenal portion, in order to increase detection of microsporidium. Examination of duodenal aspirate has not been shown to increase the detection of pathogens and should not be performed. ³⁸ The use of endoscopic capsules in HIV patients has been studied, and abnormalities in the small intestine were found in 89% of the cases. ⁴⁵ For now, its cost-effectiveness has not been evaluated, and it is not considered to be a routine examination.

Several useful radiological patterns have been described. One example is that tuberculosis tends to affect the ileocecal region with thickening of the ileum and cecum which simulates Crohn’s disease. ⁴⁶ MAC infections compromise the jejunum and cause thickening of the folds. ³ In addition to ulcers in the colon, CMV infections result in thrombosis due to vasculitis, and ischemia and perforations of the viscera can be found. ³ Kaposi’s sarcoma can affect any part of the digestive system and is seen as long, flat, or submucosal lesions associated with thickening of the folds. ⁴⁷ Non-Hodgkin’s lymphoma (NHL) usually involves the terminal ileum and causes mass-type lesions and ulcers with tumor extensions to the mesentery and adjacent ganglia (Figure 2). ⁴⁸

Third Stage: Evaluation of ART³⁴

Diarrhea associated with ART has been described in 2% to 19% of patients. ⁽⁴⁹ If it is considered that there is a relationship between ART medication and diarrhea, this third stage may precede the second. You should always have a clear idea about infectious disease before considering suspension or change of ART medications (Figure 2).

Non-Pharmacological Management

A comparison of 75 patients divided into two groups, one with a conventional diet and one with a restricted diet, has found that diarrhea had improved in the restricted diet group by 24 weeks. ⁵² Their diet was low in fat, insoluble fiber and caffeine, lactose free, and high in soluble fiber. A clinical trial of 25 patients, has found that supplementation with L-glutamine reduced the severity of diarrhea more than did placebos. ⁵³

The evidence for the use of probiotics is controversial. A clinical trial of administration of Lactobacillus GG to 17 patients for two weeks could not demonstrate positive outcomes. ⁵⁴ Another two day clinical trial with Lactobacillus strains resolved diarrhea in 12/12 patients compared to 2/12 patients who received yogurt without probiotics. ⁵⁵ A study of 69 patients with Lactobacillus strains for 25 weeks showed no improvement in symptoms related to diarrhea. ⁵⁶ Based on the results of these small studies, the use of probiotics cannot be recommended.

Pharmacological Management

Antimotility Agents

Loperamide and diphenoxylate seek to slow intestinal transit and increase water and sodium absorption. A Cochrane review of these drugs did not show positive results for diarrhea associated with HIV. ⁵⁷ A retrospective study found that 32% of patients receiving nelfinavir responded to the use of loperamide. ⁵⁸ It should be remembered that chronic use of loperamide can cause adverse effects including interactions with protease inhibitors. In any case, the use of this drug in HIV seems to be effective and safe, and should be used as the first line of treatment. ⁵⁰ The evidence for diphenoxylate is scarce and controversial. ⁵⁸ This medicine crosses the blood-brain barrier and has risks of abuse and dependence. It is suggested that it be reserved for patients who are refractory to other pharmacological measures.

Antisecretory Agents

Subcutaneous use of octreotide has been studied, but most studies date from the pre-ART era. Some studies found a reduction in the volume and frequency of bowel movements, ^59,60 but adverse effects such as hypoglycemia, biliary mud formation, nausea, abdominal pain and constipation should be taken into account. ⁵⁰ Its use should be reserved for refractory patients, and a risk/benefit analysis should be made.

Crofelemer has been approved by the Food and Drug Administration (FDA) for symptomatic improvement of non-infectious diarrhea in patients with HIV. The recommended dose is 125 mg twice a day. It acts by simultaneously inhibiting two chloride channels: the CFTR (cystic fibrosis transmembrane conductance regulator) in the apical membranes and the CaCC (calcium-activated chloride channel) in the epithelial membranes. This decreases the secretion of sodium and water into the intestinal lumen. It has minimal systemic absorption and acts directly in the intestine. ⁶¹ Consequently, there is little interaction with other medications. It has clinical effect at four weeks. ^62,63

The ADVENT study included 374 patients with noninfectious diarrhea associated with HIV which persisted despite management with loperamide. ⁶⁴ Its first phase compared doses of 125 and 500 mg of Crofelemer with placebos and found that administration of Crofelemer improved patients’ symptoms (20.5%, 19.6%, and 2%, respectively. p <0.0024). Long-term safety was evaluated in a 48 week phase III study of 250 patients. The results showed that 9.2% of adverse events could be attributed to the drug but that there were no changes in the level of CD4 + or viral load ⁶⁵. If patients who do not response after three months, the drug should be discontinued and other alternatives should be tried. This medicine has already been approved by the National Institute for the Surveillance of Drugs and Foods (INVIMA) here in Colombia.

The evidence is not strong, or the results have not been positive, for some other therapies including fiber supplements, bovine immunoglobulin, curcumin, bismuth salts and racecadotril. Consequently, they are not recommended.