Human Immunodeficiency Virus–Related Gastrointestinal Pathology: A Southern Africa Perspective With Review of the Literature (Part 1: Infections) Open Access

Seldom appreciated as such, the GI tract represents the largest lymphoid organ in the body.13 It is, therefore, a major site of viral replication and CD4 lymphocyte depletion during the acute phase of HIV infection, also demonstrating delayed and only partial CD4 T-cell restoration.14 The GI tract thus plays a pivotal role in HIV infection and is affected by a variety of OIs, often as part of multisystem disease. Table 1 outlines the etiologic organisms that may be seen in HIV-associated GI infections in southern and sub-Saharan Africa.

Many viruses may cause GI disease in HIV; those associated with nonepithelial neoplasia (Human herpesvirus 8 and Epstein-Barr virus) are discussed in part 2 of this review.

Cytomegalovirus (CMV) is well recognized as the most-common opportunistic viral pathogen in HIV, and patients with CD4 cell counts of less than 100/µL are at particular risk for GI involvement.8,15 Almost one-half of esophageal ulcers in HIV patients in one US series before HAART was available was due to CMV.16 In southern Africa, the Cape Town AIDS Cohort Study (1984–2000) found herpes simplex virus (HSV) and CMV to be the most-common viral pathogens in HIV, but no reference was made to the infection sites11; CMV was predominant in patients with CD4 cell counts less than 50/µL. A South African HIV pediatric endoscopic study found GI CMV infection in 27% of patients presenting with GI symptoms.17 My practice's experience confirms the esophagus and colorectum as the most-common GI sites affected, but almost all other GI sites, including stomach, small intestine, and appendix has been seen. Multisystem disease is often, but not always, present. Additionally, one US study found up to one-third of patients with esophageal CMV infection to have another synchronous esophageal infection, usually Candida spp or, less often, HSV.18 In the South African pediatric study, esophageal coinfection was uncommon, although GI CMV infection was accompanied by intestinal cryptosporidiosis in one-quarter of patients.17 

Cytomegalovirus esophagitis typically demonstrates distal, large, and often deep ulcers. Intestinal and colorectal pathology is more variable and may include pseudomembranes, perforations, toxic megacolon, pneumatosis intestinalis, and obstructive inflammatory masses.19 Endothelial and stromal cells are preferentially infected (Figure 1, a), but macrophages and glandular epithelium may also be involved (Figure 1, b). Characteristic of CMV are “owl-eye” inclusion bodies in the nucleus and frequent granular, basophilic, cytoplasmic inclusion bodies typically found in cells at the ulcer base. In patients who are severely immunocompromised, viral inclusion bodies may be extremely abundant and demonstrate atypical features (Figure 1, c through f).

Gastrointestinal HSV infection most often involves the esophagus but may also affect the anorectum.20 Although much less common than CMV, international literature cites HSV as the cause of approximately 5% of esophageal ulcerative lesions.8 In the Cape Town Aids Cohort Study, HSV was the most-common viral OI in patients with HIV who had CD4 cell counts greater than 200/µL, but the study included all body sites and was likely dominated by genital and oral HSV disease.11 My practice's experience with HIV-associated, GI involvement attests to HSV occurring less frequently than CMV infection. Endoscopically, HSV esophagitis typically demonstrates diffuse, erosive lesions or small, discrete, superficial ulcers, without the vesicular lesions usually seen in immunocompetent hosts.8 Herpes simplex virus characteristically infects squamous epithelium and leads to eosinophilic “ground-glass” inclusion bodies most often seen in syncytial cells at the ulcer margin (Figure 1, g and h). Cowdry type A eosinophilic inclusion bodies, with a surrounding halo and chromatin margination, may also be seen.

Human papilloma virus (HPV) is associated with anal squamous papillomas (condylomata acuminata), which are common in the context of sexually transmitted disease in southern Africa.21 Although HIV infection increases the risk for HPV-associated anal intraepithelial neoplasia and squamous cell carcinoma, it may also predispose the patient to infection by HPV.22,23 A significant association between HIV infection and multiple HPV coinfections was found in South African men.21 A recent study from Zimbabwe suggested that HIV may affect genital tract immunity immediately, with a high risk of multiple, new HPV detections immediately after HIV acquisition.24 

No reliable southern Africa data are available on other, less-common HIV-associated GI viral infections, which include adenovirus and herpes varicella zoster. Adenovirus usually involves the lower GI tract, and affected epithelium demonstrates exclusively intranuclear inclusion bodies that have a basophilic “smudged” appearance because of an indistinct nuclear membrane. Less often, the inclusion bodies appear eosinophilic with peripheral chromatin margination. Gastrointestinal infection by herpes varicella zoster is rare but is a consideration in disseminated disease, which has been documented in southern Africa in both adults and children infected with HIV.25,26 Herpes varicella zoster demonstrates inclusion bodies morphologically similar to HSV.

Although characteristic viral inclusion bodies in GI biopsies often may be focal and require several histologic levels for identification, their detection in significantly immunocompromised HIV patients is usually not difficult. Correct histopathologic diagnosis relies on identifying the infected cell type and location and the nature of the viral inclusions and associated cellular features, as well as the judicious application of immunohistochemistry. The morphologic features of the 3 most-common HIV-associated GI OI viral inclusion bodies are contrasted in Table 2.

A plethora of GI bacterial OIs has been documented in HIV, most causing an enterocolitis. The introduction of HAART has led to a dramatic decrease in these infections and a change in the etiology of this group of disorders in the developed world.8 In some respects, the range of HIV-associated bacterial GI pathology in sub-Saharan and southern Africa reflects what was seen in developed countries in the pre-HAART era. Major differences exist, however, and are mainly due to the high prevalence of mycobacterial and diarrheal disease in this region.

Mycobacterium spp, particularly Mycobacterium tuberculosis and Mycobacterium avium complex, are well documented as opportunistic GI pathogens in HIV.10 Although M avium is the more-common isolate in the developed world, it occurs less frequently in the setting of HIV in sub-Saharan Africa.27,28 In southern Africa, HIV-associated mycobacterial infections are dominated by M tuberculosis. This is likely due to the large burden of tuberculosis (TB), combined with early development of antimycobacterial immunity, which is protective against the less-pathogenic M avium.29,30 The close association between tuberculosis and HIV infection in Africa was already documented at the beginning of the HIV pandemic.31 The emergence of multidrug-resistant and extensively drug-resistant TB in this region during the past decade has, however, deleteriously affected the already alarming morbidity and mortality of HIV-associated TB.32 

Mycobacterium tuberculosis infection of the GI tract is sometimes accompanied by active pulmonary lesions, but many patients with HIV have primary extrapulmonary TB.33 In the Cape Town AIDS Cohort Study, 40% of patients with TB had primary extrapulmonary disease, although the site was not specified.11 Gastrointestinal TB most often affects the ileocecum,34 although my practice has seen tuberculosis in the setting of HIV at all levels of the GI tract. On endoscopy, ileocecal lesions are typically transverse ulcers, often with associated stricturing, but inflammatory polyps and nodules also occur. Gastric and proximal small-bowel lesions often mimic malignant ulcers. Histologic features vary from well-formed, focally necrotizing granulomas in relatively immunocompetent patients with HIV, to neutrophil-rich, histiocytic infiltrates and suppuration in the severely immunocompromised (Figure 2, a through f). Mycobacterial spindle cell pseudotumors may also occur.35 Distinction of GI TB from Crohn disease may be difficult, particularly in immunocompetent patients with HIV, although Crohn disease is rare in indigenous African patients36 and is uncommon in the setting of HIV.37 The presence of abundant, large (>400 µm), confluent granulomas demonstrating fibrillogranular (caseous) necrosis, disproportionate submucosal inflammation, histiocyte palisading at the base of ulcers, and the absence of mucosal chronicity away from foci of active disease all suggest tuberculosis.38,39 Although acid-fast M tuberculosis bacilli may be extremely scant in biopsies from immunocompetent patients with HIV, they are usually readily detected in the setting of untreated HIV. Figure 2, g, demonstrates the typical histomorphology of M tuberculosis bacilli, which is contrasted with M avium in Figure 2, h. However, a large number of intracellular TB bacilli (mimicking M avium) may sometimes be seen in severely immunocompromised individuals. Infection by Yersinia spp may resemble intestinal tuberculosis histologically but is distinguished by the absence of caseous necrosis and acid-fast bacilli, and is uncommon in patients with HIV in my laboratory's experience.

Some data are available for nonmycobacterial causes of HIV-related GI bacterial infections in southern Africa. A recent study on South African HIV-infected gold miners found Salmonella and Shigella species to be the most-common isolates,40 although the incidence of GI disease was markedly lower than in other African studies.41,42 An early South African pediatric study documented a high rate of diarrhea in patients with perinatally acquired HIV, the most-common isolates being Salmonella spp, Shigella spp, and Escherichia coli.26 Nontyphoidal Salmonella spp are particularly problematic in southern and sub-Saharan Africa because of their high rates of extraintestinal sepsis and mortality.31,43 The common occurrence of schistosomiasis in the region and the known protective effect the intravascular, adult parasitic worm affords nontyphoidal Salmonella spp44 are contributing factors, which are also significant in patients with AIDS.45 Other diarrheagenic bacterial pathogens isolated from South African patients with HIV include Campylobacter spp, Plesiomonas shigelloides, and Aeromonas spp.46 The histologic features of infection by these bacterial organisms are diverse and include those of acute self-limited colitis, severe acute inflammation mimicking ulcerative colitis, erosion/ulceration, and pseudomembrane formation.

Although HIV-associated proctitis caused by Chlamydia trachomatis, Treponema pallidum, and Neisseria gonorrhoeae is well documented, it is relatively rare in my practice's experience. The preponderance of proctitis caused by these organisms and transmitted by homosexual men may account for its rarity47 because this is an uncommon route for sexually transmitted disease in southern Africa.48 

Intestinal spirochetosis, initially described in HIV-infected homosexual men, is now known to occur in children and in various other disorders without associated HIV infection.49,50 Interestingly, my practice has often seen it in the setting of HIV, which has a predominantly heterosexual route of transmission in Southern Africa.48 In humans, intestinal spirochetosis is thought to be caused predominantly by Brachyspira aalborgi and Brachyspira pilosicoli.51 Although the clinical significance of this disease is questioned by some authors, my practice has usually found it to be symptomatic in patients with HIV who improve on antibiotic therapy. On endoscopy, minimal or no abnormalities are seen, and histology reveals the characteristic “fuzzy” thin layer of entangled organisms attached to the apical surface of the colonic epithelium (Figure 3, a) with no or minimal associated inflammatory change. The organisms are readily confirmed and distinguished from enteroadherent Escherichia coli with Warthin-Starry (Figure 3, b) and periodic acid–Schiff (PAS) stains.

Bacillary angiomatosis, caused by Bartonella henselae and Bartonella quintana, is rare but well documented in the gut.52,53 The lesions usually involve the upper GI tract (often with associated skin lesions) and demonstrate acute or chronic GI hemorrhage. One South African case report documented hematemesis as a presenting feature.52 The endoscopic appearance is that of multiple friable or nodular vascular lesions, which can mimic Kaposi sarcoma. Extensive esophageal polyposis has also been described.53 Histology reveals the typical granulation tissuelike appearance of the lesions (Figure 3, c), with scattered nuclear debris and aggregates of extracellular amphophilic granular bacterial deposits, which demonstrate a coccobacillary morphology on a Warthin-Starry stain (Figure 3, d).

Clostridium difficile–associated colitis has emerged as an important cause of bacterial diarrhea in patients with HIV in the post-HAART era; one US study found C difficile–associated colitis to be the most-common cause of HIV-associated bacterial diarrhea.54 Although not as common in the HIV setting in southern Africa, the disease is discussed further in part 2 of this review because of its drug association.

International literature cites Candida spp as the most-common HIV-associated GI fungal pathogen.12,55 This was also the finding in both adult and pediatric studies in southern Africa11,17 and is borne out by my practice's experience. Regional data show oral Candida spp infection to be very common across all CD4 strata in HIV; the esophagus is the GI site most often involved, particularly in patients with CD4 cell counts less than 200/µL.11 Esophageal infection may occur in the absence of oral thrush, and endoscopy usually demonstrates characteristic white plaques and erosions; frank ulceration, pseudomembranes, and even infarction may be seen in other parts of the GI tract. Depending on the patient's immune status, histology reveals a variable acute inflammatory response and variable numbers of Candida spp organisms, present as budding yeasts and pseudohyphae (Figure 3, e and f).

Human immunodeficiency virus–associated GI infection caused by Cryptococcus neoformans is uncommon in developed countries and is usually part of systemic disease.56 Cryptococcosis has been documented at all levels of the GI tract, with the upper tract most often involved.57,58 In southern Africa, C neoformans is a common fungal pathogen and an important cause of HIV-associated mortality, seen predominantly in patients with CD4 cell counts less than 50/µL.11,40,59 Although it rarely affects the GI tract in my practice, it usually does so in disseminated disease and is associated with a high mortality. Endoscopy may reveal nodular lesions, ulceration, and deep mural involvement. Histology confirms the characteristic encapsulated, narrow-neck budding, pleomorphic fungal yeasts with a surrounding inflammatory response. This may have granulomatous features, but in cases of advanced HIV, the response most often varies from suppurative and necrotizing to completely absent. The fungal yeasts are positive on PAS (diastase resistant) and silver stains, whereas the capsule of variable thickness demonstrates positivity using mucicarmine, Alcian blue, colloidal iron, and Fontana-Masson stains.

Pneumocystis jirovecii (formerly Pneumocystis carinii) GI infection almost always occurs as part of disseminated disease in severely immunocompromised patients, with aerosolized pentamidine prophylaxis being a major risk factor for GI involvement.60,61 Data on HIV-associated P jirovecii infection in southern Africa seem to indicate that it may not be as common as in other parts of the continent or in the developed countries before the HAART era.11,25,26,40 Involvement of the GI tract at any level may occur, but the esophagus, stomach, and colon are most often affected.60–63 Endoscopic findings are nonspecific and erosive, ulcerative, nodular or polypoid lesions may be seen. The histologic response varies and may be weakly granulomatous to histiocytic, often demonstrating plasma cells. Organisms can be identified in the characteristic foamy and necrotic exudate using silver-based and PAS stains.

Gastrointestinal parasitic infections are common in cases of HIV in southern and sub-Saharan Africa, largely because of their high prevalence in subtropical regions and because of prevailing poor socioeconomic conditions.64–66 Coccidian infections predominate in the setting of HIV.

Many reports from before HAART therapy was developed found Cryptosporidium parvum to be the most-common cause of diarrhea in patients with AIDS.66–68 The scant data available on patients from southern Africa seem to confirm this, with one pediatric study reporting cryptosporidiosis as the most-common HIV-associated GI parasitic OI.17 My practice's recent series of upper, double-lumen, and lower endoscopic GI biopsies on treatment-naïve patients with advanced HIV (CD4 < 200 cells/µL) who presented with diarrhea identified Cryptosporidium spp to be the most-common GI OI in 9 of 34 patients (26%; unpublished data). Although cryptosporidiosis most often affects the proximal small bowel, concomitant involvement of the colorectum is frequently seen. Gastric, pancreaticobiliary, and disseminated disease usually occurs in severely immunocompromised patients and has a dismal outcome.69 Typically, no endoscopic abnormalities are present. Small-bowel histology demonstrates villous atrophy, crypt hyperplasia, epithelial disarray, and prominent, mixed inflammatory cell infiltration with numerous eosinophils. Similar inflammatory changes occur at other involved GI sites. Organisms are readily identified as 2- to 5-µm basophilic spheres protruding from below the apical membrane of epithelial cells and stain positively with Warthin-Starry, Giemsa, and Gram stains (Figure 4, a and b).

Entamoeba histolytica, a common pathogenic amoeba with a worldwide distribution, is endemic to parts of southern Africa.70 It usually infects healthy individuals but has a documented association with HIV, particularly in homosexual men.71–73 A recent South African study reported a significantly higher E histolytica seroprevalence among rural patients with HIV, with the highest risk in patients with CD4 cell counts less than 200 cells/µL.74 Although E histolytica typically affects the right colon, involvement of other parts of the large or small bowel and dissemination with peritonitis and abscess formation (usually in the liver and lung) may occur in HIV cases. My practice has seen isolated cases of HIV-associated amoebic colitis complicated by bowel perforation, amoebic peritonitis, and patient demise. The bowel segment affected by amebiasis characteristically demonstrates necrotizing acute inflammation and undermining “flask-shaped” ulcers, but rarely, tumoral masses (so-called amebomas) may occur. Numerous parasites (often mimicking histiocytes) are usually present in the necroinflammatory debris and demonstrate erythrophagocytosis, distinguishing this organism from nonpathogenic E dispar (Figure 4, c and d). Erythrophagocytosis, as well as the pale “washed-out” appearance of the parasite nucleus and strong PAS (diastase sensitive) cytoplasmic positivity allows distinction from histiocytes (Figure 4, e).

Microsporidial GI infections in HIV are most often caused by Enterocytozoon bieneusi and Encephalitozoon (Septata) intestinalis. In southern Africa, many cases were reported75 in Zimbabwe as early as 1995, the first South African case was documented76 in 1998, and there were isolated subsequent cases reported77 in 2000. The parasites most often infect the small bowel and are an important cause of persistent diarrhea in HIV.78 No official data exist for southern Africa HIV-associated microsporidiosis. The parasites are, however, easily missed on stool microscopy as well as routine hematoxylin-eosin–stained biopsy sections (because of their intracellular location, small size, and granular appearance) and are undoubtedly underdiagnosed in this region. A high index of suspicion is required for histologic identification and modified trichrome as well as Brown-Brenn/Gram or Warthin-Starry stains are recommended to prevent false-negative diagnoses on biopsy.79 Examination under polarized light may highlight the organism's polar filament, but this is a notoriously insensitive histologic detection technique.

Giardia lamblia is a flagellate that usually infects otherwise healthy individuals and often occurs in children. It has, however, been reported in association with AIDS, particularly in homosexual men.80 Although no data are available to confirm or refute that association in southern Africa, my practice has seen cases of giardiasis in patients with HIV. The high prevalence of giardiasis in southern Africa and the predominantly heterosexual spread of HIV in the region, however, make these cases likely to represent incidental coinfections.

Isospora belli is another, less-common coccidian that most often involves the small bowel, although colorectal and disseminated disease have been documented.81 Endoscopic and histologic features are similar to cryptosporidiosis, although lamina propria fibrosis may be seen in chronic cases. Organisms are large (15–20 µm), usually located in a perinuclear or subnuclear, intraepithelial location, and stain positively with Giemsa, PAS, and methenamine silver stains. Asexual forms are usually crescentic to ovoid (“banana-shaped”), whereas sexual forms are round to oval and demonstrate a prominent nucleus (Figure 4, f and g).

Toxoplasma gondii may rarely involve the GI tract in HIV, where it is seen as part of disseminated disease.82,83 The stomach or, less often, the colon is involved, and endoscopy may reveal no abnormality, ulceration, or diffuse mucosal/mural thickening.84 Histologic features vary from nonspecific inflammation to necrosis, and pseudocysts with tachyzoites, as well as cysts with bradyzoites, may be seen (Figure 4, h). Careful histomorphologic examination, supplemented with PAS and Giemsa stains and immunohistochemistry, confirm the tissue diagnosis. Polymerase chain reaction is also of value in distinguishing this organism from Histoplasma and Leishmania species, particularly in severely immunocompromised patients who may have negative results with Toxoplasma spp serology.85 

Cyclospora cayetanensis, the most recently identified coccidian, presents with similar pathologic features to Cryptosporidium and Isospora species.86,87 Organisms in histologic sections are documented to be of similar size or slightly larger than Cryptosporium spp and are usually located in a parasitophorous vacuole in the upper part of the epithelial cell. They are acid-fast and auramine positive, but negative for PAS, Giemsa, Gram, and silver stains. This parasite has been reported in South Africa,88 but no data are available for HIV-related GI infection by C cayetanensis in the region. No biopsied cases on record exist from my practice's laboratory.

Strongyloides stercoralis is a nematode more commonly seen in central and northern Africa, where an association with HIV has been documented.89 In southern Africa, a recent article reported this parasite in the HIV setting with hyperinfection leading to mesenteric lymphadenopathy and intestinal pseudo-obstruction.90 

In 2009, an estimated two-thirds of the global HIV burden and three-quarters of the world's AIDS-related deaths were in sub-Saharan Africa, with the highest HIV prevalence rates seen in southern Africa. Despite encouraging indications of a containment of HIV spread in this region, there remains a large population of patients in southern Africa who are HIV-infected and immunocompromised and who are susceptible to a vast array of OIs. These OIs frequently involve the GI tract and are often part of systemic disease. Although much of the HIV-related infectious GI pathology in southern Africa mirrors that seen in the pre-HAART era in the developed world, numerous infections endemic to this region are responsible for pathologic manifestations seldom seen in developed countries. Furthermore, the profound immunosuppression often seen in HIV patients in this region may lead to unusual histologic features, involvement of uncommon GI sites, and infection by more than one opportunistic pathogen. The cornerstone of correct histopathologic diagnosis of HIV-associated GI OIs in the resource-limited setting of southern Africa remains careful morphologic evaluation of routine hematoxylin-eosin–stained sections, combined with a high index of suspicion. This should be supplemented with a thorough knowledge of the patient's clinical presentation, judicious use of ancillary stains, and close correlation with microbiologic studies.

The author wishes to thank Mr Eric Liebenberg, Division of Anatomical Pathology, Faculty of Health Sciences, University of Witwatersrand, Johannesburg, South Africa, for technical assistance with microphotographic material. The case in Figure 4, h, is provided courtesy of M. Shaw, MMed, Windhoek, Namibia.