X-Linked Agammaglobulinemia

The typical patient with X-linked agammaglobulinemia (XLAG) is susceptible to bacterial infections because of the absence of all circulating immunoglobulin subtypes; mature circulating B cells are low to absent. This disorder is characterized by an inability to make antibodies to virtually all antigens. The molecular basis of most cases of XLAG was elucidated in 1993, when a defect in the BTK (Bruton tyrosine kinase) gene was found^37,38; subsequent studies have identified numerous deleterious mutations.^39–41 The BTK gene encodes a nonreceptor tyrosine kinase expressed in B-cell and myelomonocytic cell lineages but not in T cells. BTK functions in intracellular signaling pathways essential for pre–B-cell maturation, but the exact mechanism by which the defects in BTK lead to B-cell maturation arrest remains unclear. XLAG may have more phenotypic diversity than has previously been recognized, because adults with mild or no clinical symptoms but with deficiencies in BTK have been described.^42–44 Age at onset, disease severity, and genotype are roughly associated with mutation severity (as classified based on structural and functional consequences) in some but not all cohorts.^39,40

GI manifestations are less common in XLAG than in CVID, perhaps because of preserved T-cell function in XLAG,⁴⁵ although persistent or recurrent diarrhea is reported in 23% to 29% of patients.^39,46 Age at onset of GI symptoms is younger than in CVID patients, and autoimmune diseases are less common. Small intestinal and colonic mucosal biopsies in the XLAG patient without GI symptoms are notable only for the lack of plasma cells in the lamina propria, giving the lamina propria an empty appearance. Mucosal architecture is unremarkable, and villous blunting is not seen. Approximately one third of patients are seen initially with GI complaints, most commonly diarrhea or perirectal abscess, and 10% in one study had chronic GI symptoms, either from persistent infection with G. intestinalis, Salmonella, or enteropathic Escherichia coli or secondary to bacterial overgrowth. No cause for chronic diarrhea was found in half of these patients.⁴⁷ Chronic infection with rotavirus is also reported in this population.⁴⁸ Because biopsies are not routinely performed for this disorder, few descriptions of histopathologic findings are available, but moderate blunting of duodenal villi with crypt hyperplasia and an increase in lamina propria inflammatory cells are reported in acute infections.⁴⁹ Degenerative changes may be noted in epithelial cells on the surface of the villus with no increase in crypt apoptosis⁵⁰; crypt cells are spared, and the crypt zone undergoes a compensatory hyperplasia. The histologic changes of acute rotavirus infection are reported to resemble celiac disease but are patchier and quickly revert to normal with resolution of infection.⁵¹

In addition to GI infections, a chronic ulcerating inflammatory condition, clinically similar to Crohn disease, that is manifested by recurrent diarrhea, malabsorption, ulcers, and small bowel strictures (Fig. 5.1). A prominent lymphocytic inflammatory infiltrate without plasma cells or granulomas is seen in the affected areas.^23,52 In one case, enterovirus was found by polymerase chain reaction in inflamed ileum and adjacent mesenteric lymph nodes, suggesting that in some XLAG patients infection may be responsible for these lesions.⁵³

Patients with XLAG are at increased risk for malignancy, even in childhood. The most common malignancy in this group is NHL, which often involves the GI tract, and many of these cases occur in children younger than 10 years of age.⁵⁴ There are rare reported cases of gastric adenocarcinoma⁵⁴ and colorectal adenocarcinoma.⁵ The increased incidence of colorectal carcinoma for patients with XLAG was calculated as 30-fold in one study,⁵ although other registry studies have reported few or no colorectal cancers in their patients with XLAG.^46,55 In most of the reported cases, XLAG patients with colorectal carcinoma are young adults in their 20s who are seen with advanced-stage tumors. In one reported case, multiple colorectal adenomas in addition to carcinoma were found.⁵

X-Linked Hyperimmunoglobuin M Syndrome

X-linked hyperimmunoglobulin M syndrome (XHIM) results from a mutation in the gene for CD40 ligand, which leads to loss of isotype switching. T cells from patients with this disorder lack the CD40 ligand and therefore do not interact with CD40 on the B-cell surface, an event necessary for immunoglobulin class switching. These patients have very low levels of IgG and IgA and normal or elevated levels of IgM.⁵⁶ They are susceptible to pyogenic infections similar to those encountered in XLAG, and in addition are susceptible to Pneumocystis carinii pneumonia. A variety of intracellular pathogens such as mycobacterial species, fungi, and viruses (e.g., CMV, adenovirus) are implicated in causing disease in these patients. The most common site of infection is the upper or lower respiratory tract (approximately 50% and 80% of cases, respectively).⁵⁶ Disseminated infection^57,58 and esophageal infection with Histoplasma capsulatum are also reported in XHIM.

Diarrhea occurs in one third to one half of patients^56,59 and follows a chronic course in most. Chronic watery diarrhea may be caused by Cryptosporidium infection; G. intestinalis, Salmonella, and Entamoeba histolytica have also been implicated, although in most patients no pathogen is identified.⁵⁶ NLH involving the GI tract is reported in approximately 5% of patients.⁵⁹ Lymphoid hyperplasia may also result in hepatosplenomegaly, lymphadenopathy, and enlargement of the tonsils.⁶⁰ IBD was reported in two patients with XHIM and chronic diarrhea; clinical details were not provided.⁵⁹ Sclerosing cholangitis is a common and serious complication (affecting about 20% of European patients) and is often related to chronic infection with Cryptosporidium; liver transplantation may be necessary.⁵⁹ In one European series, three of five patients infected with hepatitis B developed hepatocellular carcinoma.⁵⁹

Patients with XHIM are prone to autoimmune hematologic diseases, including cyclic or chronic neutropenia, and oral and perianal ulcers are common during neutropenic episodes.⁵⁹ Massive proliferation of IgM-producing plasma cells may involve the GI tract, liver, and gallbladder, usually in the second decade of life, and may prove fatal.⁶¹ High-grade neuroendocrine carcinoma of the colon has been reported in this disorder,^62–64 and there is an increased incidence of liver and biliary tract tumors.⁶³

Hyperimmunoglobulin E Syndrome

Also known as Job syndrome, hyperimmunoglobulin E syndrome is a rare, multisystem disorder characterized by recurrent elevated serum IgE, eczema, and sinopulmonary infections.⁶⁵ Three genetic etiologies have been identified: loss of function of DOCK8 in the autosomal recessive form of the disorder,⁶⁶ mutations in STAT3 in the more common autosomal dominant form,⁶⁷ and a single reported case of Tyk deficiency.⁶⁸ In addition to findings related to the immune system, characteristic facial features and dental and skeletal abnormalities occur in the autosomal dominant form, and severe viral cutaneous infections are seen in the autosomal recessive form.⁶⁵ Chronic diarrhea and disorders resembling IBD are not reported in hyper-IgE syndrome. GI manifestations of the disease appear limited to mucocutaneous candidiasis, tissue-invasive fungal infections with Cryptococcus (reported in the esophagus⁶⁹ and colon⁷⁰), and ileocecal histoplasmosis mimicking Crohn disease.^71,72 Perforation of the colon, probably related to infection with staphylococcal species, has also been reported,⁷³ as well as diverticulitis in a young patient.⁷⁴ Patients with hyper-IgE syndrome do not appear to be at increased risk for primary GI malignancy.

Infections in CVID

Chronic infection with G. intestinalis is a common problem in patients with CVID and may or may not cause clinical symptoms. In some cases, malabsorption, steatorrhea, and villous abnormalities can be reversed if Giardia is eradicated. Small bowel mucosal abnormalities in giardiasis include villous blunting, increased intraepithelial lymphocytes, and NLH. The trophozoite form of the organism can be identified on small bowel biopsy (Fig. 5.2). The prevalence of Giardia infection in this population appears to be decreasing, but giardiasis remains a significant cause of chronic diarrhea in CVID.¹⁵

Other GI infections are less common in CVID. Cryptosporidiosis is occasionally found. The prevalence of common bacterial intestinal infections (e.g., Salmonella, Campylobacter) does not appear to be increased. Although prolonged antibiotic use is common in these patients, an increase in pseudomembranous colitis has not been reported.¹⁵ On occasion, viral and fungal organisms infect the GI tract in CVID patients, but such infections are less common in CVID than in acquired immunodeficiency syndrome (AIDS). Cytomegalovirus (CMV) infection involving the esophagus, stomach, jejunum, and ileocecal area and resulting in multiple ulcers and obstructing strictures has been reported in a patient with CVID.¹⁵

In the stomach, a nonspecific increase in lamina propria lymphocytes is seen in some patients with CVID (Fig. 5.3, A); increased apoptosis of gastric epithelial cells is present in some cases^23,24 (see Fig. 5.3, B). In a study of gastric biopsies from 34 patients with CVID and dyspepsia, 41% of patients were infected with Helicobacter pylori. All H. pylori–positive patients and 20% of H. pylori–negative patients had chronic gastritis, and 50% of those infected with H. pylori had multifocal atrophic gastritis. Ten percent of H. pylori–negative patients had multifocal atrophic gastritis.²⁵ Atrophic gastritis resembling autoimmune atrophic gastritis on clinical and morphologic grounds (see Fig. 5.3, C) and resulting in pernicious anemia may occur in the absence of demonstrable anti–parietal cell antibodies in these patents. Atrophic gastritis may develop at a very young age in patients with CVID, and it has been reported in a 6-year-old who developed multifocal gastric adenocarcinoma at age 11.²⁶

Adults with CVID are also at increased risk for gastric adenocarcinoma. It has been estimated that patients with CVID have a 47-fold increase in gastric carcinoma compared with the general population of Great Britain,²⁷ and gastric carcinoma ultimately develops in 5% to 10% of CVID patients, usually many years after the onset of hypogammaglobulinemia.

Small Bowel

In the small bowel, a sprue like lesion with villous blunting occurs in some patients with CVID and is associated with severe malabsorption, often requiring parenteral nutrition. Villous atrophy associated with CVID generally lacks the degree of crypt hyperplasia seen in celiac disease (Fig. 5.4, A), but may be indistinguishable on biopsy. In general, the lamina propria inflammatory infiltrate is not as prominent as in celiac disease, and enterocyte maturation is normal, with preservation of the brush border.²³ Most CVID patients with this small bowel lesion do not respond to a gluten-free diet, although an elemental diet may be beneficial, and most respond to corticosteroids, at least initially.²⁸ Plasma cells are absent or are found only in very small numbers in the lamina propria. Surface intraepithelial lymphocytes are often markedly increased (see Fig. 5.4, B), even in the absence of villous atrophy. In some cases, an increase in apoptotic bodies is found in crypt epithelial cells (see Fig. 5.4, C). Clinical autoimmune enteritis with loss of goblet cells has also been reported.²⁴

Granulomatous enteropathy has also been reported in patients with CVID and may be associated with protracted diarrhea unresponsive to antibiotic therapy. Poorly formed non-necrotizing granulomas are found in the lamina propria in multiple sites in the GI tract, including the stomach, small intestine, and colon^24,29; the diarrhea usually resolves with intravenous immunoglobulin therapy.

NLH in the GI tract is characterized by multiple discrete hyperplastic lymphoid nodules in the lamina propria and submucosa of the small intestine (Fig. 5.5), large intestine, or both, and is probably a result of chronic antigenic stimulation. The germinal centers of the follicles are composed of proliferating B cells with scattered tingible body macrophages; the mantle zones contain mature and immature B cells, and the extramantle zones contain a mixture of cell types including B cells, T cells, and macrophages. NLH is found in as many as 60% of patients with CVID but may be seen in the setting of giardiasis without antibody deficiency. In contrast to NLH in CVID patients, plasma cells are present in the extramantle zones in nonimmunodeficient patients. NLH is not considered a malignant disorder. However, malignant lymphomas of the GI tract in patients with immunodeficiencies often arise in a background of NLH, and clonal immunoglobulin gene rearrangement has been demonstrated in NLH in the GI tract of a child with CVID.³⁰ Consistent with these observations, the most common malignancy in CVID is NHL, which affects approximately 8% of patients¹⁸; these lymphomas often originate in extranodal sites, with small bowel the most common GI site. Most of these lymphomas are of B-cell origin; they include diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma.¹⁸

Chronic inflammatory processes involving small or large bowel that are clinically similar to IBD develop in some patients with CVID. In some patients, the small bowel is the primary site of involvement and the lesions resemble Crohn disease, with transmural inflammation and small bowel obstruction. Granulomas usually are not present in these Crohn disease-like disorders.³¹

Large Bowel

The colitis occurring in CVID is variable in morphology. In some patients, the inflammatory process is limited to the colon and clinically mimics ulcerative colitis. Mucosal architectural distortion with crypt destruction is present, although crypt distortion is less pronounced than in most cases of ulcerative colitis, with less crypt branching (Fig. 5.6, A). Neutrophils are present in the lamina propria and crypt epithelium (see Fig. 5.6, B). In contrast to ulcerative colitis, plasma cells are not present in the lamina propria in CVID-associated colitis, and an increase in CD8+ T cells (compared with normal controls and those with IBD) has been reported in the colon of CVID patients.³² In some cases, the crypt destruction and mucosal distortion is accompanied by increased apoptosis, and the histology is similar to that of colonic graft-versus-host disease (GVHD).^23,24 Milder cases of colitis in CVID may resemble lymphocytic colitis, characterized by increased intraepithelial lymphocytes and minimal mucosal distortion,³³ and an atypical form of collagenous colitis with pseudomembranes has been reported in one patient.³⁴ The etiology and pathogenesis of colitis in these patients remain largely unknown. The association of chronic GI inflammatory disorders and autoimmune disorders in these patients, and the resemblance of the lesions to other disorders of immune dysregulation, imply that the colitis of CVID may be autoimmune in origin.

Adenocarcinoma of the colon is reported in young patients with CVID. Small cell neuroendocrine carcinoma of the cecum was reported in a 16-year-old boy, who died of liver metastases 5 months after diagnosis.³⁵ In another case, 9 adenocarcinomas and 20 adenomas were present synchronously in the colon of a 22-year-old man with CVID.³⁶

Omenn Syndrome

Omenn syndrome is an autosomal recessive type of SCID with clinical and pathologic features of GVHD. The immunologic hallmark of the disease is expansion of an oligoclonal population of T cells and a near absence of B cells.⁷⁶ Infants with Omenn syndrome are seen with diffuse erythroderma, hepatosplenomegaly, lymphadenopathy, and failure to thrive⁸¹; chronic diarrhea and alopecia are common. Hypereosinophilia and hypogammaglobulinemia are characteristic. Paradoxically, serum IgE levels are increased, although B lymphocytes are not detectable in the circulation, lymph nodes, or skin. Activated circulating T cells are normal to increased in number but constitute an oligoclonal population. The underlying basis for these findings in Omenn syndrome is impairment but not complete loss of the V(D)J recombination process as a result of mutations in RAG1 or RAG2, the recombination activating genes.⁷⁶ Mutations in these genes were first identified in a subset of SCID patients with T⁻B⁻ SCID. The occurrence of this type of SCID and Omenn syndrome in the same kindred furnished the clue that Omenn syndrome was caused by mutations in the same genes. Differences between T⁻B⁻ SCID and Omenn syndrome can be explained by the presence of two entirely defective alleles in SCID and the presence of one marginally functional allele that is capable of establishing the oligoclonal T-cell population in patients with Omenn syndrome. Infants with SCID with maternal T-cell engraftment may exhibit GVHD symptoms indistinguishable on clinical grounds from Omenn syndrome,⁸² and a diagnosis of Omenn syndrome depends on excluding this possibility by appropriate human leukocyte antigen typing or molecular analysis. Published accounts of the histopathologic changes in Omenn syndrome are scant, but skin changes resemble those of GVHD,^83,84 and numerous apoptotic crypt cells are found in colonic biopsies in a pattern similar to that of GVHD (unpublished observations). Crypt injury and an increase in lamina propria eosinophils may also be seen (Fig. 5.8).

Chronic Mucocutaneous Candidiasis

Chronic mucocutaneous candidiasis is a heterogeneous group of disorders characterized by persistent Candida infection of the skin, nails, and mucous membranes. Autoimmune disorders and a polyglandular endocrinopathy syndrome including pernicious anemia are common, occurring in more than 50% of patients. There is a high frequency of association with thymoma and systemic lupus erythematosus.⁸⁹ Mutations in STAT1 have been identified in the autosomal dominant form of the disease,^90,91 and the autosomal recessive form has been linked to deficiency in interleukin-17 receptor A.⁹² Immune defects include disorders of T-cell immunity with variable B-cell involvement. The most common GI manifestation is esophageal candidiasis. Although superficial infection with Candida is a defining characteristic, infections with other fungi (e.g., H. capsulatum) and bacteria are common.⁹³

Wiscott-Aldrich Syndrome

Wiskott-Aldrich syndrome, characterized by early onset of profound thrombocytopenia with small platelets, eczema, and recurrent infections, is inherited as an X-linked recessive disease. Platelets and T cells are most severely affected. The genetic basis of Wiskott-Aldrich syndrome, described in 1994, is a mutation of the WASP gene, which encodes an intracellular protein expressed exclusively in hematopoietic cells.⁹⁴ This protein is involved in transduction of signals from cell surface receptors to the actin cytoskeleton and is important in cytoskeletal architecture and cell trafficking and motility. Diarrhea is reported in patients with this disorder but has been poorly characterized.⁸⁷ Bloody diarrhea in these patients is often attributed to thrombocytopenia, and biopsies may not be performed because of the risk of hemorrhage. A Crohn’s disease-like inflammatory process with cobblestone appearance and inflammatory pseudopolyps involving the descending and transverse colon has been reported in Wiskott-Aldrich syndrome.⁹⁵ Massive hemorrhage from aneurysms involving the liver, small bowel mesentery, and kidney has been reported.⁹⁶

Chronic Granulomatous Disease

In chronic granulomatous disease (CGD), phagocytic cells are unable to reduce molecular oxygen to create the superoxide anion and its metabolites necessary for eradication of certain catalase-positive intracellular microbes. CGD is genetically heterogeneous, resulting from a mutation in any of four components of reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase. The most common form of the disease, accounting for 70% of cases, is X-linked recessive; four other forms are autosomal recessive.⁹⁷ As a result of this defect, patients with CGD suffer from recurrent bacterial and fungal infections; abscesses in a variety of sites and pneumonia are common. They are also prone to develop inflammatory and rheumatic diseases, such as an IBD-like condition and a lupus-like syndrome. GI manifestations are relatively rare in CGD, but reported cases can be broadly grouped into obstructive and inflammatory categories.

Obstruction can occur in patients with CGD at a number of levels of the GI tract, from esophagus to small bowel. Gastric outlet obstruction is more common in the X-linked form of the disease.⁹⁷ In some cases, the obstruction is caused by infiltration of the viscus wall by pigment-laden macrophages (the histologic hallmark of CGD) or by granulomatous inflammation. In other cases, the obstruction is reportedly secondary to a functional disturbance in GI motility, although infiltration of the deep layers of the organ by macrophages often cannot be excluded. Esophageal obstruction occurs in 1% of CGD patients⁹⁷; biopsies of the esophageal mucosa usually show nonspecific findings or reflux esophagitis⁹⁸ but may demonstrate pigmented macrophages. Involvement of the gastric antrum and pylorus is somewhat more common, occurring in 16% of patients, and gastric outlet obstruction may be the first manifestation of CGD. Granulomas, giant cells, and macrophages laden with brown-yellow fine pigment are commonly present in gastric biopsy specimens,⁹⁹ but in some cases only nonspecific inflammation is seen.¹⁰⁰ Small bowel obstruction is relatively rare in CGD but is occasionally reported in the context of an inflammatory process.¹⁰¹ In a review of small bowel and rectal biopsies from nine patients with CGD, pigment-laden macrophages were found in the lamina propria at both sites. In the small bowel, the macrophages were located deep in the mucosa adjacent to crypts, but when numerous, they also extended into the villus core (Fig. 5.9). In rectal biopsies, the number of pigmented histiocytes was quite variable, ranging from rare scatted cells to large numbers of histiocytes accumulating between the base of the crypts and the muscularis mucosae. Granulomas with giant cells were also present in rectal biopsies from some patients. In one of eight cases, distortion of crypt architecture without crypt abscesses was seen.¹⁰²

Chronic inflammatory processes that are indistinguishable from IBD affecting the small and large bowel may occur in CGD patients¹⁰³; as with obstructive lesions of the GI tract, these lesions are more common in the X-linked form of the disease.⁹⁷ Polymorphisms in genes unrelated to NADPH oxidase may modify the clinical phenotype in CGD; certain polymorphisms in the genes for myeloperoxidase and Fcγ receptors are strongly associated with GI complications.¹⁰⁴ Involvement of the small bowel in CGD may produce fistulas, longitudinal ulcers, stenosis, and non-necrotizing granulomatous inflammation that can be mistaken for Crohn disease¹⁰⁵; discontinuous inflammation and perianal disease may also contribute to the difficulty in distinguishing the two entities.¹⁰⁶ The granulomas seen in intestinal lesions in CGD are often more florid than is usually seen in Crohn disease, but granulomas are not present in all cases. In a study of colitis in one CGD patient, the presence of an acute and chronic inflammatory infiltrate confined to the colonic mucosa, crypt abscesses, and lack of granulomas were more suggestive of ulcerative colitis than Crohn disease. Mucosal architectural distortion and ulceration were not as prominent as is usually the case in ulcerative colitis, however, and pigmented macrophages were present in the lamina propria.¹⁰³

Miscellaneous Immune Deficiency Syndromes

Other rare disorders of immunity occasionally associated with GI manifestations include leukocyte adhesion deficiency, in which delayed wound healing and susceptibility to bacterial and fungal infection lead to necrotizing enterocolitis.¹⁰⁷ A chronic inflammatory process with multiple aphthous ulcers involving the gastric antrum, terminal ileum, cecum, and right colon, which resolved with bone marrow transplantation, has also been reported in leukocyte adhesion deficiency,¹⁰⁸ and a case of rectal ulcer resembling Crohn disease has been reported in a pediatric patient.¹⁰⁹

Immune dysregulation, polyendocrinopathy, and enteropathy, X-linked (IPEX) syndrome, caused by mutations in FOXP3, usually manifests in affected males with severe watery diarrhea early in life. The entire GI tract may be involved and primarily shows GVHD-like histologic changes with prominent crypt apoptosis (Fig. 5.10). Small bowel disease with villous atrophy mimicking celiac disease has also been reported in IPEX.^110,111

Acute GVHD

On endoscopic examination, the appearance of the GI mucosa in acute GVHD is variable, ranging from only mucosal edema and erythema to more severe changes such as ulcers and mucosal sloughing.¹¹⁹ The major histologic features of GVHD in the GI tract are epithelial cell apoptosis and a relatively sparse mononuclear inflammatory cell infiltrate (Fig. 5.11, A). Apoptotic epithelial cells are found primarily in the regenerative compartment of the mucosa, such as the crypt in the colon and small intestine and the neck area of gastric glands. In the colon, the apoptotic cells are particularly conspicuous and are termed “exploding crypt cells”; these cells contain intracytoplasmic vacuoles filled with karyorrhectic nuclear debris (see Fig. 5.11B). Apoptotic cells are smaller and less conspicuous in the gastric mucosa (Fig. 5.12). In more severe cases of acute GVHD, crypt abscesses may be seen, and destruction and loss of crypts is seen. In the most severe cases, mucosal sloughing and extensive ulceration occur. In the stomach, granular eosinophilic necrotic cellular debris without neutrophils may be present in the lumina of injured gastric glands.¹²⁰ Villous blunting is commonly seen in small bowel GVHD. A grading system for acute GVHD affecting the colon has been proposed¹²¹ (Fig. 5.13 and Table 5.6); however, correlations with clinical symptoms and patient outcome are weak.

The changes that occur in the GI tract in acute GVHD are not entirely specific. The differential diagnosis includes drug-related injury, infection, recurrent hematologic malignancy, and other causes of immune activation (Table 5.7). In particular, mycophenolate mofetil (MMF) treatment may cause active colitis with ulcers, marked crypt cell apoptosis, and a mixed lamina propria inflammatory infiltrate that can mimic GVHD (Fig. 5.14).¹²² Other reported patterns of injury include IBD-like changes and, more rarely, ischemic colitis.¹²³ Normal biopsy findings in sites distant from these GVHD-like lesions should raise the question of MMF-associated colitis rather than GVHD¹²⁴; improvement after discontinuation of MMF is also good evidence that the injury was drug related. Use of proton pump inhibitor (PPI) therapy has been associated with an increase in apoptotic epithelial cells in the gastric mucosa (Fig. 5.15), mimicking the histologic changes seen in GVHD.¹²⁵

Changes similar to GVHD are reported in colonic biopsies from patients with severe T-cell deficiencies,⁷⁹ malignant thymoma,¹²⁶ and primary immune disorders such as CVID.^23,24 In the patient who has undergone bone marrow transplantation, the effects of cytoreductive therapy (Fig. 5.16) may resemble changes of GI GVHD in the early posttransplantation period; therefore, a diagnosis of GVHD must be made with caution before day 21 after transplantation. Recurrence of hematologic malignancies, particularly acute lymphoblastic leukemia, may also mimic acute GVHD.¹²⁷ CMV infection may produce mucosal damage characterized by apoptotic epithelial cells, mimicking GVHD; differentiation from GVHD relies on the demonstration of viral inclusions.¹²⁰GVHD and CMV infection may occur simultaneously, making it difficult to separate the effects of each process on the GI tract. Infection with Clostridium difficile has also been reported to be associated with GI GVHD and a high nonrelapse mortality rate in this group; it is postulated that C. difficile toxin may predispose to increased severity of GVHD.¹²⁸

Chronic GVHD

Chronic GVHD is clinically similar in many ways to some of the collagen vascular diseases and has been compared to autoimmune disorders such as scleroderma, Sjögren syndrome, and primary biliary cirrhosis. Chronic GVHD involves multiple organs, such as salivary gland, mouth, eye, and upper respiratory tract, that are not involved by acute GVHD.¹²⁰

In chronic GVHD, skin changes of dermal fibrosis may resemble scleroderma, and involvement of the oral squamous mucosa leads to painful ulcers and submucosal fibrosis. Involvement of minor salivary glands results in an oral sicca syndrome. In advanced cases, ulcers and submucosal fibrosis occur in the esophagus (Fig. 5.17), the most commonly affected site in the GI tract.¹²⁴ Small bowel involvement is less common; when present, it is associated with diarrhea. Focal fibrosis of the lamina propria and segmental submucosal fibrosis, with minimal mucosal changes, has been reported.¹²⁹ In colonic biopsies, chronic colitis similar to that seen in ulcerative colitis has also been reported in allogeneic bone marrow transplant recipients.¹³⁰ These changes consist of mild to moderate crypt distortion and crypt atrophy, and it is unclear whether the mucosal architectural distortion is caused by chronic GVHD or by other factors. In one study, similar findings of mild chronic active colitis, with granulomas in some cases (Fig. 5.18), were reported in 10% of patients undergoing umbilical cord blood stem cell transplantation, occurring 88 to 314 days after transplantation. Although patients were culture negative, this “cord colitis syndrome” responded to antibiotic therapy, suggesting an infectious etiology.¹³¹

Infections

CMV remains the most common pathogen in HIV-infected patients, and CMV infection can involve any segment of the GI tract, most commonly the esophagus and colon. CMV esophagitis often manifests with distal esophageal ulceration. CMV primarily infects endothelial cells, followed by macrophages; biopsy specimens obtained from the ulcer bed are, therefore, more likely to demonstrate characteristic CMV cytopathic effects. Endoscopic features in CMV gastritis include patchy erythema, erosions, or multiple small ulcers. Unlike other sites in the GI tract, in the stomach the epithelial cells are preferentially infected. CMV colitis can manifest as colitis with or without ulcers. As in the esophagus, characteristic CMV inclusions can be seen in stromal and endothelial cells.

Although GI herpes simplex virus (HSV) infection occurs less frequently than CMV infection, approximately 5% of esophageal ulcerative lesions in HIV-infected patients are caused by HSV infection.¹³⁸ HSV esophagitis can manifest as either vesicular or ulcerative lesions. Unlike CMV esophagitis, HSV characteristically infects squamous epithelium.

One of the important differential diagnoses for CMV and HSV esophagitis in HIV-infected patients is idiopathic esophageal ulcer. HIV patients with idiopathic esophageal ulcer always are seen with severe odynophagia and weight loss, which often respond to therapy with corticosteroid or thalidomide or both.¹³⁹ Endoscopically, HIV-associated idiopathic esophageal ulceration appears as large, irregular ulcers in the middle or distal esophagus. To diagnose idiopathic esophageal ulcer, exclusion of infectious etiologies is required.

Bacterial pathogens involving the GI tract in the HIV-positive population include C. difficile, mycobacteria, and spirochetes. C. difficile–associated colitis is the most common cause of bacterial diarrhea in HIV-infected patients after HAART.¹⁴⁰ GI MAC infection can be seen in severely immunocompromised patients, involving the stomach, the small intestine (Fig. 5.20, A), and, rarely, the colon. Endoscopic presentations include normal-appearing mucosa, friability, multiple raised nodules, or ulceration. Microscopically, the lamina propria of the intestinal mucosa may be stuffed with distended macrophages containing the organisms, which can be confirmed by a special stain for acid-fast bacilli (see Fig. 5.20, B). Periodic acid–Schiff (PAS) stain characteristically reveals abundant delicate bacilli in macrophages (see Fig. 5.20, C).

Human intestinal spirochetosis is a common cause of diarrhea in HIV patients and preferentially infects the surface epithelium of the distal colon and rectum. In addition to HIV-infected individuals, intestinal spirochetosis is also diagnosed in general population without HIV infection.¹⁴¹ The prevalence of intestinal spirochetosis varies considerably from region to region. For example, in the Western countries, the prevalence of intestinal spirochetosis in rectal biopsies is 2% to 7%, whereas in developing countries it is much higher, ranging from 11.4% to 32.6%. Among homosexual and HIV-infected men, the rate is even higher, up to 54%. Intestinal spirochetosis is much more common in men than in women. Two strains of Bachyspira have been identified as being responsible for intestinal spirochetosis—Brachyspira aalborgi and Brachyspira pilosicoli—with B, aalborgi being the major causative agent in Western countries.

Because many cases of intestinal spirochetosis are asymptomatic, there is much debate as to whether intestinal spirochetosis is a pathogen or a commensal. However, accumulating evidence supports the notion that intestinal spirochetosis can be the cause of GI symptoms in a subset of patients, especially in homosexual men, HIV patients, and children.^142–146 Association of intestinal spirochetosis with invasive colitis and hepatitis, rectal discharge, rectal bleeding, and even spirochetemia has been reported. Improvement of symptoms after eradication of the spirochetes is seen in individuals with symptomatic intestinal spirochetosis.

For a long time, intestinal spirochetes have been described as noninvasive.¹⁴⁷ However, some studies have demonstrated invasion of spirochetes beyond the surface epithelium.¹⁴⁸ The presence of spirochetes in epithelial cells, lamina propria, macrophages, and even Schwann cells has been reported. In addition, invasive intestinal spirochetosis is associated with immediate-type immune reaction of the host, featured by a marked increase of IgE-producing plasma cells in the lamina propria and intraepithelial mast cells. Stunting, destruction, and loss of microvilli are seen in invasive cases and can result in reduction of the resorptive surface, leading to diarrhea. Invasive intestinal spirochetosis has been correlated to GI symptoms in the general population, whereas homosexual and HIV-infected men are more likely to be symptomatic regardless of invasion, for unclear reasons.

The most common symptoms associated with intestinal spirochetosis include diarrhea, abdominal pain, altered bowel movement habits, and rectal bleeding.^142–145 Intestinal spirochetosis can affect the rectum, the colon, or both, with the rectum the most severely involved area. Colonization of appendiceal epithelium by intestinal spirochetosis occurs frequently.¹⁴¹ In one study, spirochetes were found in 7.8% of appendectomy specimens. The endoscopic appearance of the colon is largely normal; however, some subtle changes (e.g., erythema) may be present. Biopsy reveals long, undulating bacteria vertically attached to the brush border, forming a blue bushy layer on hemotoxylin and eosin (H&E) staining (Fig. 5.21, A). The organisms stain dark black with the Warthin-Starry stain (see Fig. 5.21, B). The colonic mucosa is always unremarkable, with no increase in chronic inflammation and no active colitis. However, in a small subset of patients, mild inflammatory changes such as increased intraepithelial lymphoctyes can be seen. A severe acute inflammatory reaction with crypt abscesses and ulcers was reported in two patients with advanced HIV infection.¹⁴⁸

In general, no treatment is needed for asymptomatic cases. If intestinal spirochetosis is identified as the sole intestinal pathology in a symptomatic patient, it should be treated with antibiotics to eradicate the spirochetes. Metronidazole is the drug of choice for the treatment of intestinal spirochetosis. Most cases treated with metronidazole show symptom improvement with eradication of the bacteria in follow-up biopsies.^142,144

Candida is the most common HIV-associated fungal pathogen, with the esophagus the site most often involved. Esophageal candidiasis is characterized by white or yellow plaques with surrounding mucosal erythema endoscopically. Biopsy of the plaques reveals necroinflammatory exudates, budding yeast forms, and pseudohyphae. In HIV-infected patients, histoplasmosis is most likely to involve the ileocecal region, occasionally leading to GI bleeding, obstruction, perforation, and stricture. Intestinal mucosal biopsies reveal marked infiltration of the lamina propria by macrophages containing budding yeasts.

GI parasitic infections are relatively uncommon in HIV-infected patients after HAART. They mainly occur in the small intestine. Infecting agents include Cryptosporidium, Microsporidium, Isospora, and Giardia. In cryptosporidiosis, the parasite inhabits the microvillous brush border of the intestinal epithelium, causing enfacement of the brush border. The intestinal epithelium may be atrophic and in disarray. A relatively mild active colitis may be seen in the colon, with cryptitis and a few crypt abscesses (Fig. 5.22). Microsporidium is difficult to identify on H&E-stained sections; special stains such as Giemsa may be beneficial, and electron microscopy is the gold standard for confirming the presence of the organism in the surface epithelial cells.

HIV Enteropathy

GI dysfunction, as manifested by d-xylose malabsorption, is common, even in early HIV disease. It may be a manifestation of HIV enteropathy, defined as a reduction in small bowel villous surface area associated with chronic diarrhea in the absence of enteric pathogens. The pathogenesis of HIV enteropathy is not well understood. The chronic diarrhea may be caused by an unidentified pathogen, but there is evidence that diarrhea is directly related to local infection by the virus. Studies have shown that HIV-infected patients show improvement in clinical symptoms after initiation of HAART. Studies of intestinal permeability, epithelial cell barrier function, and cytoskeletal integrity have demonstrated changes in HIV-infected subjects after administration of antiviral agents alone.¹⁴⁹ These studies indicate that medications should also be considered as a cause of diarrhea in these patients, and they may account for up to 45% of noninfectious cases¹⁵⁰; commonly implicated medications are nelfinavir, ritonavir, saquinavir, indinavir, and didanosine.

In small bowel biopsies, HIV enteropathy is characterized by relatively mild villous blunting without well-developed crypt hyperplasia.¹⁵¹ The degree of villous atrophy is typically less than that seen in celiac disease. The histology of the colon in HIV enteropathy is less well understood. Increased epithelial cell apoptosis has been reported in association with HIV infection¹⁵²; however, it is unclear whether this is related to the presence of the virus, other immune mediators, or antiretroviral therapy. The presence of an opportunistic pathogen, especially Cryptosporidium, Microsporidium, Isospora, or Giardia in the small intestine and Salmonella, Shigella, Mycobacterium, Cryptosporidium, E. histolytica, and CMV in the colon, must always be ruled out in these patients.

Malignancy

The effective use of HAART in the treatment of HIV has led to a gradual decline in infectious diseases and an increase in HIV-associated malignancies (see Table 5.6). The most prevalent cancers in this population are Kaposi sarcoma and AIDS-related NHL. Kaposi sarcoma is still the most common HIV-associated malignancy, despite a decline in incidence since advent of HAART. Studies have reported GI involvement in 40% of cases at initial presentation and in as much as 80% at autopsy.¹⁵³ Endoscopically, Kaposi sarcoma appears as flat to raised, purple plaques. Microscopically, the lesion is composed of plump spindle cells, which often form fine vascular lumina containing red blood cells (Fig. 5.23). Hemosiderin and eosinophilic hyaline droplets may be present. Kaposi sarcoma is caused by human herpes virus 8 (HHV-8). Immunohistochemical stain for HHV-8 is useful in confirming the diagnosis.

The AIDS-related NHL lymphomas are predominantly of B-cell lineage and include Burkitt lymphoma (Fig. 5.24), DLBCL (immunoblastic, centroblastic, and anaplastic variants), primary effusion lymphoma (PEL), and plasmablastic lymphoma.^153,154 The GI tract is the most common site of extranodal NHL, including Burkitt lymphoma and DLBCL.^155,156 Classic PEL affects the peritoneal cavity, whereas solid PEL may be seen in extraserous sites such as large intestine and lymph nodes. Plasmablastic lymphoma has been documented in the oral cavity and anorectum.¹⁵³ The development of these HIV-associated malignancies is often attributable to coinfection by viruses such as HHV-8 (also called Kaposi sarcoma–associated herpesvirus) and Epstein-Barr virus. In addition to these more common HIV-associated cancers, large database studies have shown an association of HIV infection with other malignancies. This list includes Hodgkin lymphoma, multiple myeloma, leukemia, anal squamous cell carcinoma, head and neck squamous cell carcinoma, esophageal carcinoma, and gastric carcinoma.^153,157