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Gastrointestinal manifestations in primary immunodeficiency

Gastrointestinal manifestations in primary immunodeficiency
Authors:
Nima Rezaei, MD, PhD
Payam Mohammadinejad, MD
Atefeh Zeinoddini, MD
Hassan Abolhassani, MD, PhD
Section Editor:
Luigi D Notarangelo, MD
Deputy Editor:
Anna M Feldweg, MD
Literature review current through: Nov 2022. | This topic last updated: Oct 18, 2022.

INTRODUCTION — This topic review will provide a brief overview of the gastrointestinal (GI) immune system, review the most common GI complications of primary immunodeficiency (PID), and discuss specific GI disorders in some of the more common PIDs. Initial testing for immune problems, monitoring for GI complications among PID patients, and treatment considerations are also reviewed. More detailed approaches to patients with suspected PID and the medical management of immunodeficiency are discussed separately:

(See "Approach to the child with recurrent infections".)

(See "Approach to the adult with recurrent infections".)

(See "Laboratory evaluation of the immune system".)

(See "Primary immunodeficiency: Overview of management".)

OVERVIEW — Hundreds of PIDs have been identified and classified into 10 major categories [1]. Patients with PID have dysregulated immune processes, which can result in an increased susceptibility to infectious diseases, autoimmune disorders, and malignancies.

Within the GI tract, PID may present with recurrent GI infections; autoimmune, allergic, or lymphoproliferative disorders; or less commonly, malignancies. GI manifestations are the second most common complications of PID after pulmonary disease, affecting up to one-half of PID patients, depending on the disorder present [2,3]. Failure to recognize an underlying PID in such cases delays diagnosis and appropriate treatment, which could result in considerable morbidity and even mortality [4,5].

IMMUNE SYSTEM OF THE GASTROINTESTINAL TRACT — The GI tract is considered the largest organ in the immune system, with a vast surface area and the largest reservoir of lymphocytes in the human body [6]. The GI immune system consists of physical barriers, gut-associated lymphoid tissue, secondary mesenteric lymphoid organs, and immune cells and proteins.

The GI immune system is constantly exposed to a variety of foreign antigens, including those from bacteria, viruses, and parasites, as well as foreign dietary proteins [7]. A balance between immune responses to harmful micro-organisms and tolerance to nonpathogenic antigens and commensal microbiota is essential for immune homeostasis in the GI tract, a process that generally favors the development of tolerance. The GI immune system is mainly regulated by T lymphocytes, specifically regulatory T cells, which are also responsible for cellular immunity and initiation of antigen-specific immune responses [8,9].

Role of secretory IgA — Dimeric secretory immunoglobulin (Ig)A, which is synthesized and secreted in the GI tract (and thus distinct from monomeric serum IgA), plays an active role in the regulation of the GI immune system by inducing tolerance to antigens with insignificant pathogenesis, as well as providing protection against invasive micro-organisms. It is possible that dysregulation of IgA results in inflammatory processes in the GI tract [10]. Also, defects in either humoral or cellular immunity could result in uncontrolled inflammatory processes, damage to the mucosal surface of the GI tract, and increased risk of developing chronic inflammatory, autoimmune, and even malignant disorders.

Breast milk secretory IgA has specific antibodies to the enteric microbes encountered by the mother (eg, the enteromammary immune system [11]), making breast milk feeding crucial to the survival of infants in developing countries.

Secretory IgA may play an immunomodulatory role in the GI tract through the following mechanisms:

Helping to prevent binding of bacteria and viruses to intestinal epithelium by forming complexes with attachment sites for epithelial cells on the surface of micro-organisms [10].

Trapping antigens from micro-organisms and dietary proteins in the mucus, preventing antigen presentation, and facilitating immune exclusion [12].

Possibly facilitating biofilm formation of normal flora in the GI tract, thus promoting immune exclusion as well as preventing bacterial overgrowth of pathogenic micro-organisms [7].

Initiating immune responses in the GI tract by participating in antigen sampling under noninflammatory situations [10,13]. This is achieved by selective transportation by IgA of antigens to dendritic cells in Peyer patches [13].

When released by local plasma cells, trapping micro-organisms that managed to pass beyond the epithelial barrier of the GI tract and driving them back into the GI lumen (through the polymeric immunoglobulin receptor) or assisting in their clearance (through the IgA Fc receptor) [14,15].

The biologic functions of serum and secretory IgA, including immunity, homeostasis, and the role of secretory IgA in breast milk, are reviewed in more detail separately. (See "Structure and biologic functions of IgA", section on 'Functions'.)

Role of microbiome dysbiosis — The composition of the GI microbiota is under the control of the immune system, and can in turn impact the development and function of the both innate and adaptive immunity. Therefore, primary immunodeficiency can lead to dysbiosis due to defective immunosurveillance at the level of the intestinal mucosa. This defect in mucosal barrier function can lead to increased penetration of pathogens and chronic GI inflammation or autoimmune diseases due to continuous activation of lymphocytes. Studies have shown that the specific type of microbial dysbiosis (known as "low alpha diversity") and microbial translocation might explain disturbed immune response in specific cell types in PID patients. Health-associated microbial communities are depleted in the patients with cellular and humoral immunodeficiency. Moreover, patients with immune dysregulation present with dysbiosis linked to lipopolysaccharides translocation with pronounced inflammatory markers [16,17].

GASTROINTESTINAL MANIFESTATIONS OF PRIMARY IMMUNODEFICIENCY — Typical GI presentations of different types of PID include intractable diarrhea, malabsorption, failure to thrive, or inflammatory bowel disease (IBD) [18].

Infections — Infectious diarrhea is the most common GI manifestation in many types of PID, and infectious etiologies should be excluded before other causes are considered. Compared with the same infection in an immunocompetent host, GI infections in PID patients may have one or more of the following characteristics [12,19]:

Persist longer or be more severe

Require more intensive and prolonged antimicrobial therapy

Be caused by atypical and opportunistic organisms

The type of organism causing infectious diarrhea sometimes provides clues about the underlying type of immunodeficiency [12]:

Patients with defects in both B and T cells are susceptible to infections by bacterial, viral, and fungal organisms.

Bacterial infections are commonly observed in B cell defects.

Viral and fungal infections are characteristic of less severe T cell defects.

Impaired phagocytosis results in both bacterial and fungal infections.

The table summarizes the most common organisms responsible for GI infections among different types of PID (table 1).

Autoimmune and inflammatory disorders — Autoimmune and inflammatory GI disorders can be the presenting illness in PID patients, due to the failure of central and peripheral tolerance. Local dysregulation of the GI immune system may result in inappropriate immune responses that lead to autoimmunity or uncontrolled inflammation. Ineffective immune responses that do not fully clear invading pathogens, such as those seen in phagocyte disorders, can further provoke such processes. Different GI disorders are characteristic of certain types of PID [20,21].

Celiac disease — Celiac disease, also called celiac sprue, is a common autoimmune disorder resulting from inappropriate immune responses to gluten, a protein present in bread and cereals. Celiac disease can be asymptomatic, but it may also result in malabsorption and an increased risk of malignancies, most commonly lymphoma. The clinical course of classic celiac disease in patients with PID, such as that seen in selective IgA deficiency (sIgAD), is identical to that in immunocompetent patients. (See "Epidemiology, pathogenesis, and clinical manifestations of celiac disease in adults", section on 'Prognosis'.)

Diagnosis of celiac disease may be more difficult in patients with sIgAD, as a commonly used screening test is the measurement of IgA antibodies against tissue transglutaminase. To avoid this diagnostic pitfall, either serum IgA should be measured as well to detect IgA-deficient individuals or IgG-based tests should be measured instead. This is discussed separately. (See "Diagnosis of celiac disease in adults", section on 'IgA deficiency' and "Diagnosis of celiac disease in children", section on 'Immunoglobulin A deficiency'.)

Inflammatory bowel disease — Ulcerative colitis and Crohn disease are the most common types of inflammatory bowel disease (IBD). Patients with certain types of PID (eg, antibody defects and chronic granulomatous disease) are at an increased risk of developing IBD compared with immunocompetent individuals [22,23]. There appears to be an intersection of genes that contribute to PID and chronic GI inflammation [24-27].

The GI manifestations of IBD include diarrhea, abdominal pain, rectal bleeding, vomiting, and weight loss, although extraintestinal manifestations, such as arthralgias, erythema nodosum, digital clubbing, and liver problems are also common [28,29]. In some types of PID (eg, common variable immunodeficiency), a nonspecific colitis (enteropathy) may resemble the clinical course of IBD, but enteropathy does not respond to IBD therapy as expected, as discussed later in this review. (See 'Gastrointestinal complications of primary immunodeficiency resembling other diseases' below.)

The clinical manifestations and diagnosis of IBD in adults and children are reviewed in more detail elsewhere. (See "Clinical manifestations, diagnosis, and prognosis of ulcerative colitis in adults" and "Clinical manifestations, diagnosis, and prognosis of Crohn disease in adults" and "Clinical presentation and diagnosis of inflammatory bowel disease in children".)

Other GI autoimmune disorders — Other common types of GI autoimmune disorders include pernicious anemia, chronic autoimmune hepatitis, and autoimmune sclerosing cholangitis. These are mainly reported in antibody-deficient patients. (See "Autoimmunity in patients with inborn errors of immunity/primary immunodeficiency".)

Nodular lymphoid hyperplasia — Nodular lymphoid hyperplasia (NLH) is a benign condition that is found in patients with PID, especially antibody deficiencies, as well as in apparently healthy individuals. Lesions are usually located in the small intestine but sometimes in the colon or stomach. It is more common in children than in adults. The presence of NLH in the absence of any other abnormal finding is most probably a normal finding, whereas large lesions, particularly if accompanied by flattened intestinal villi in adult patients, should raise suspicion of an immunodeficiency.

NLH is histologically marked by mitotically active and hyperplastic germinal centers accompanied by a prominence of mantle cell lymphocytes in the lamina propria, which may also be observed in superficial submucosa [30]. NLH may cause malabsorption due to mucosal flattening and a reduction of the intestinal surface area [12]. Whether NLH is associated with development of lymphoma is a matter of controversy [31-34]. (See "Clinical presentation and diagnosis of primary gastrointestinal lymphomas", section on 'Predisposing conditions'.)

Massive NHL lesions, which may result in obstruction or chronic diarrhea and weight loss, should be treated. These lesions are often very responsive to oral glucocorticoids, although they occasionally require surgical interventions in cases of obstruction [35].

Other GI lymphoproliferative disorders — A significant proportion of PID patients with different types of combined immunodeficiency, antibody deficiency, or immune dysregulation may develop deranged liver function due to unexplained hepatomegaly (most of the time in association with splenomegaly), and they are also susceptible to mesenteric lymphadenopathy [1].

Food allergy and intolerance — Patients with certain types of PIDs, such as hyperimmunoglobulin E syndrome secondary to DOCK8 (dedicator of cytokinesis 8) deficiency [36], X-linked immune dysregulation with polyendocrinopathy (IPEX) [37], and Wiskott-Aldrich syndrome [38], are prone to food allergy and food intolerance. Defects in mucosal immunity, resulting in abnormal expression of food allergens to the immune system, may also be important, as atopy and food intolerances are common in sIgAD [39].

Some studies, mainly from Middle Eastern countries, reported a prevalence of food allergy among PID patients as high as 20 percent, although one study from the United States reported a prevalence of about 1.8 percent, which was even lower than that in the normal population [40]. This difference may have been due to the variations in the different types of PID patients included.

Malignancies — Patients with PIDs associated with DNA repair defects, chronic tissue inflammation, higher susceptibility to oncogenic viruses, and impaired specific immunity are at an increased risk of developing malignancies of the GI tract [41]. In a study of 3658 PID patients, GI cancers were recorded in 0.3 percent of patients and constituted 8 percent of all documented cancer types [42]. The most common were lymphoma and adenocarcinoma, but liver cancer was also reported. Although the underlying mechanism of malignant transformation is not clearly understood in most cases, several factors could contribute, including Helicobacter pylori infection, impaired gastrin secretion, atrophic gastritis, NLH, frequent radiologic imaging, and long-term use of immunosuppressive agents for the management of autoimmune disorders of the GI tract [43,44]. (See "Malignancy in primary immunodeficiency".)

Other disorders — Occasionally, PID can present with other disorders, including GI anomalies, such as hepatic sinusoidal obstruction syndrome (formerly called hepatic veno-occlusive disease), exocrine pancreatic insufficiency, multiple intestinal atresia, and neuronal dysplasia of the intestine [1,45].

CLINICAL CLUES THAT SUGGEST IMMUNODEFICIENCY — Certain clinical presentations are highly suggestive of the presence of an underlying PID:

Early onset of GI complications, especially inflammatory bowel disease (IBD) and pernicious anemia [18]. (See "Clinical presentation and diagnosis of inflammatory bowel disease in children".)

Infections in the GI tract (or elsewhere) that are recurrent, severe, poorly responsive to conventional antimicrobial agents, or caused by opportunistic organisms.

Noninfectious GI disorders, such as IBD and celiac disease, which do not respond well to the conventional therapeutic approaches.

Unexpected recurrence or relapse of either infectious or noninfectious GI complications despite receiving standard therapy of adequate dose and duration.

Histopathologic findings that are somewhat different from what is expected in classic diseases with similar clinical findings.

A general discussion of the clinical patterns and warning signs of immunodeficiency is found separately. (See "Approach to the child with recurrent infections", section on 'Clinical patterns suggestive of immunodeficiency'.)

INITIAL TESTS OF IMMUNE FUNCTION — Initial assessment of the immune system should be performed in any individual presenting with GI manifestations in whom there is suspicion of an underlying PID. We suggest the following initial laboratory tests:

Complete blood count (CBC) with differential

Lymphopenia (defined as an absolute lymphocyte count <2500 cells/microliter in infants or <1500 cells/microliter in adults) is characteristic of a variety of combined cellular and antibody deficiency immunodeficiencies. Lymphopenia in patients with PID may also be due to excessive loss of lymphocytes into the GI lumen or their trapping in the GI tract as a result of an inflammatory condition. (See "Severe combined immunodeficiency (SCID): An overview".)

Leukocytosis can sometimes be seen in chronic infections. Leukocytosis (>8500 cells/microliter) is characteristic of chronic granulomatous disease, specifically if accompanied by anemia, which is most commonly microcytic and hypochromic. (See "Chronic granulomatous disease: Pathogenesis, clinical manifestations, and diagnosis".)

Anemia may be present due to chronic infection, blood loss, or autoimmune hemolytic anemia.

Thrombocytopenia with small platelet size may suggest the diagnosis of Wiskott-Aldrich syndrome (see "Wiskott-Aldrich syndrome"). Thrombocytosis can be seen with chronic inflammation.

Total protein and albumin – We measure total protein, albumin, and the calculated ratio of albumin to globulins, termed the A/G ratio. The A/G ratio is calculated from measured total protein, measured albumin, and calculated globulin (total protein minus albumin). Because disease states affect the relative amounts of albumin and globulin, the A/G ratio may provide a clue as to the cause of the change in protein levels in PID patients, including GI protein loss or liver disease.

Quantitative measurement of immunoglobulin levels – The results of serum IgG, IgM, and IgA titers should be compared with those of age-matched healthy controls, information that is normally provided by the laboratory performing the tests (table 2). This is particularly important in young children. IgE should also be measured if there is a possibility of hyperimmunoglobulin E syndrome.

Flow cytometry assessment of lymphocyte subpopulations – Flow cytometry uses monoclonal antibodies to identify and quantitate hematopoietic cells that have specific antigens termed "cluster designations" (CDs). A typical panel of markers used to identify the major subset of lymphocytes includes CD3, CD4, CD8, C19/20, and CD16/56. A CBC with differential should be performed on a blood specimen obtained at the time of the flow cytometric analysis to determine absolute numbers of the lymphocyte subpopulations. The table lists standard markers and the lymphocyte populations they define (table 3).

Flow cytometry is invaluable in the assessment of lymphocyte subpopulations in patients with opportunistic infections or severe or persistent lymphopenia [46]. Standard flow cytometry analysis will be abnormal in almost all cases of severe combined immunodeficiency and in many instances of other combined immunodeficiencies (table 4). (See "Flow cytometry for the diagnosis of primary immunodeficiencies".)

Assessment of alpha-1-antitrypsin clearance in stool – In patients with hypogammaglobulinemia, the determination of alpha-1-antitrypsin clearance in the stool can help distinguish a protein-losing enteropathy from a PID. (See "Protein-losing gastroenteropathy", section on 'Diagnosis'.)

Referral and advanced testing — The results of the initial evaluation of the immune system should provide helpful information regarding the presence of immunodeficiency and more importantly, probable impairment in cellular and/or humoral immune systems. More advanced tests should be performed after referral of the patients to an allergist/immunologist. The final and definite diagnosis of PID patients should be confirmed with genetic evaluation since many defects have overlapping clinical phenotypes. A more detailed description regarding the evaluation of the immune system is discussed separately. (See "Laboratory evaluation of the immune system".)

GASTROINTESTINAL COMPLICATIONS IN SPECIFIC PRIMARY IMMUNODEFICIENCIES — Some GI complications are predominantly observed in certain PIDs, as summarized in the table (table 5).

Antibody defects

Selective IgA deficiency — Selective IgA deficiency (sIgAD) is the most common form of PID and is characterized by markedly reduced serum and secretory IgA levels in the presence of normal levels of IgM and IgG in an individual older than four years of age. While most patients with sIgAD are asymptomatic, others develop recurrent respiratory and GI infections, autoimmune and allergic disorders, as well as anaphylactic reaction to transfusion [47]. (See "Selective IgA deficiency: Clinical manifestations, pathophysiology, and diagnosis".)

Infections with Giardia lamblia have been reported among sIgAD patients. (See "Selective IgA deficiency: Clinical manifestations, pathophysiology, and diagnosis", section on 'Gastrointestinal'.)

In contrast, these patients seem to maintain effective immune responses against other micro-organisms. This finding has led to several theories about possible compensatory mechanisms, including the following:

Total IgG and IgG1 subclass antibodies are increased and may compensate for the lack of serum IgA [48].

IgM is transported from the mucosa into the intestinal lumen, taking bacteria and other pathogens with it [49].

Compared with IgA1, production of IgA2, the predominant secretory subclass of IgA in the large intestine, is less impaired in patients with sIgAD [6].

Celiac disease, inflammatory bowel disease (IBD), nodular lymphoid hyperplasia (NLH), and food allergy are each independently associated with sIgAD:

sIgAD patients are at a 5- to 15-fold increased risk for developing celiac disease, compared with the normal population, and its prevalence was reported as high as 8 percent among these patients [23,50]. Between 1 to 2 percent of all patients with celiac disease also have sIgAD [48]. Celiac disease in sIgAD patients responds well to a gluten-free diet [51].

Both ulcerative colitis and Crohn disease (meeting conventional diagnostic criteria) are associated with sIgAD. (See "Selective IgA deficiency: Clinical manifestations, pathophysiology, and diagnosis", section on 'Inflammatory bowel disease'.)

NLH has been reported in patients with sIgAD [35]. There may be an association between NLH, GI lymphomas, and gastric cancer [52].

Food allergy is common among sIgAD patients and has been observed in about 25 to 30 percent of these patients in some series [39,40]. Food allergy and intolerance in sIgAD patients are frequently observed in the absence of other atopic manifestations and can be IgE-mediated, non-IgE-mediated, or mixed, although the first form seems to be more prevalent [40,47].

Common variable immunodeficiency — Common variable immunodeficiency (CVID) is a heterogeneous PID characterized by impaired differentiation of B cells and antibody production. Defects in other immune components are present in up to one-half of patients. The clinical presentation of CVID includes recurrent bacterial infections, most notably of the upper and lower respiratory tract, GI complications, and an increased incidence of inflammatory disorders and malignancies [44,53]. (See "Clinical manifestations, epidemiology, and diagnosis of common variable immunodeficiency in adults" and "Pathogenesis of common variable immunodeficiency" and "Treatment and prognosis of common variable immunodeficiency" and "Common variable immunodeficiency in children".)

GI complications are reported in 20 to 60 percent of patients with CVID, and it is not uncommon for patients to present with isolated involvement of the GI tract [6,54]. Diarrhea is the most common disorder, followed by malabsorption and weight loss. The frequency of GI complications is higher in CVID patients with mutation in genes involved in activation of PI3K-AKT signaling (PI3KCD, PI3KR1) and defective NFKB signaling (NFKB1, NFKB2) pathways [1,55].

Infections are the leading cause of diarrhea in patients with CVID. Frequently implicated causes include acute and chronic infections with G. lamblia and cytomegalovirus (CMV) and acute infections with Campylobacter jejuni, Salmonella, Cryptosporidium parvum, and norovirus [44,54,56]. H. pylori infection is also common and may be related to the development of environmental metaplastic atrophic gastritis and possibly pernicious anemia, which can develop decades earlier in CVID patients compared with immunocompetent individuals [44,57-59]. (See "Metaplastic (chronic) atrophic gastritis", section on 'Environmental metaplastic atrophic gastritis'.)

Common noninfectious disorders include IBD-like autoimmune enteropathy, autoimmune hepatitis, pernicious anemia, and sprue-like diseases that do not respond to a gluten-free diet [60], as well as NLH, hepatomegaly, and GI lymphadenopathy [4]. This is discussed more below (see 'In CVID' below). Nonnecrotizing, nontuberculoid, sarcoid-like hepatic granulomas have been reported in CVID patients, with fibrinoid degeneration of collagen surrounded by histiocytes on histology.

GI bleeding can be observed in CVID patients associated with idiopathic thrombocytopenic purpura.

Liver involvement is documented in at least 10 percent of CVID patients. It varies from asymptomatic elevated alkaline phosphatase, to infections, autoimmune hepatitis, lymphoproliferation (infiltration of inflammatory cells, granulomas, nodular regenerative hyperplasia), malignancies, intrahepatic biliary obstruction (primary biliary cholangitis, primary sclerosing cholangitis), hepatopulmonary syndrome secondary to cryptogenic liver disease, liver cirrhosis, and portal hypertension. In patients with CVID, liver complications are significantly linked with lymphocytic enteropathy, suggesting a pathogenic role of the gut-liver axis [55].

GI malignancies, including lymphoma and gastric adenocarcinoma, appear to be more prevalent among CVID patients compared with the normal population in some studies [61]. (See "Clinical manifestations, epidemiology, and diagnosis of common variable immunodeficiency in adults", section on 'Gastric cancers'.)

X-linked agammaglobulinemia — X-linked agammaglobulinemia (XLA) is characterized by a defective B cell development, due to a mutation in Bruton's tyrosine kinase (BTK), resulting in a lack of mature B cells and impaired immunoglobulin production. Recurrent respiratory infections are the most common findings in patients with XLA. (See "Agammaglobulinemia", section on 'X-linked agammaglobulinemia'.)

Chronic diarrhea and malabsorption, mainly due to infections by G. lamblia, Salmonella, Campylobacter, Cryptosporidium, and rotavirus, are the most common GI disorders in XLA patients. Several cases of severe neurogenic sequelae secondary to enteroviral infections with coxsackievirus and echovirus have been reported in patients with XLA [62-64]. The prevalence of these infections is reduced by immune globulin therapy.

Small bowel immune dysregulation characterized by strictures and transmural fissures resembling Crohn disease has been reported in association with XLA due to hypomorphic BTK mutations. However, there are no granulomas in this condition, and plasma cells are absent [62].

Gastric and colorectal adenocarcinoma have been reported [65-68]. In contrast, NLH is not seen in XLA due to the absence of germinal centers.

Hyperimmunoglobulin M syndromes — Hyperimmunoglobulin M (HIGM) syndromes are a heterogeneous group of rare disorders caused by defects in class-switch recombination, resulting in reduced levels of IgG, IgA, and IgE and impaired antibody production and/or T cell function. Serum levels of IgM are normal or elevated. X-linked HIGM (X-HIGM) syndrome is the most common type of HIGM syndrome resulting from mutations in the CD40 ligand (CD40LG) gene and is characterized by susceptibility to recurrent bacterial and opportunistic infections and liver disease. Autosomal recessive forms of HIGM due to mutations in CD40, activation-induced cytidine deaminase (AICDA), and uracil N-glycosylase (UNG) genes also exist. (See "Hyperimmunoglobulin M syndromes".)

Protracted and recurrent infectious diarrhea has been reported in up to one-half of patients with HIGM. Failure to thrive (FTT) and weight loss may also be observed. C. parvum is the most commonly found pathogen, but infections with G. lamblia, Salmonella, and Entamoeba histolytica may also be found [69]. However, the exact responsible pathogen may remain unknown in approximately one-half of cases. In one study of 79 X-HIGM patients, 5 developed progressive sclerosing cholangitis, and C. parvum was presumed to be responsible in four cases [70]. Chronic cholangiopathy is known to be associated with fatal liver cancer in HIGM patients with CD40 ligand or CD40 deficiency [71].

Combined T and B cell immunodeficiency

Severe combined immunodeficiency — Severe combined immunodeficiency (SCID) is a group of genetic disorders characterized by impairment of both cellular and humoral immunity resulting from a variety of defects in the development and function of both T and B cells as well as natural killer cells. Typically, SCID patients become ill before three months of age. Without a curative therapy, such as hematopoietic cell transplantation (HCT), infants affected by SCID usually do not reach their first birthday due to severe and life-threatening infections. (See "Severe combined immunodeficiency (SCID): An overview".)

Persistent mucocutaneous candidiasis of the oral cavity, esophagus, and anus are observed commonly in infants with SCID, which can cause difficulties in oral intake. Intractable or recurrent diarrhea caused by viral and bacterial infections is also common. The most common pathogen is rotavirus, but picornavirus, parvovirus, norovirus, adenovirus, CMV, Salmonella, G. lamblia, Escherichia coli, and Cryptosporidium may also be found [72]. Chronic diarrhea has been associated with the live virus vaccines (eg, rotavirus) given at an early age in the United States and some other countries [73].

Many countries still use the oral polio vaccine in the national childhood immunization schedule, and patients with PID can become chronically infected due to defective clearance. The majority of the patients with chronic polio vaccine infection have only diarrhea due to the local effects of the enterovirus infection before the virus develops into a neurovirulent form. PID patients may shed the virus for months or years, and the excreted virus may become neurovirulent [74]. Although clearance of enterovirus requires both humoral and cellular immunity, patients with SCID have an increased risk of delayed poliovirus clearance compared with antibody deficiencies [74].

Pathology studies of small intestine mucosa of SCID patients may reveal villous atrophy due to damage from viral and bacterial infections or nonspecific colitis, which may mimic autoimmune enteropathy. However, antienterocyte antibodies and plasma cells are absent, and the lamina propria is hypocellular.

In patients with Omenn syndrome with leaky autosomal recessive forms of SCID characterized by chronic diarrhea, FTT, and hepatosplenomegaly, laboratory and histologic studies may show oligoclonal T cells of maternal origin and an intestinal graft-versus-host appearance. (See "T-B-NK+ SCID: Pathogenesis, clinical manifestations, and diagnosis", section on 'T-B-NK+ SCID without radiation sensitivity due to RAG defects (includes most cases of Omenn syndrome)' and "T-B-NK+ SCID: Pathogenesis, clinical manifestations, and diagnosis", section on 'Omenn syndrome phenotype'.)

Allogeneic bone marrow transplantation or even blood transfusion may result in graft-versus-host disease (GVHD) or GVHD-like process involving the small intestine and colon with four pathological grades: Grade 1: apoptotic epithelial cells, Grade 2: crypt or gland destruction, Grade 3: focally denuded or ulcerated mucosa, Grade 4: diffusely denuded or ulcerated mucosa [18,75]. The susceptibility to viral GI infections increases during bone marrow transplantation immunosuppression mainly with CMV, adenovirus, and herpes simplex virus [76].

LRBA and CTLA4 deficiencies — Lipopolysaccharide-responsive beige-like anchor (LRBA) protein deficiency causes an autosomal recessive combined immunodeficiency with severe autoimmune and inflammatory manifestations, including IBD and autoimmune cytopenias [77]. Chronic diarrhea is a frequent and often severe symptom. In the majority of the cases, no pathogen is identified [77]. The spectrum of GI tract tissue pathology can be variable, ranging from villous atrophy and blunting to normal villi. Cytotoxic T lymphocyte-associated protein 4 (CTLA4) proteins expressed constitutively in regulatory T cells to confer inflammation suppression and clinical phenotype of patients with CTLA4 deficiency is similar to LRBA-deficient patients [78,79].

Bare lymphocyte syndrome — Major histocompatibility complex (MHC) class II deficiency or bare lymphocyte syndrome is a combined immunodeficiency with decreased helper T cells, normal or decreased serum immunoglobulin levels, and absent MHC II expression on lymphocytes. The main GI manifestations of these patients are chronic diarrhea (in 30 to 40 percent of patients) due to C. parvum infection, hepatomegaly, and progressive liver/biliary tract disease [80,81].

Adenosine deaminase deficiency — Adenosine deaminase (ADA) deficiency is a systemic purine metabolic disorder associated with defective lymphocyte development and function. The clinical phenotypic spectrum varies from late-onset combined immunodeficiency diagnosed in the second to fourth decades to SCID that can be diagnosed by age 12 months. ADA-deficient patients often have persistent diarrhea when the disease presents in childhood or chronic autoimmune phenomena affecting the liver (autoimmune hepatitis) in the late-onset forms [82].

Other combined immunodeficiency — Several other combined immunodeficiencies can present with GI disorders. These include inducible T cell costimulatory (ICOS) deficiency (may present with IBD and gastroenteritis), magnesium transporter 1 (MAGT1) deficiency (recurrent GI infections), B cell leukemia/lymphoma 10 (BCL10) deficiency (gastroenteritis), and interleukin (IL)-21 and IL-21 receptor deficiencies (severe early-onset colitis) [1].

Disorders of phagocyte function

Chronic granulomatous disease — Chronic granulomatous disease (CGD) is a group of genetic disorders characterized by impaired bacterial killing by phagocytes, resulting in recurrent and severe infections with certain bacterial and fungal pathogens. Mutation in genes encoding the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase complex is responsible for CGD. X-linked CGD is far more common than autosomal recessive forms, such that most patients are male. (See "Chronic granulomatous disease: Pathogenesis, clinical manifestations, and diagnosis" and "Chronic granulomatous disease: Treatment and prognosis".)

The prevalence of GI complications among CGD patients is approximately 50 percent, which is higher in X-linked CGD compared with autosomal recessive forms:

CGD patients may present with diarrhea, malabsorption, FTT, abdominal pain, and perianal abscesses or fissures.

Infectious complications include hepatic abscess caused mainly by Staphylococcus aureus, S. typhi, and Pseudomonas aeruginosa.

Granulomata formation can be found anywhere in the GI tract, presenting with dysphagia, dysmotility, and even obstruction requiring surgical intervention. Noncaseating granulomatous colitis resembling Crohn disease has been reported.

Severe congenital neutropenia — Severe congenital neutropenia is a heterogeneous group of disorders characterized by chronic severe neutropenia (absolute neutrophil count less than 500/uL). Severe neutropenia increases the risk of ulcers in the mouth and along the GI tract, allowing the development of Clostridium bacteremia, which can be fatal. (See "Congenital neutropenia".)

Shwachman-Diamond syndrome — Shwachman-Diamond syndrome is a unique defect in ribosome synthesis due to SDS gene mutation presenting with pancytopenia, chondrodysplasia, and chemotactic dysfunction of neutrophils. Patients can present with diarrhea and malabsorption due to exocrine pancreatic insufficiency. (See "Shwachman-Diamond syndrome".)

Well-defined syndromes with immunodeficiency

Ataxia-telangiectasia — Ataxia-telangiectasia (AT) is characterized by impaired DNA repair due to a defect in the ataxia-telangiectasia mutated gene (ATM) with an autosomal recessive pattern on inheritance. The clinical presentation of AT includes facial and conjunctival telangiectasias, recurrent infections, progressive ataxia, and increased susceptibility to malignancy. Dysphagia often develops in the second decade of life [83]. AT patients may develop adenocarcinomas and lymphoreticular malignancies of the GI tract [84,85]. (See "Ataxia-telangiectasia".)

Wiskott-Aldrich syndrome — Wiskott-Aldrich syndrome (WAS) is an X-linked combined immunodeficiency of T cell lymphopenia and impaired antibody production despite a normal number of B cells. WAS results from mutations in the gene encoding the WAS protein (WASp), which is a key regulator in cell signaling and reorganization of cytoskeleton processes in hematopoietic cells [86]. The main clinical features of WAS are thrombocytopenia, eczema, and recurrent infections. WAS patients are also at an increased risk of developing autoimmune and malignant disorders. (See "Wiskott-Aldrich syndrome".)

The most common GI complication observed in WAS is GI bleeding, which may present shortly after birth as hematemesis or melena and can be life-threatening.

IBD-like colitis is observed in up to 10 percent of cases [87,88].

Hyperimmunoglobulin E syndrome — Hyperimmunoglobulin E syndrome (HIES) is a group of PIDs with autosomal dominant and autosomal recessive patterns of inheritance. HIES is characterized by recurrent staphylococcal and viral infections, chronic eczema, and remarkably high serum levels of IgE [89]. Serum IgE levels generally range from 1000 to greater than 50,000 international units/mL. (See "Autosomal dominant hyperimmunoglobulin E syndrome".)

Sixty percent of patients with autosomal dominant HIES present with GI symptoms, which are mainly gastroesophageal reflux disease [90].

Patients with HIES may develop disseminated GI infections with Cryptococcus and Histoplasma [91-94].

Colon diverticulitis and perforation have also been reported [90,91].

Severe food allergy is common in DOCK8 (dedicator of cytokinesis 8) deficiency, which is considered a type 2 HIES with an autosomal recessive pattern of inheritance [95]. (See "Combined immunodeficiencies", section on 'Dedicator of cytokinesis 8 deficiency'.)

Hepatic veno-occlusive disease with immunodeficiency — Hepatic veno-occlusive disease with immunodeficiency syndrome is due to mutations in the SP110 gene. The syndrome is characterized by decreased memory T and B cells and hypogammaglobulinemia associated with obstruction of small veins in the liver, hepatic fibrosis manifesting as hepatosplenomegaly or hepatic failure, CMV and Candida infections, and cerebrospinal leukodystrophy [96]. It usually presents within the first six months of life.

Cartilage-hair hypoplasia — Patients with cartilage-hair hypoplasia have a defect in cell cycle control resulting in impaired lymphocyte proliferation, short-limbed dwarfism, and bone marrow failure. Neuronal dysplasia of the intestine has been reported in this syndrome leading to GI obstruction, malabsorption, or Hirschsprung-like disease [97]. (See "Cartilage-hair hypoplasia".)

Immunodeficiency with multiple intestinal atresias — Mutations in tetratricopeptide repeat domain 7A (TTC7A) protein affect both T cell numbers and antibody production and present with multiple intestinal atresias. This syndrome presents due to the essential role of TTC7A protein in proper development, preservation, and/or function of both thymic and GI epithelium [98].

Diseases of immune dysregulation

IPEX and IPEX-like syndromes — Immune dysfunction, polyendocrinopathy, enteropathy, X-linked (IPEX) is a rare PID characterized by immune dysregulation, polyendocrinopathy, and enteropathy. IPEX is caused by mutations in the transcription factor Foxp3 (FOXP3) gene [99]. IPEX-like syndromes, including CD25 deficiency and signal transducer and activator of transcription 5b deficiencies, are probably as prevalent as IPEX and may present similarly to IPEX. (See "IPEX: Immune dysregulation, polyendocrinopathy, enteropathy, X-linked".)

Almost all patients with IPEX develop watery diarrhea, which can also be mucoid or bloody, before three months of age. This may result in malabsorption, FTT, and the need for parenteral nutrition in severe cases. Severe enteropathy may resemble food allergy (either IgE-mediated or food-protein enterocolitis) but is often less responsive to dietary modifications and gut rest [100]. Histologic findings of the intestine can be similar to those of IBD, celiac disease, or GVHD [101]. Without curative interventions, patients usually die before two years of age due to severe malnutrition and electrolyte imbalances or severe infections. (See "IPEX: Immune dysregulation, polyendocrinopathy, enteropathy, X-linked", section on 'Gastrointestinal manifestations'.)

IL-10 and IL-10 receptor deficiencies — Interleukin (IL)-10 plays an important role in the regulation of the immune system by downregulating inflammatory processes, probably by inhibiting the production of proinflammatory cytokines like IL-12 and tumor necrosis factor (TNF). IL-10 controls the growth and differentiation of a variety of cells in the immune system, including T and B cells, natural killer cells, granulocytes, and endothelial cells [102].

Early-onset IBD has been reported in patients with IL-10 and IL-10 receptor (IL-10R) deficiencies due to loss-of-function mutations in genes encoding IL-10, IL-10R1, or IL-10R2. IBD presents before three months of age as a severe and progressive colitis with perianal involvement and extraintestinal manifestations including folliculitis and arthritis. In one study on 66 children who were diagnosed with IBD before five years of age, 16 (24.2 percent) had either IL-10 or IL-10R deficiencies [103]. Despite the availability of several therapies including glucocorticoids, immunomodulating agents, and even surgical intervention, long-term management of IBD is not satisfactory in these patients [104]. HCT has been successful in several patients [103]. (See "Genetic factors in inflammatory bowel disease", section on 'Specific genes'.)

XIAP deficiency — Deficiency of the X-linked inhibitor of apoptosis (XIAP), also known as X-linked lymphoproliferative syndrome type 2 (XLP2), is inherited as an X-linked trait and is characterized by an increased risk of episodes of hemophagocytic lymphohistiocytosis and IBD with features of Crohn disease [105]. The IBD associated with XIAP deficiency is often severe and drug-resistant and is a cause of death in 10 percent of the patients [105]. Crypt abscesses, granulomas, and ulcerations may affect the whole GI tract. Remission of the GI symptoms has been reported after HCT, arguing for a hematopoietic defect at the basis of IBD [106,107].

Autoinflammatory disorders

Familial Mediterranean fever — Familial Mediterranean fever (FMF) is an inherited autoinflammatory disorder, usually in people of Mediterranean origin, which is characterized by recurrent fevers and abdominal pain and inflammation of the peritoneal lining in 90 percent of patients. Most patients present during childhood. About 10 to 20 percent of FMF patients present with diarrhea, and after diagnosis, patients can develop diarrhea due to colchicine intolerance. The disease is caused by dysfunction of inflammasomes due to mutations in the Mediterranean fever (MEFV) gene, which results in uncontrolled increases in IL-1 levels. Long-term complications from FMF include small bowel obstruction secondary to adhesive disease from recurrent peritonitis, ascites, and amyloidosis. (See "Clinical manifestations and diagnosis of familial Mediterranean fever".)

Periodic fever with aphthous stomatitis, pharyngitis, and adenitis — Periodic fever with aphthous stomatitis, pharyngitis, and adenitis is the most common periodic fever disease in children and is due to a dysregulated innate immunity. The main GI manifestations in these patients are aphthous stomatitis and shallow oral ulcers in 65 to 75 percent of patients. Other gastrointestinal symptoms include abdominal pain and vomiting. (See "Periodic fever with aphthous stomatitis, pharyngitis, and adenitis (PFAPA syndrome)".)

Other autoinflammatory disorders — Blau syndrome (presenting as Crohn disease due to a defect in monocytes), ADAM17 (ADAM metallopeptidase domain 17) deficiency (presenting with early-onset diarrhea due to defective TNF production), PLCG2 (phospholipase C, gamma-2) deficiency (presenting with gastroenteritis), and familial cold autoinflammatory syndromes (presenting with severe enterocolitis) are additional autoinflammatory disorders associated with GI disorders [1]. (See "The autoinflammatory diseases: An overview".)

Defects in intrinsic and innate immunity

Mendelian susceptibility to mycobacterial disease — Mendelian susceptibility to mycobacterial disease (MSMD) is due to defects in the interferon-gamma and IL-12 loop. Patients have a predisposition to weakly virulent mycobacteria, such as Bacillus Calmette–Guérin vaccines and environmental mycobacteria. MSMD patients are also prone to mycobacterial GI and liver abscess and nontyphoidal Salmonella gastroenteritis. (See "Mendelian susceptibility to mycobacterial diseases: Specific defects".)

Chronic mucocutaneous candidiasis — Chronic mucocutaneous candidiasis (CMCC) is a heterogeneous group of innate immune defects in the detection and immune response against chronic noninvasive fungal infections of all mucous membranes [1]. Chronic or recurrent candidal infection of the oral cavity and GI tract and inflammatory bowel disease (IBD) can be detected in the patients with autoimmune regulator (AIRE), IL-17, STAT1, and CARD19 deficiencies. (See "Chronic mucocutaneous candidiasis".)

Complement deficiencies

Hereditary angioedema — Hereditary angioedema is an autosomal dominant genetic condition due to absent or decreased function of the SERPING1 gene that causes C1 inhibitor deficiency. Patients present with episodic attacks of angioedema involving the skin, mucous membranes, and bowel wall. Angioedema of the bowel wall presents with abdominal pain, diarrhea, and occasionally ascites and may mimic an acute surgical abdomen. Levels of C4 are markedly reduced in the majority of patients in the most common forms of the disease. (See "Hereditary angioedema: Epidemiology, clinical manifestations, exacerbating factors, and prognosis", section on 'Gastrointestinal attacks'.)

GASTROINTESTINAL COMPLICATIONS OF PRIMARY IMMUNODEFICIENCY RESEMBLING OTHER DISEASES — Some GI manifestations observed among PID patients may clinically resemble other GI diseases, particularly inflammatory bowel disease (IBD) and celiac disease. However, the underlying pathophysiology differs, and these disorders often respond poorly to the conventional treatments, which can serve as a clinical clue to the presence of an immune disorder.

IBD-like disorders — The pathogenesis of IBD is not entirely understood, but it is generally believed that dysregulation of immune reactions to normal flora results in a hyperinflammatory condition that is responsible for the signs and symptoms. However, IBD could also result from a failure to induce appropriate inflammatory responses, leading to impaired removal of foreign antigens from the GI tract [108]. This theory is supported by the observation of impaired production of proinflammatory cytokines, including tumor necrosis factor, interferon-gamma, interleukin (IL)-4, IL-5, IL-13, and IL-15 by the macrophages of patients with Crohn disease [109]. This may explain the high predisposition of patients with specific types of PID to IBD-like disorders. (See "Immune and microbial mechanisms in the pathogenesis of inflammatory bowel disease".)

In CVID — Common variable immunodeficiency (CVID) patients are predisposed to an IBD-like disease presenting with diarrhea, malabsorption, and weight loss, which may resemble either Crohn disease or ulcerative colitis. Histopathologic studies of the colon in patients affected by this disorder are consistent with those of IBD, but some differences can be observed in CVID patients, including an abundance of apoptotic cells, an absence of plasma cells in lamina propria, and no preponderance of eosinophils as observed in some immunocompetent IBD cases [18].

In CGD — Chronic granulomatous disease (CGD) patients are predisposed to the development of an IBD-like disease resembling Crohn disease that does not include the extraintestinal manifestations of classic IBD (eg, arthralgias, erythema nodosum, digital clubbing, and liver problems). Histopathologic findings indicative of Crohn-like colitis of CGD are the presence of pigment-laden macrophages, particularly in bowel areas spared from inflammation, a high number of eosinophils, and severely decreased number of neutrophils in the lamina propria [110,111]. (See "Chronic granulomatous disease: Pathogenesis, clinical manifestations, and diagnosis", section on 'Gastrointestinal'.)

Sprue-like disease in CVID — CVID patients may develop a celiac or sprue-like disease presenting with diarrhea, bloating, severe malabsorption, and weight loss. Pathologic small bowel findings may resemble those of celiac disease, including villous atrophy, crypt hyperplasia, and intraepithelial lymphocytosis. Increased apoptotic bodies may also be observed in crypt epithelial cells, but this is not common.

Several discriminating features can distinguish sprue-like disease in CVID patients from classic celiac disease in immunocompetent individuals. Patients with sprue-like disease and underlying CVID are more likely to demonstrate the following [18,112-114]:

Reduced numbers or absence of plasma cells in the lamina propria

Preservation of intestinal epithelial cells at villous tips

Absence of antibodies against gliadin, tissue transglutaminase, endomysium, or reticulin

Negative results of HLA DQ2/DQ8 genetic testing

Lack of improvement in symptoms despite a gluten-free diet

MONITORING PATIENTS WITH PRIMARY IMMUNODEFICIENCY FOR GASTROINTESTINAL COMPLICATIONS — Upon the diagnosis of PID, patients should be investigated regarding the possible past and present GI complications based on knowledge about the most prevalent or serious GI complications in different types of PID (table 5). GI involvement is present at the time of diagnosis in many PID patients. In addition, a history of GI symptoms may hint toward probable GI complications in the future.

Patients with a diagnosis of PID should be periodically assessed for the development of GI complications during the course of their disease. This assessment may range from careful questioning to surveillance colonoscopy or other imaging tests.

In patients with documented GI complications, the timeline of the follow-up and appropriate testing should be decided jointly by a gastroenterologist and an immunologist.

OVERVIEW OF MANAGEMENT — Management depends upon the type of PID present, but an overview is provided here.

Prevention of GI infections — In order to decrease the risk of GI infections, especially those caused by Cryptosporidium, it may be recommended that PID patients drink only water that has been previously boiled. Bottled water may be reliably clean in some countries but not in others [115-117]. Use of professionally fitted filters with a pore size less than 1 micrometer has also been recommended by some experts [18]. These considerations are more important in developing countries where patients may or may not always have access to high quality water.

Prophylactic antimicrobials — There is no unified approach to the administration of prophylactic antibiotics in patients in PID and a lack of evidence regarding efficacy. One exception to this statement is chronic granulomatous disease (CGD), in which there is a consensus that several specific antimicrobial agents are helpful. (See "Chronic granulomatous disease: Treatment and prognosis", section on 'Antimicrobial prophylaxis'.)

For most patients with PID, a decision on the administration of prophylactic antibiotics must be made on an individual basis, taking into account the most important organisms that cause serious and life-threatening infections, the clinical status of the patient, and the previous history of infections. Antimicrobial prophylaxis for different diseases is reviewed in the specific topic reviews.

Patients who receive long-term prophylactic regimens should be monitored for the side effects of those specific drugs. The authors and many other experts favor a "rotation" approach to decrease the risk of antimicrobial resistance. This approach involves changing the antibiotic used for prophylaxis every three to six months to another type of antibiotic that covers the same spectrum of organisms but uses a different mechanism of action. This is discussed elsewhere.

Treatment of infections — GI infections should be treated with appropriate antimicrobial agents based upon culture results. Patients with PID generally need more aggressive antibiotic therapy with longer durations compared with immunocompetent individuals. Administration of antibiotics should not be discontinued before assuring the complete clearance of the pathogenic organism. Special attention should be paid to the outcome of past antibiotic administration in the same patient. For the management of infections that need prolonged antibiotic administration, combination antibiotic therapy may be recommended, similar to the approach in patients with secondary immunodeficiencies (eg, HIV), although information on the probable influences of these practices on antimicrobial resistance is lacking [118].

Immune globulin — Immune globulin therapy, which contains primarily IgG, is a critical component of the treatment of many forms of PID and dramatically reduces rates of sinopulmonary infections. However, immune globulin is not similarly effective for the prevention of GI infections, nor does it appear to reduce the occurrence of noninfectious GI complications.

One possible exception to the above generalization is Clostridioides difficile-induced colitis, which can be treated and also possibly prevented by immune globulin therapy, although studies are conflicting. Many patients receiving immune globulin also require frequent antibiotic treatment, and they are presumedly at increased risk for C. difficile colitis. However, they do not appear to suffer disproportionately from this infection [12]. The benefit of immune globulin may be attributable to the presence of anti-C. difficile antibodies. (See "Clostridioides difficile infection in adults: Treatment and prevention", section on 'Alternative therapies'.)

In patients who require immune globulin therapy and have GI complications that could cause enteral protein loss, periodic assessment of serum IgG level is recommended to assure that they are receiving adequate treatment [119].

In antibody-deficient patients with chronic diarrhea, including that due to chronic norovirus infection, orally administrated immune globulin has been used successfully in case reports [120-122].

Immune modulators — Glucocorticoids, administered for short periods and at relatively low doses, seem to be beneficial in the management of inflammatory processes, as well as for reversing the changes in mucosal structure caused by sprue-like disease in common variable immunodeficiency (CVID) and inflammatory bowel disease (IBD)-like diseases in both CVID and CGD patients [112]. Careful dose adjustment and monitoring for complications are recommended in the management of PID cases with severe enteropathy due to autoimmune conditions that are treated with glucocorticoids. Recurrence after discontinuation has been reported [18]. Despite this, long-term administration of glucocorticoids should be avoided when possible.

Colchicine is an indispensable treatment in patients with familial Mediterranean fever during the symptom-free phase. However, during acute episodes, colchicine may lead to worsening of GI complaints, which can be alternatively combined with methylprednisolone, anti-interleukin (IL)-1, or antitumor necrosis factor (TNF) drugs [123].

In CGD patients, interferon-gamma stimulates superoxide release and can be used as a prophylactic agent for GI disorders. However, anti-TNF is contraindicated because it can increase the risk of severe and fatal infections. (See "Chronic granulomatous disease: Treatment and prognosis".)

Biologics and immunomodulators, including infliximab, 6-mercaptopurine, and azathioprine, are also used for the management of IBD and IBD-like diseases in PID patients, similar to immunocompetent patients. Standard doses of 6-mercaptopurine and azathioprine used in the management of IBD appear to be too low to significantly impair cellular or humoral immunity [18,124]. Infliximab seems to be beneficial in PID patients with severe enteropathy [125]. Such PID patients, particularly with T cell defects, should be monitored for probable fungal infections [18]. Anti-IL-1 (anakinra), anti-mTOR (mechanistic target of rapamycin), and cytotoxic T lymphocyte-associated protein 4 (CTLA4) fusion protein (abatacept) were used successfully in the management of inflammatory GI complications of PID patients with autoinflammation [126], immune dysregulation [18], and lipopolysaccharide-responsive beige-like anchor/CTLA4 deficiencies [78], respectively.

Avoidance of live vaccines — Live vaccines are contraindicated in patients with severe forms of PID, as discussed in detail elsewhere. (See "Immunizations in patients with primary immunodeficiency", section on 'Safety'.)

PID patients can become infected by the live attenuated oral polio vaccine and may develop vaccine-associated paralytic poliomyelitis or put the community at risk by serving as a reservoir of poliovirus. Two safe virus-specific antivirals are being developed and may be used as a combination (eg, pocapavir and V-7404). Pocapavir is being considered for use in poliovirus-excreting PID patients on a compassionate use basis. (See "Enterovirus and parechovirus infections: Clinical features, laboratory diagnosis, treatment, and prevention", section on 'Antiviral drugs'.)

Surgical interventions — Excisional surgery may be needed in the management of liver abscesses and GI obstruction due to granuloma formation in CGD patients [127]. Surgical intervention should also be considered in other PID patients with GI obstruction due to very large nodular lymphoid hyperplasia lesions or IBD and IBD-like diseases [128].

Parenteral nutrition — Some PID patients with severe malabsorption may require parenteral nutrition to compensate for the loss of essential nutrients and prevent skeletal and neurologic defects [124,129]. Since a catheter may act as a source of infection, this intervention should be performed for periods as short as possible, and patients should be carefully monitored for possible signs of catheter-related bloodstream infection. (See "Intravascular non-hemodialysis catheter-related infection: Clinical manifestations and diagnosis".)

Hematopoietic cell transplantation — Hematopoietic cell transplantation (HCT) is the only curative therapy available for several types of PID. Hence, not only will HCT prevent further development of GI complications due to PID, it seems to be the only therapeutic option in a limited number of PID cases with severe GI complications that are unresponsive even to aggressive therapeutic regimes [104]. However, HCT itself is associated with several GI complications, such as acute graft-versus-host disease and liver injury due to sinusoidal obstruction syndrome [130]. (See "Hematopoietic cell transplantation for severe combined immunodeficiencies".)

SUMMARY

The gastrointestinal (GI) tract is considered the largest organ of the immune system, with a vast surface area and the largest reservoir of lymphocytes in the human body. Defects in either humoral or cellular immunity can result in uncontrolled inflammation, damage to the mucosal surface of the GI tract, and increased risk of developing chronic infectious, inflammatory, autoimmune, and even malignant disorders. (See 'Infections' above and 'Immune system of the gastrointestinal tract' above.)

GI disorders affect up to 50 percent of patients with different types of primary immunodeficiency (PID) [2,3]. Typical GI presentations of various PIDs include intractable diarrhea, malabsorption, failure to thrive, or inflammatory bowel disease (IBD) [18]. (See 'Gastrointestinal manifestations of primary immunodeficiency' above.)

Infectious diarrhea is the most common complication of many PIDs (table 1), although noninfectious GI disorders are also prevalent. Autoimmune and inflammatory disorders, including nodular lymphoid hyperplasia, celiac disease, IBD, and food allergy, as well as malignancies (most commonly lymphoma and adenocarcinoma), are seen in patients with specific types of PID (table 5). (See 'Autoimmune and inflammatory disorders' above and 'Malignancies' above.)

PID should be suspected in individuals with recurrent and severe GI infections and non-GI infections, as well as in patients with noninfectious GI disorders, such as IBD, which present much earlier than normal, respond poorly to conventional treatments, or are accompanied by unusual histopathologic findings. (See 'Clinical clues that suggest immunodeficiency' above.)

Initial assessment of an individual with a clinical suspicion of PID should include complete blood count with differential followed by laboratory evaluation of both humoral and cellular immunity. Quantitative assessment of immunoglobulin (Ig)G, IgM, and IgA and sometimes IgE is appropriate if antibody deficiency or hyperimmunoglobulin E syndrome is suspected. Flow cytometry to assess lymphocyte populations is useful in the detection of some cellular defects. Referral to an allergist/immunologist is suggested for more advanced testing. (See 'Initial tests of immune function' above.)

Some GI disorders in patients with PID share clinical features of well-described GI diseases, especially IBD and celiac disease, but differ in pathophysiology and usually respond poorly to conventional treatments. (See 'Gastrointestinal complications of primary immunodeficiency resembling other diseases' above.)

Patients with a diagnosis of PID should be monitored periodically for development of GI complications. The timeline of the follow-up points and the diagnostic approaches should be decided jointly by a gastroenterologist and an immunologist based on the risk assessment of developing GI complications in the particular PID patients. (See 'Monitoring patients with primary immunodeficiency for gastrointestinal complications' above.)

The management of PID depends on the disorder present. Antibiotic prophylaxis should be considered in PID types with a predisposition to severe episodes of infections and high-risk individuals for these infections. In the management of acute episodes of infection, special attention should be paid to the outcome of past antibiotic administration in the same patient.

Immune globulin replacement therapy, which is highly effective in preventing sinopulmonary infections, is ineffective in the prevention and treatment of most GI complications in PID patients. Administration of immune modulators for the management of noninfectious GI complications should be performed with caution regarding the probability of further immune suppression resulting in severe infections. Severe PIDs are sometimes treated with hematopoietic cell transplantation. (See 'Overview of management' above.)

ACKNOWLEDGMENTS — We are saddened by the death of Asghar Aghamohammadi, MD, PhD, who passed away in November 2020. UpToDate wishes to acknowledge Dr. Aghamohammadi's past work as an author for this topic.

The UpToDate editorial staff acknowledges E Richard Stiehm, MD, who contributed as a Section Editor to an earlier version of this topic review.

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Topic 99315 Version 23.0

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