Primary immunodeficiency diseases (PIDs) represent a heterogeneous group of genetically determined disorders that influence the development and function of different components of adaptive and innate immunity. PIDs include antibody deficiencies (IgA deficiency, common variable immunodeficiency, X-linked agammaglobulinemia, and the hyper IgM syndrome) and combined B-cell and T-cell deficiencies, the most serious form being severe combined immunodeficiency (SCID). In the chapter, a summary of the gastrointestinal infections of viral origin, associated with the most common forms of PIDs is presented. The risk of infection by live polio and rotavirus vaccine strains and the importance of early diagnosis of PID in the context of oral vaccination is assessed.
Chapter 1.3
Immunodeficiencies: Significance for Gastrointestinal Disease
H. Marcotte
L. Hammarström Division of Clinical Immunology and Transfusion Medicine, Department of Laboratory Medicine, Karolinska Institutet at Karolinska University Hospital Huddinge, Stockholm, Sweden
Abstract
Keywords
primary immunodeficiency
gastrointestinal infection
viral infection
rotavirus
poliovirus
norovirus
1. Primary immunodeficiency
Primary immunodeficiency diseases (PIDs) represent a heterogeneous group of genetically determined disorders that influence the development and function of different components of adaptive and innate immunity (Al-Herz et al., 2014). Since the first official scientific publication of a PID patient 60 years ago (Bruton, 1952), more than 250 additional diseases have been described and characterized (Al-Herz et al., 2014). Antibody deficiencies occur when a patient has too few B cells or B cells that do not function properly. Antibody deficiency accounts for nearly half of all PID cases and includes IgA deficiency, X-linked agammaglobulinemia (XLA), the hyper IgM syndrome (HIGM) and common variable immunodeficiency (CVID) (Table 1.3.1). Combined B-cell and T-cell deficiencies comprise around 20% of all PIDs and can arise when the body produces too few B cells and T cells or when the B cells and T cells that are produced do not function correctly. Severe Combined Immunodeficiency (SCID) is the clinically most serious type of combined immunodeficiency. Phagocyte defects, including Chronic Granulomatous Disease (CGD), and complement deficiencies represent around 18 and 5% of all PIDs, respectively (Grumach and Kirschfink, 2014; Song et al., 2011).
Table 1.3.1
Primary Immunodeficiencies and Gastrointestinal Infections
| Immunodeficiency | Phenotype | Prevalence | Altered gene | Age of manifestation | Gastrointestinal infections |
| IgAD | IgA: <0.07g/L | 1/600 (1/155–1/18,550) | Multiple, unknown Possibly HLA, B cell (IGHA1, IGHA2, CLEC16A) or T cell (TACI) defect, or viral response (IFH1) defect | All ages | G. lamblia C. jejuni Salmonella Rotavirus |
| CVID | • IgG deficit: <3 g/L • IgA deficit: <0.05 g/L • IgM concentration normal or low: <0.3 g/L | 1/20,000–1/50,000 | Multiple, unknown Possibly B cell (CD19, CD20, CLEC16A) or T cell (ICOS, TACI, BAFFR) defect | All ages | G. lamblia C. jejuni Salmonella C. parvum C. difficile Cytomegalovirus Helicobacter pylori |
| X-linked agammaglobulinemia | • Low to absent B cells • Low to absent immunoglobulin | 1/70,000–1/100,000 (male) | Btk (Bruton’s tyrosine kinase) in B cells | Childhood | G. lamblia Campylobacter fetus Salmonella spp. C. difficile Enterovirus Rotavirus |
| X-linked hyper IgM syndrome | • IgG, IgA, IgE concentration reduced • IgM normal or elevated | 1/1,000,000 (male) | T cells (CD40L) | Childhood | G. lamblia C. parvum C. difficile Yersinia Salmonella E. histolytica Rotavirus |
| SCID | Defect in T and B cells | 1/50,000–1/100,000 | >12 genes (including common gamma chain, adenosine deaminase, JAK3, RAG1, RAG2, IL7R) | Infancy Neonatal | C. jejuni G. lamblia Rotavirus Poliovirus Norovirus |
Adapted from Alkhairy and Hammarström (2015).
PIDs are characterized by various clinical symptoms including a high degree of susceptibility to various types of infections, autoimmunity, inflammation, allergies, and cancer. The main challenge of current immunology is to establish the diagnosis of PID before the onset of clinical symptoms and start therapy as soon as possible in order to prevent the complications and consequences of untreated or nonappropriately treated disease. Patients with antibody deficiency are generally treated either with immunoglobulin replacement (IVIG) while bone marrow or stem cell transplantation is the most common treatment for patients with combined deficiencies. Bacterial infections in PID patients are usually controlled with antibiotics.
2. Gastrointestinal disorders in PID patients
2.1. Selective IgA Deficiency
IgAD is defined as serum IgA levels equal to or below 0.07 g/L with normal serum IgM and IgG levels in individuals of 4 years of age or older. The threshold of 4 years of age is used to prevent a premature diagnosis of IgAD, which may be transient in children due to a delayed maturation of the immune system. IgAD is the most common PID with an estimated frequency of 1/600 in the Caucasian population but it may vary from 1/155 to 1/18,550, depending on the ethnic background (Wang and Hammarström, 2012). The phenotypic feature of IgAD is a failure of B lymphocyte differentiation into plasma cells producing IgA. The exact etiology is unknown and may result from either a T or B cell defect. However, the major histocompatibility complex (MHC), in particular the ancestral human leukocyte antigen (HLA)-A1, B8, DR3, DQ2 (8.1) haplotype, has previously been reported to be associated with disease development (Alkhairy and Hammarström, 2015; Wang and Hammarström, 2012). In addition, non-MHC genes, such as interferon-induced helicase 1 (IFH1) and C-type lectin domain family 16, member A (CLEC16A) have also been shown to be associated with IgAD (Ferreira et al., 2010). Mutations in the TNFRSF13B gene have been seen in some families with transmembrane activator and cyclophilin ligand interactor (TACI)-related IgAD but no cause–effect relationship has been found (Pan-Hammarström et al., 2007; Salzer et al., 2005). Genetic defects in the IGHA1 and IGHA2 genes have been associated with selective IgA1 and IgA2 deficiencies.
IgA normally provides immunologic protection at the mucosal membranes, with a daily production of IgA exceeding that of all other antibody classes combined, presumably reflecting its important role. While the majority of IgAD individuals discovered by screening of blood donors are asymptomatic at the time of diagnosis, some individuals develop recurrent infections, allergic diseases and autoimmune manifestations. IgAD is commonly considered a mild disorder, with approximately 65–70% of the affected individuals being reported as asymptomatic. However, in a recent case study using gender- and age-matched controls, IgAD individuals were found to have a significantly increased proneness to respiratory infections and increased prevalence of allergic diseases and autoimmunity, with a total of 84.4% being affected by any of these diseases, compared to 47.6% of matched controls (Jorgensen et al., 2013). IgA deficiency is also associated with an increased frequency of celiac diseases, Crohn’s disease and ulcerative colitis (Jorgensen et al., 2013). Gastrointestinal infections and steatorrhea also occur with increased frequency, with Giardia lamblia, Campylobacter jejuni, and Salmonella spp. being the most implicated (Ammann and Hong, 1971; Spickett et al., 1991).
2.1.1. Selective IgA Deficiency and Gastrointestinal Viral Infections
IgA deficiency has also been associated with an increase in gastrointestinal viral infections. In humans and animals, intestinal rotavirus-specific IgA is a correlate of protection against rotavirus (see Chapter 2.9). This suggests that intestinal IgA may be essential in the immune response to the virus. Protection from rotavirus infection requires B cells; mice lacking B cells (μMt mice on a C57Bl/6 background) are not protected from rotavirus reinfection (Franco and Greenberg, 1995; McNeal et al., 1995). Support for the importance of IgA for rotavirus immunity also comes from studies in J-chain deficient (J chain−/−) mice, which cannot transcytose IgA or IgM into the intestinal lumen. J chain−/− mice have difficulty clearing a primary rotavirus infection and are not protected from reinfection (Schwartz-Cornil et al., 2002). Mice lacking IgA (IgA−/−) also exhibit a substantial and significant delay in clearance of the initial infection compared to wild type mice (Blutt et al., 2012) and excrete rotavirus in the stool up to 3 weeks after the initial exposure as compared to 10 days in wild type mice. Importantly, IgA−/− mice fail to develop protective immunity against multiple repeat exposures to the virus. All IgA−/− mice excreted virus in the stool upon reexposure to rotavirus while wild type mice were completely protected against reinfection, indicating a critical role for IgA in the establishment of immunity against this pathogen.
There are very few well controlled studies that address the question of whether or not IgA deficiency predisposes individuals to an increased susceptibility to and recurrence of gastrointestinal viral infections. IgAD patients show significantly elevated serum levels of rotavirus-specific IgG antibodies, suggesting a compensatory role of IgG in systemic rotavirus infection and a possible protraction of rotaviral persistence/shedding after infection although the disease is ultimately resolved (Istrate et al., 2008; Günaydın et al., 2014). To date, there has not been any report of an increased frequency or severity of infection by other enteropathogenic viruses (ie, capable of producing disease in the intestinal tract) such as norovirus or astrovirus in IgAD individuals. Elucidation of the role of the gastrointestinal IgA response to norovirus and astrovirus has, however, been restricted by the absence of small animal models in which pathogenesis and immunity is similar to that observed in humans. There is limited evidence that protection from both norovirus and astrovirus infections correlates with mucosal virus-specific IgA in humans (Blutt and Conner, 2013).
Nonenteropathogenic viruses do not infect a significant number of intestinal cells and do not cause gastrointestinal diseases. They invade the body by either breeching or crossing the epithelium of the gastrointestinal tract. However, poliovirus induces a secretory IgA response that appears to neutralize the virus and is associated with protection and decreased virus shedding in the stool (Buisman et al., 2008). An intestinal IgA response is also induced with the live replicating oral polio vaccine (OPV), and it is considered that OPV prevents infection through IgA-mediated viral neutralization in the intestine (Blutt and Conner, 2013). It has been reported that poliovirus can be detected in the stool of IgAD patients for a longer period than in normal individuals after oral vaccination with live attenuated virus, suggesting that IgAD patients have an impaired capacity to eliminate the virus (Savilahti et al., 1988).
Although studies in humans correlate increases in viral-specific IgA levels at the mucosal surface with either the cessation of virus excretion or protection against infection and disease (Chapter 2.9), IgA deficient patients do not appear to present overt clinical manifestations. In most individuals with IgA deficiency, the deficiency is not complete, and thus it is possible that even relatively low levels of IgA produced in patients with deficiency are sufficient to prevent infection. Although IgAD patients have a concomitant lack of IgA in external secretions (Norhagen et al., 1989; Savilahti, 1973), a low proportion of individuals with low levels of serum IgA may actually have sufficient secretory IgA at their mucosal surfaces and thus remain asymptomatic (Ammann and Hong, 1971). We have previously identified a few IgAD and CVID patients with normal level of secretory IgA (Hammarström, unpublished data). Furthermore, other antibody isotypes, in particular IgM transported to the mucosal surface, may compensate for the loss of IgA in selected cases (Savilahti, 1973). This is supported by the fact that patients with CVID are more symptomatic and susceptible to gastrointestinal infections than IgAD patients (see later).
2.2. Common Variable Immunodeficiency
Common variable immunodeficiency (CVID) is the second most common primary immunodeficiency syndrome with an estimated prevalence of 1/20,000 to 1/50,000 in the general population. The diagnosis is based on a marked reduction in serum levels of both IgG (usually <3 g/L) and IgA (<0.07 g/L); IgM is reduced in about half the patients (<0.3 g/L) (Agarwal and Mayer, 2013). Patients have also a poor or absent antibody production to vaccines, such as tetanus or diphtheria toxoids. In a few cases, IgAD can evolve gradually into CVID over a period of months to decades. A linkage of IgAD and CVID was previously observed among family members and patients with these two disorders, suggesting that they may share a common genetic background (Schäffer et al., 2006; Vorechovský et al., 1995).
The pathogenesis of CVID has not been delineated clearly; however, mutations in several genes associated with B-cell development, including autosomal recessive mutations in the genes encoding BAFF-R, TACI, CD20, CD19, CD81, CD21, inducible T cell costimulatory (ICOS) and lipopolysaccharide (LPS)-responsive beige-like anchor (LRBA), have been found in a small number of patients. A recent metaanalysis also suggests involvement of selected HLA alleles and the CLEC16A gene (Li et al., 2015). CVID is the most common symptomatic primary antibody deficient syndrome and characterized by upper and lower respiratory tracts infections caused by Streptococcus pneumoniae, Moraxella catarrhalis, and Haemophilus influenzae. The most common age of the onset of symptoms in patients with CVID generally appears during adolescence or early adulthood (Agarwal and Mayer, 2013). In addition to infection, CVID patients have a wide range of clinical manifestations, including autoimmune disease (mostly immune thrombocytopenic purpura and autoimmune hemolytic anemia), granulomatous/lymphoid infiltrating disease, enteropathy, and an increased incidence of malignancies.
Gastrointestinal symptoms are common in CVID patients and up to 50% of the patients have chronic diarrhea with malabsorption (Hermans et al., 1976; Cunningham-Rundles and Bodian, 1999), withG. lamblia being the most common cause, while C. jejuni, Salmonella spp., Cryptosporidium parvum, and Clostridium difficile have also be implicated (Agarwal and Mayer, 2009; Daniels et al., 2007; Hermaszewski and Webster, 1993; Sicherer and Winkelstein, 1998). Inflammatory bowel like-diseases resembling Crohn’s disease and ulcerative colitis, atrophic gastritis, achlorhydria, gastric carcinoma, and gastrointestinal lymphoma have also been reported (Daniels et al., 2007; Hermaszewski and Webster, 1993). In addition, H. pylori has been suggested to be a significant infectious agent causing gastritis in CVID (Daniels et al., 2007; Quinti et al., 2007; Agarwal and Mayer, 2009). In CVID patients with gastrointestinal symptoms, histological lesions are observed in approximately 80% of biopsies sampled from the stomach, small bowel or colon (Malamut et al., 2010). A striking characteristic of CVID patients is the absence of intestinal plasma cells, pointing to a local defect in secretory antibodies (Malamut et al., 2010; van de Ven et al., 2014).
2.2.1. CVID and Viral Infections
Cases of CVID patients infected with echovirus, coxsackievirus, and poliovirus (particularly the vaccine strain), which in some cases may lead to death, have also been reported (Table 1.3.2) (Halliday et al., 2003; de Silva et al., 2012). The age of onset of nonpolio enteroviral infection was very variable, and was not confined to childhood while most polio cases occurred in childhood following immunization with live attenuated oral vaccines (OPV). Cytomegalovirus (CMV) infections are an infrequent complication of this disorder, and very few cases resulting in gastrointestinal diseases have been reported, occasionally occurring after long term high dose steroids (Chapel and Cunningham-Rundles, 2009; Cunningham-Rundles and Bodian, 1999; Daniels et al., 2007; Freeman et al., 1977).
Table 1.3.2
Gastrointestinal Viral Infections in Patients with PIDs
| Immunodeficiency | Infection | Strain | Patients | Outcome in immunodeficient patients | References |
| IgAD | Poliovirus | Vaccine strains (OPV) | Control study: • 8 IgAD individuals, 6–23 years • 9 controls, 23–43 years | • Higher virus load in the stool • Longer shedding of virus (>5 weeks) | Savilahti et al. (1988) |
| Rotavirus | wt | Control study: • 62 IgAD individuals without gastrointestinal diseases, 23–76 years • 62 controls, 8–69 years | • IgA deficient individuals develop higher serum IgG titers | Istrate et al. (2008) | |
| wt | Control study: • 783 IgAD individuals • 1009 controls | • Individuals with combined IgA and TLR3 deficiency show increased specific IgG titers as compared to individuals with impaired TLR3 only | Günaydın et al. (2014) | ||
| CVID | Various gastrointestinal viruses | wt | Observational study: • 54 antibody deficient patients (48 CVID + CVID-like), 4–18 years • 66 healthy donors, 4–18 years | • Increased prevalence of gastrointestinal viruses (particularly norovirus, parechovirus and adenovirus) • More symptoms (abdominal ache, diarrhea, thin stool) | van de Ven et al. (2014) |
| Norovirus | wt | • 8 patients with CVID enteropathy, 25–66 years • 10 patients with CVID but no entheropathy | • Persistent (>22 months) fecal excretion of norovirus in all patients with CVID enteropathy • Clearance of virus in three patients associated with resolution of symptoms | Woodward et al. (2015) | |
| Cytomegalovirus | wt | 20 CVID patients, 9 children (<10 years) and 21 adults | • 2 patients with cytomegalovirus infection | Daniels et al. (2007) | |
| Enteroviral infections | wt | 20 CVID patients from various studies | • 14 with nonpolio enteroviral infection (echoviruses, Coxsackie viruses) and 6 with poliovirus infection • Enterovirus detected in various sites including the stool • Various neurological symptoms • Death occurred in one third of polio cases and half of the nonpolio cases | Halliday et al. (2003) | |
| Poliovirus | Vaccine strain (OPV) | 51 PID patients screened for poliovirus | • A case of CVID patient (8 years old) with prolonged virus excretion (>6 months) | de Silva et al. (2012) | |
| XLA | Rotavirus | wt | 201 males with XLA from a registry | • 4 cases with rotavirus induced chronic/recurrent diarrhea • Rotavirus isolated from 8% of the patient with diarrhea | Winkelstein et al. (2006) |
| Enteroviral infections | wt | 47 cases from various studies | • 42 with nonpolio infection (echoviruses, poliovirus) and 5 with polio infection • Enterovirus detected in various sites including the stool • Various neurological symptoms • Death occurred in one third of polio cases and half of nonpolio cases | Halliday et al. (2003) | |
| Poliovirus | Vaccine strain (OPV) | 4 cases from various studies | • A 5 year old XLA patient with prolonged virus excretion • A 15 month old XLA patient with prolonged virus excretion (4 months) and acute flaccid paralysis • 2 XLA patients with flaccid paralysis | de Silva et al. (2012), Shahmahmoodi et al. (2008), Winkelstein et al. (2006) | |
| XHIGM | Rotavirus | wt | 79 males with XHIGM from a registry | • 2 patients with rotavirus infection • Isolated from 8% of the patients with diarrhea | Winkelstein et al. (2003) |
| Enteroviral infections | wt | 5 cases from various studies | • 5 with nonpolio infection (echoviruses, Coxsackie viruses) | Halliday et al. (2003) | |
| SCID | Chronic rotavirus infection | wt | 6 cases from different studies | • Prolonged diarrhea and persistent fecal excretion of rotavirus (>8 weeks) • Two patients died and had systemic spread of rotavirus at death • In one case, rotavirus infection reversed by HSCT | Saulsbury et al. (1980), Oishi et al. (1991), Gilger et al. (1992), Frange et al. (2012), Patel et al. (2012) |
Vaccine strains (Rotateq or Rotarix) | >10 cases from different studies, 3–9 months old | • Prolonged diarrhea and persistent rotavirus vaccine excretion (up to 6 months) • In one child, the prolonged excretion was resolved following successful cord-blood transplantation | Werther et al. (2009), Bakare et al. (2010), Patel et al. (2010), Uygungil et al. (2010), Donato et al. (2012) | ||
| Norovirus | wt | Prospective study: • 62 children with PID | • Prolonged virus excretion in one SCID (6 months old) patient • Norovirus shedding associated with gastrointestinal symptoms | Frange et al. (2012) | |
| wt | 2 cases from two studies | • Prolonged virus excretion | Chrystie et al. (1982), Xerry et al. (2010) | ||
| Poliovirus | Vaccine strain (OPV) | Screening of 51 PID patients for poliovirus | • Three cases of SCID patients (4–5 months of age) with poliovirus infection • The three patients died before there was a possibility to measure the duration of excretion | de Silva et al. (2012) |
IgAD, IgA deficiency; CVID, common variable immunodeficiency; XLA, X-linked agammaglobulinemia; XHIGM, X-linked hyper IgM syndrome; SCID, Severe Combined Immunodeficiency.
A small proportion of patients (5–15%) suffering from CVID develop a characteristic and severe enteropathy, the cause of which is unknown but might be associated with viral infections (Woodward et al., 2015). A recent study on gastrointestinal viruses in children with antibody deficiencies (48 CVID and 6 XLA patients) showed that antibody deficient patients show an increased presence of gastrointestinal viruses (particularly norovirus, adenovirus, parechovirus) and that these patients frequently have gastrointestinal symptoms (abdominal ache, diarrhea and thin stool) (van de Ven et al., 2014) (Table 1.3.2). CVID and XLA patients that tested positive for gastrointestinal viruses also showed diminished levels of serum IgA and secretory IgA in fecal samples. Furthermore, a significant association between mucosal inflammation and the presence of enteric viruses was observed in the patients, but not in healthy controls. These findings suggest that hypogammaglobulinemia, particularly a decreased IgA production, might be associated with prolonged intestinal virus replication and that this may result in an increased risk for chronic mucosal inflammation such as CVID related enteropathy (van de Ven et al., 2014). Similarly, persistent fecal excretion of norovirus was found in CVID patients with duodenal villous atrophy and malabsorption (Table 1.3.2) (Woodward et al., 2015). Clearance of the virus spontaneously or following ribavirin therapy was temporally associated with complete resolution of symptoms, restoration of duodenal architecture, and resolution of intestinal mucosal inflammation. However, ribavirin as an effective antiviral therapy for norovirus infection requires further evaluation.
Severe enteropathy appears to be unique to a subset of patients with CVID and is not reported in other immunodeficiencies (Chapel et al., 2008). Recent evidence described earlier suggests an association between norovirus infection and enteropathy, and patients with CVID enteropathy should be tested for the presence of this virus. Furthermore, since CVID patients with a lower IgA level appear to be more prone to viral infections, secretory IgA concentrations should also be determined in order to better understand the susceptibility to virus infection in these patients. Finally, the development of the microbiota is closely related to intestinal IgA excretion, and it would be relevant to evaluate the microbiome of the antibody deficient patients and healthy controls (van de Ven et al., 2014). The microbiome of antibody deficient patients with low intestinal IgA levels might significantly differ from that of patients with normal intestinal IgA secretion and influence the susceptibility to viral and bacterial infections and development of enteropathy (Lindner et al., 2015; Xiong and Hu, 2015).
2.3. X-Linked Agammaglobulinemia
XLA accounts for 85% of known cases of agammaglobulinemia and is caused by a deficiency of Bruton’s tyrosine kinase (BTK), causing a defect in early B-cell development. The disorder has a prevalence of roughly 1/100,000 newborns and has been reported in various ethnic groups worldwide. Being an X-linked disease, only males are affected and females are asymptomatic carriers. The majority of patients develop recurrent or persistent bacterial infections including otitis media, conjunctivitis, sinusitis, pneumonia, diarrhea, and skin infections within the first 2 years of life (Winkelstein et al., 2006; Papadopoulou-Alataki et al., 2012). Over half of the patients developed symptoms referable to their immunodeficiency before 1 year of age, and more than 90% by 5 years of age (Winkelstein et al., 2006). The most frequent clinical manifestations are upper and/or lower respiratory tract infections due to encapsulated bacteria (S. pneumonia, H. influenza, H. parainfluenza), Staphylococcus or Pseudomonas (Winkelstein et al., 2006). Chronic or recurrent diarrhea is observed in more than 20% of the patients with G. lamblia as the main causative agent, followed by rotavirus, enterovirus, Campylobacter fetus, Salmonella spp., C. difficile, H. pylori, and Shigella spp. (Winkelstein et al., 2006).
2.3.1. XLA and Viral Infections
Rotavirus is one of the most commonly isolated pathogen (after G. lamblia) infecting around 2% of the patient with XLA and 9% of those with diarrhea (Table 1.3.2) (Winkelstein et al., 2006). Severe viral infections are rare in XLA patients, but these patients have a unique susceptibility to acute or chronic meningoencephalitis caused by enteroviruses such as echovirus, Coxsackie virus and poliovirus (Halliday et al., 2003; Winkelstein et al., 2006). The virus enters the host via the oral cavity and respiratory tract, then invades and replicates in the upper respiratory tract and small intestine, with a predilection for lymphoid tissues in these regions (Peyer’s patches, mesenteric lymph nodes, tonsils, and cervical lymph nodes). Virus then enters the bloodstream, resulting in a minor viremia and dissemination to a variety of target organs, including the central nervous system (CNS). Enteroviruses have been isolated from a variety of sites, usually from the CSF, and occasionally outside the central nervous system such as the stool and respiratory tract; these sites possibly being the primary site of infection. The infections are chronic in nature and may take the form of meningoencephalitis, dermatomyositis, hepatitis, and/or arthritis. (Winkelstein et al., 2006). Death is frequent and was shown to occur in half of nonpolio cases and a third of polio cases (Halliday et al., 2003; Winkelstein et al., 2006). XLA patients can also show prolonged virus excretion of the polio vaccine strains through vaccination or contact, and in some cases symptoms of polio-like disease can lead to death (Wang et al., 2004; Shahmahmoodi et al., 2008; de Silva et al., 2012; Winkelstein et al., 2006).
Although patients with other PID are also susceptible to enteroviral infections, XLA patients are particularly prone which may partly be due to the fact that they have the most severe antibody deficiency. The death of many of these patients might be prevented with earlier diagnosis of PID (Section 3.2) and immediate institution of high level immunoglobulin replacement therapy (Plebani et al., 2002; Winkelstein et al., 2006).
2.4. Hyper IgM Syndrome
The most common form of the hyper IgM (HIGM) syndrome is inherited as an X-linked trait (XHIGM) which occurs at a frequency of around 1/1,000,000 males. Mutations in the CD40 ligand (CD40L) gene are known to cause XHIGM, in which T-cell and B-cell interaction is disrupted, thus preventing T-cell-dependent isotype switching from IgM to IgG or IgA and a subsequent selective increase in IgM level and a reduced level of the other immunoglobulin classes. Intermittent or chronic neutropenia is found in half of the patients and is often associated with oral ulcers, proctitis (inflammation and ulceration of the rectum), skin infections and sepsis (Winkelstein et al., 2003). HIGM syndromes with a pure humoral defect linked to intrinsic B-lymphocyte anomalies are attributed to mutations in genes coding for enzymes involved in isotype switching including activation-induced cytidine deaminase (AID) and uracil-DNA glycosylase (UNG).
Most patients with HIGM develop clinical symptoms, particularly respiratory infection with Pneumocystis carinii, during their first or second year of life and nearly all before the age of four (Winkelstein et al., 2003). HIGM patients could have distinct clinical infectious complications based on the type of genetic background and exact type of the syndrome. Protracted or recurrent diarrhea caused by C. parvum, G. lamblia, C. difficile, Entamoeba histolytica, Salmonella spp., Yersinia spp. and rotavirus, is reported in 35–50% of the XHIGM patients although an infectious agent cannot be identified in half of the cases (Winkelstein et al., 2003; Levy et al., 1997).
2.4.1. XHIGM and Viral Infections
Only a few publications are available on gastrointestinal viral infections in patients with the XHIGM syndrome although cases of nonpolio enterovirus (echovirus, Coxsackie virus) infection have been reported (Halliday et al., 2003; Cunningham et al., 1999; Winkelstein et al., 2003). In one study, rotavirus was isolated in 2.5% of the patient and 8% of those with diarrhea (Table 1.3.2) (Winkelstein et al., 2003). No other viruses were isolated and no etiologic agent was detected in 50% of the patients with diarrhea which might explain the apparent low impact of virus in patients with XHIGM (Winkelstein et al., 2003). Another reason might be that in the intestinal mucosa of XHIGM patients, secretory IgM or a low level of secretory IgA antibody originating from T-cell-independent class switching may be sufficient for protection against gastrointestinal viruses. Intestinal bacteria can trigger T-cell–independent IgA2 class switching (Cerutti et al., 2011). LPS can activate B cells through Toll-like receptors (TLRs), and polysaccharides can activate B cells through their B-cell receptors. Furthermore dendritic cells produce IgA class switching recombination-inducing factors, such as APRIL and IL-10, after receiving instructing signals from bacteria and intestinal epithelial cells via TLR ligands and thymic stroma lymphopoietin. In mice, B-1 cells express unmutated IgA antibodies that have not been subjected to somatic hypermutation and recognize multiple specificities with low affinity. In T-cell deficient mice, these antibodies provide limited protection against some pathogens, including rotavirus (Franco and Greenberg, 1997). Although humans seem to lack B-1 cells, they have additional B-cell subsets that might be involved in T-cell-independent IgA responses. The intestinal lamina propria of XHIGM patients includes IgA-producing B cells and plasmablasts that contain AID, a hallmark of ongoing class switching recombination (Cerutti et al., 2011).
2.5. SCID
Severe Combined Immunodeficiency (SCID) represents a group of genetic defects causing severe deficiencies in the number and/or function of T, B, and natural killer cells. The overall incidence is 1 in 50,000–100,000 births and involves at least 12 different molecular causes including the genes of the common gamma chain, adenosine deaminase and JAK3. SCID is fatal if not treated, usually by hematopoietic stem cell transplantation (HSCT). Patients with SCID are highly susceptible to recurrent infections with a variety of pathogens including P. jiroveci, C. albicans, cytomegalovirus, respiratory syncytial virus (RSV), herpes simplex virus (HSV), adenoviruses, influenza viruses, parainfluenza viruses, and mycobacteria. They are particularly susceptible to viral infections and viral reactivations after allogeneic HSCT. Gastrointestinal infections are generally caused by G. lamblia, C. jejuni, norovirus, and rotavirus (Aguilar et al., 2014; Frange et al., 2012).
2.5.1. SCID and Viral Infections
A few cases of SCID patients infected with norovirus have been reported in the literature (Xerry et al., 2010; Frange et al., 2012; Chrystie et al., 1982). Some of the infections occur in hospital settings and the viral shedding may last up to 1 year.
The contribution of the adaptive immune responses in clearance of rotavirus from the stool is well defined and depends on lymphocytes. Mice lacking T and B lymphocytes (SCID and Rag 2−/−) are unable to clear a primary rotavirus infection from the intestine and chronically shed rotavirus (Franco et al., 1997; Kushnir et al., 2001). Cases of wild type rotavirus infection have indeed been reported in SCID children with prolonged diarrhea and persistent fecal excretion of rotavirus (Table 1.3.2). A 7-month-old male infant with SCID who had persistent rotavirus gastroenteritis and viremia despite oral and intravenous immunoglobulins administration was cured following HSCT (Patel et al., 2012). IVIG alone was not efficient in clearing the infection maybe because both immunoglobulins and CD8+ T cells are important in clearing the rotavirus infection. Clearance of chronic rotavirus infection in SCID mice can be achieved by adoptive transfer of immune CD8+ T lymphocytes in the absence of antibodies (Dharakul et al., 1990).
Children affected by SCID can also become ill from live viruses present in some vaccines including poliovirus and rotavirus (Table 1.3.2). There are several case reports of severe gastroenteritis with prolonged vaccine virus shedding and prolonged diarrhea in infants administered live, oral rotavirus vaccine that were later identified to have SCID (Table 1.3.2). The interval from vaccination to the onset of symptoms ranged from 1 to 33 days (median 12 days) (Bakare et al., 2010; Patel et al., 2010). Most cases were associated with viral shedding lasting from 1 to at least 7.5 months (median of at least 5.5 months). In one child, prolonged excretion was resolved following successful cord-blood transplantation (Werther et al., 2009).
2.6. Other Immunodeficiency Diseases and Genetic Factors
No increase of gastrointestinal viral infections has been reported in patients with other prevalent immunodeficiency such as phagocyte (CGD) and complement defects. CGD patients show a normal immunity to most viruses, and the role of complement is probably not crucial in the defense against viruses at mucosal surface and in the mucosa. However, there are more than 250 PIDs and some of them have been associated with viral infections. For example, some combined immunodeficiency disorders [deficiency in IL-2-inducible T-cell kinase (ITK), magnesium transporter 1 (MAGT1), signaling lymphocyte activation molecule (SLAM)–associated protein (SH2D1A), macrophage stimulating 1 (MST1), phosphoinositide 3-kinase delta (PI3K-δ), lipopolysaccharide responsive beige-like anchor protein (LRBA), CD27, etc.], diseases of immune dysregulation [deficiency in caspase recruitment domain-containing protein 11 (CARD11), protein kinase C (PRKCδ)], and defects in innate immunity [signal transducer and activator of transcription 1-alpha/beta (STAT1) deficiency] have been associated with Epstein-Barr-Virus and/or cytomegalovirus infection (Al-Herz et al., 2014). Furthermore, mutation in genes encoding IL-10, IL-10 receptors, STAT1, LRBA, forkhead box P3 (FOXP3), autoimmune regulator (AIRE), an E3 ubiquitin ligase (ITCH), and the T-cell receptor alpha constant region gene (TRAC), can lead to chronic diarrhea, enteropathy and/or inflammatory bowel disease (Al-Herz et al., 2014). Those PIDs might also be associated with an increase in the incidence of gastrointestinal viral infections, but little information is available to date.
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