Gastrointestinal Manifestations in Children with Immunodeficiency Referred to a Tertiary Hospital

Immunodeficiency disorders, whether acquired or inherited, significantly impact immune pathways (1). Primary immunodeficiencies (PIDs) arise from genetic anomalies, immunosuppressive treatment, and acquired immunodeficiency syndrome (AIDS), all of which compromise immune function (2). The human gastrointestinal (GI) tract hosts the largest microbiota burden, containing trillions of microorganisms, including approximately 4,000 commensal species (3, 4). The gut mucosa and gut-associated lymphoid tissue (GALT), along with the microbiota, regulate immunity and defend against pathogens and food antigens (5, 6). Immunodeficiency disorders disrupt this system, allowing pathogens to breach the mucosal barrier, potentially leading to infections or virus-induced malignancies (2). Patients with PID frequently present with GI symptoms, including chronic diarrhea, low body mass, abdominal pain, and failure to thrive (FTT). These symptoms can result in inflammation, infection, autoimmunity, or malignancy (7).

Despite the frequency of these manifestations, there is a significant knowledge gap in their understanding and management. This study was conducted to explore GI manifestations in Iranian pediatric patients with PIDs. The findings provide valuable information for formulating more effective diagnostic criteria and treatment protocols, thereby enhancing patient care and stimulating further research in pediatric immunology and gastroenterology.

This was a cross-sectional study conducted on children who were retrospectively evaluated for immunodeficiency disorders. Participants were selected from medical records at Mofid Children's Hospital, Tehran, Iran, from 2011 to 2022, a tertiary care hospital for children with immunodeficiency disorders. As this was a retrospective study, informed consent was not obtained from the participants.

Of the 43 children with immunodeficiency evaluated in this study, 25 (58.1%) were male and 18 (41.9%) were female. The mean age was 46.68 ± 51.89 months (3.89 ± 4.32 years). Primary immunodeficiency (PID) was observed in 25 patients (58%), and CID in 18 (42%). The most common immunodeficiency disorder was CID in 11 patients (25.6%), followed by SCID in 6 (14%), interleukin-10 (IL-10) deficiency in 3 (7%), and common variable immunodeficiency (CVID) in 3 (7%). Other immunodeficiency disorders included major histocompatibility complex (MHC) II deficiency, neutropenia, Wiskott-Aldrich syndrome (WAS), autoimmune polyendocrinopathy, Mendelian susceptibility to mycobacterial diseases (MSMD), leukocyte adhesion deficiency type 1 (LAD-1), Shwachman-Diamond syndrome (SDS), congenital neutropenia, early-onset inflammatory bowel disease (IBD), phosphoglucomutase 3 (PGM3) deficiency, and chronic granulomatous disease (CGD).

Table 1 displays the clinical manifestations of the patients. The most frequent clinical manifestations were diarrhea in 24 patients (55.8%) and vomiting in 21 (48.8%). Additionally, the predominant presentation in patients with CID was vomiting (7/11), while patients with SCID most commonly presented with diarrhea (4/6) and poor feeding (4/6) (data not presented in the table). Upper endoscopy and colonoscopy were performed on 14 and 11 patients, respectively (Figure 1). Erythema of the esophagus (3/14), stomach (5/14), and duodenum (3/14) were the most common findings of upper endoscopy. Nodularity of the colon (4/11) and erythema of the rectum (4/11) were the most frequently observed findings in colonoscopy.

Figure 1.

Findings of upper endoscopy and colonoscopy in children with immunodeficiency (data represented as numbers)

The most frequently observed histopathologic findings were chronic esophagitis (6/14) in the esophagus, chronic gastritis (11/14) in the stomach, chronic inflammation (7/14) in the duodenum, and increased/enlarged lymphoid follicles in the colon (4/11) and rectum (6/11) (Figure 2). Abdominal CT or US revealed splenomegaly and hepatomegaly as the most frequent findings, occurring in 2 out of 43 patients (4.6%) and 9 out of 43 patients (20.9%), respectively (Figure 3). The laboratory test results of the patients are presented in Table 2.

Figure 2.

Histopathologic findings in children with immunodeficiency (data represented as numbers)

Figure 3.

Abdominal computed tomography (CT) and ultrasound (US) findings in children with immunodeficiency (data represented as numbers)

Table 3 shows that symptoms including nausea, vomiting, abdominal pain, fatigue, and jaundice are more prevalent among patients with CID compared to those with PID. Nausea was reported in 24% of PID children, whereas it was reported in 33.3% of CID patients. Vomiting, the most common symptom, was observed in 61.1% of children with CID, compared to 36% in PID patients. Additionally, physical examination revealed that 24% of PID children had splenomegaly, whereas only 16.7% of CID patients exhibited this condition. The analysis of symptoms specific to PID and CID is presented in Table 3.

In our evaluation of 43 children with immunodeficiency, most affected by CID, we found diarrhea and vomiting to be the predominant GI manifestations. This is consistent with the research of Akkelle et al., which demonstrated that the most typical presentation in children with PID was persistent diarrhea (1). Moreover, in their study on children with PID, Abdalla et al. reported both diarrhea and vomiting in 39% of patients, without any significant difference between various PID groups (2). While enteropathy may be more specific to PIDs with abnormalities in more than one immune system component, diarrhea is a common symptom across many PIDs (3). This was corroborated by our study, where diarrhea was a frequent finding in SCID patients. Both rotavirus and cytomegalovirus are common GI infections in SCID patients that may lead to malabsorption and recurrent diarrhea (4-6).

Following the respiratory system, the GI tract is the second most affected system by PIDs. The GI system is considered the body’s largest immunological organ and functions as a critical barrier to infections. Infectious, inflammatory, immunological, or malignant conditions may be GI-related in PIDs (7). Along with a variety of commensal bacteria, the gut mucosa and GALT, the body’s largest lymphoid organ, play intricate and crucial roles in the maturation and regulation of the immune system (10). The GI mucosal immune system is directly affected by immunodeficiency disorders. Selective IgA deficiency, CVID, and Bruton agammaglobulinemia are examples of PIDs that can affect B-cell immune response, while DiGeorge syndrome affects T-cell immune response, SCID involves B- and T-cell response, and CGD impacts macrophage and neutrophil defense (11-13).

Three patients in our study had IL-10 deficiency, two of whom experienced diarrhea (data not presented in the table). The IL-10 is a cytokine that regulates inflammation and is secreted by macrophages, regulatory T-cells, and B lymphocytes. Both extra-intestinal and intestinal tissues contain IL-10 and its receptors. Early-onset IBD may be caused by defects in IL-10 and its receptors (14).

Wiskott-Aldrich syndrome was another immunodeficiency disorder identified in this study, affecting the WAS protein, which is essential for B and T lymphocyte signaling. Susceptibility to infection is caused by defects in this protein (15). Colitis, malabsorption, and bloody diarrhea are examples of gut symptoms in WAS (16).

Common variable immunodeficiency was the third most common immunodeficiency disorder in the current study. Numerous inflammatory illnesses of the GI tract, both viral and noninfectious, can adversely affect patients with CVID (17). Due to alterations in the immune system in CVID patients, the definition of GI pathology varies significantly among this population (18). Diarrhea has been reported as a symptom in 20% to 60% of cases (19). GI infections caused by Giardia, Salmonella, Campylobacter, and cytomegalovirus (CMV) are frequently observed in individuals with CVID (20). Noninfectious GI pathologies in patients with CVID include microscopic colitis, celiac disease, lymphocytic gastritis, granulomatous disease, pernicious anemia, acute graft-versus-host disease, IBD, CVID-enteropathy, and small-bowel lymphoma (21). In a study from Italy, GI symptoms in 13 children with CVID included diarrhea, vomiting, dyspepsia, epigastric discomfort, constipation, and abdominal pain (22).

After the lungs, the GI tract is the organ system most often affected in CVID, with up to 50% of CVID patients experiencing GI problems. Moreover, up to 10% of these patients may be affected by non-infectious chronic enteropathy, which might resemble conditions such as celiac disease or IBD (23, 24). Additionally, GI cancers, such as non-Hodgkin B-cell lymphoma, are linked to CVID (25). According to Al-Hussieni et al., CVID patients are more likely to develop infectious diseases in the GI tract, making GI symptoms one of the most significant presentations in these patients. These manifestations might occur early in the course of the disease or later on (26).

The majority of individuals with CVID have recurrent infections due to low antibody levels, characterized by decreased IgG, IgA, and/or IgM levels and limited antibody production (27). In cohorts of the CVID population, reports of IBD mimicking Crohn's disease or ulcerative colitis have been made (25, 28). Reported symptoms include weight loss, persistent diarrhea, rectal bleeding, abdominal pain, and malabsorption. Inflammatory bowel disease -like disease can also manifest as a follow-up to the diagnosis of CVID. Endoscopic characteristics include cobblestone and longitudinal ulcers. Histologically, it can resemble collagenous colitis, lymphocytic colitis, and colitis linked to graft-versus-host disease (19). Tissue pathologic examination indicates a deficiency of plasma cells and an increase in CD81 T-cell infiltrates in the lamina propria. Additionally, compared to controls, lamina propria mononuclear cells from CVID patients may produce higher levels of IL-12 and interferon-gamma, but not IL-23 or IL-17, indicating a different mechanism of inflammation (29).

In the current study, the most frequent findings of upper endoscopy were erythema of the esophagus, stomach, and duodenum. The most typical colonoscopy results were erythema of the rectum and nodularity of the colon. In the study by Akkelle et al., congestion and antral nodularity were the two prominent findings in the stomach, while the esophagus was normal in more than half of the PID patients (1).

Imaging is crucial for diagnosis, determining the degree, detecting complications, and assessing the effectiveness of therapy in GI symptoms of immunodeficiency (30). In patients with suspected GI illness, US is a commonly used, reasonably priced, and safe imaging technique that aids in localizing intestinal abnormalities (31). Important findings suggestive of bowel disease include certain distinguishing characteristics, such as abnormal motility, dilated bowel loops, enlarged mesenteric lymph nodes, interloop fluid, and bowel wall thickening (31). The abdominal US most frequently revealed hepatomegaly, ascites, and free fluid, and less commonly splenomegaly, mural thickening of the colon and bowel loops, intra-abdominal abscess, gallstone, hepatic cyst abscess, and intussusception in our patients.

On the other hand, due to its broad availability and usefulness, CT plays a crucial part in the imaging assessment of GI symptoms of immunodeficiency. A better assessment of intestinal wall thickening, mesenteric lymph nodes, perforation, and extra-intestinal symptoms is possible using CT. It is also used to confirm and evaluate the disease extent and stage of different cancers linked to immunocompromised conditions (32, 33). Consistently, our study revealed splenomegaly, hepatomegaly, abscess formation, ascites, gastric wall thickening, and dilatation of small bowel loops in abdominal CTs of children with immunodeficiency.

In our study, hepatomegaly was observed in 20.9% of the evaluated children, highlighting its relatively high frequency among this population. The presence of hepatomegaly in these children can be attributed to several factors, including chronic infections, inflammation, and the body’s immune response to persistent pathogens (34, 35). Our findings are consistent with previous studies that reported similar frequencies of hepatomegaly in children with PID disorders (36, 37), although some studies reported a higher frequency of hepatomegaly in these children (38).