Endoscopic and histopathological hints on infections in patients of common variable immunodeficiency disorder with gastrointestinal symptoms

We retrospectively reviewed 21 CVID patients with GI symptoms who underwent endoscopy and biopsy. The key findings included: (i) Chronic diarrhea with malabsorption was the predominant clinical manifestation of CVID enteropathy. (ii) Small bowel was mainly affected with distinctive endoscopic features such as mucosal edema, villous atrophy, and extensive NLH. Accordingly, the histopathology revealed villous atrophy, increased IELs, NLH, and decreased plasma cells in duodenum and terminal ileum mucosa. (iii) Diffuse and obvious NLH may be an endoscopic sign of infections, especially for Giardia and bacteria.

In our CVID cohort, 23% (20/87) of patients experienced diarrhea, with a high malabsorption rate as determined by D-xylose absorption test. Quinti I reported chronic diarrhea was observed in 22.4% of CVID patients and resulted in a significant malabsorption in 8.1% [5]. Chapel H reported 9% CVID enteropathy, which was defined as biopsy-proven lymphocytic infiltration in lamina propria and interepithelial mucous with villous atrophy, insensitive to gluten withdrawal [6]. However, CVID enteropathy lacks universal definition, with estimated prevalence of 9% ~ 34% [22]. Endoscopy could give a general clue for villous atrophy with confirmation by histopathology [7, 19]. Previous studies found intestinal villous atrophy in approximately 30% ~ 50% of CVID patients with GI symptoms [21,22,23]. We found he duodenal villous atrophy was over 85%, which was higher than previous reported. IM Andersen categorized CVID enteropathy into severe and non-severe types based on whether there were weight loss, malnutrition, and severe GI-loss [22]. In our cohort, 85% of patients were under weight, and 52% presented with nutritional anemia, suggesting severe disease manifestation. Some disparities in findings might arise due to sample size limitations, disease severity, and regional factors. Other conditions displaying villous atrophy need to be differentiated including celiac disease, autoimmune enteropathy, tropical sprue, protracted viral or bacterial infection, giardiasis, T-cell lymphoma, food protein hypersensitivity, and graft-versus-host disease [20, 24]. CVID patients have hypoimmunoglobins, profoundly decreased plasma cells and NLH in mucosa, and resistance to gluten-free diet [21, 23]. So, the clinical history, biopsy histopathology and therapy response could help to get accurate diagnosis.

Further differentiation is required when CVID enteropathy presents with hypoalbuminemia from conditions like protein loss enteropathy (PLE). PLE can be caused by different mechanisms: increased lymphatic pressure, mucosal erosions, and increased mucosal permeability. It has been reported that PLE has lower infection and lymphoproliferation rate, higher serum levels of IgG, and mildly decreased to normal serum levels of IgA (> 0.5 g/L) than CVID. However, PLE can occur during CVID and requires higher IgG replacement therapy dosage [25]. There are 10 patients with hypoalbuminemia in our study, who all had obvious low IgA levels. Nine of them lack plasma cells in gut biopsy, and the other one with mild hypoglycaemia had no etiology of PLE. All above support their CVID diagnosis.

NLH shows pseudopolypoid appearance with multiple or occasionally innumerable nodules measuring 2–3 mm and usually not exceeding 10 mm in diameter of duodenum or ileum mucous under endoscopy, sometimes through the whole small bowel [4, 10, 11, 23, 26]. Biopsy could confirm the diagnosis of NLH in microscopic view, however, it is dependent on the biopsy site and hard to evaluate the gross degree. Endoscopy is a good compensatory tool for the general evaluation. NLH had been reported in following conditions: CVID, selective IgA deficiency syndrome, giardiasis, H. pylori infection (gastric-NLH), food hypersensitivity, HIV, familial adenomatous polyposis, and GI malignancy, especially lymphoma [9, 17, 26]. Our data suggests that diffuse and obvious NLH may indicate infections, especially with Giardia and bacteria. A previous study on infections in 252 CVID patients showed that 47% had GI symptoms, 14% had Giardia lamblia infection and 19% had other GI bacterial infections [13]. Giardia lamblia could be one of the antigenic stimulators and associated with NLH in patients with or without immunodeficiency syndromes, leading to watery diarrhea, steatorrhea, and malabsorption [17, 27,28,29]. It is reported that diffuse NLH of the bowel associated with CVID and refractory giardiasis markedly improved after successfully treating giardiasis [30]. The pathogenesis of NLH is still unknown. Infection maybe a trigger of mucosal immune response and disturbance. Repetitive stimulation of infectious agents probably lead to the hyperplasia of lymphoid follicles [9]. Lymphoproliferation was also present elsewhere in CVID, such as splenomegaly and lymphadenopathy. Similarly, H. pylori infection could cause gastric nodularity which could be normal after H. pylori eradication treatment. Increased IELs might also be an immune compensation and dysregulation. In all, infections could cause both acute diarrhea and chronic immune dysregulation in CVID enteropathy. Our study showed that diffuse and obvious NLH might be an endoscopic clue for infections in these patients. Although NLH may be related to high risk of malignancy, we do not find in our study.

The reason for the variance in CVID manifestations, with some patients developing GI symptoms and others not, remains unclear. T-cell dysfunction and autoimmunity against intestinal tissue, absence of mucosal plasma cells and defective antibody production, especially mucosal IgA, have been reported [3]. On the other hand, infections maybe also an important factor such as chronic norovirus [22]. Early diagnosis and IVIG replacement therapy (0.4 to 0.5 g/kg/month) can reduce the incidence of respiratory tract infection. However, IVIG did not improve diarrhea, especially in patients with lower serum IgA titers. Different options have been used to treat GI symptoms, for example, antibiotics such as metronidazole or ciprofloxacin, 5-aminosalicylic acid, and immunosuppressive agents such as corticosteroids, azathioprine, and infliximab [2, 12]. Endoscopy is a good general evaluation providing useful information for mucosal change and possible co-infections. The endoscopic and histopathological assessment should be performed in CVID with GI symptoms to facilitate diagnosis and treatment.