Gut inflammation in CVID: causes and consequences

Figures & data

Figure 1. CVID enteropathy. A suggested etiology model of CVID enteropathy where the size of the circles reflects the suggested impact on the complex enteropathy phenotype.

Table 1. An overview of some of the definitions used for CVID enteropathy

Author, publication year	Definitions of CVID enteropathy	Exclusion of infection	Symptomatic	Histological
Chapel, 2008	Biopsy-proven lymphocytic infiltration in lamina propria and interepithelial mucous with villous atrophy, insensitive to gluten withdrawal.		v	v
Chapel, 2012 (improved diagnosis)	Enteropathy – unexplained, excluding infective, autoimmune, and gluten sensitive enteropathies	v	?	v
Li, 2015;	Diarrhea for three months with exclusion of infectious cause	v	v
Farmerl, 2018	A utoimmune gastrointestinal disease was defined as chronic diarrhea with protein wasting and/or biopsy-proven evidence of immune pathology in the absence of active infection*	v	v	v
Shulzhenko, 2018	A concomitant history of chronic diarrhea or unexplained weight loss>5% of total body weight over the previous six months with changes in more than one parameter consisting of body mass index, serum albumin, serum protein and number of liquid stools		v
Van Schewick, 2020	Longstanding diarrhea or proven mucosal abnormality on biopsy not attributable to infection. This could be further classified according to the presence or absence of gastrointestinal inflammation, malabsorption, and histological abnormalities**	v	v	v

*Patients were further subcategorized as either autoimmune enteropathy according to biopsy-proven evidence of cell dropout (e.g., parietal or goblet), villous blunting, increased intra-epithelial lymphocytosis, and/or follicular lymphoid hyperplasia, or as inflammatory bowel disease according to biopsy-proven lymphoid aggregates and/or granulomas with a consideration of Crohn’s disease or ulcerative colitis

**proposal of diagnosis

Figure 2. CVID enteropathy sub-classes. CVID enteropathy divided into the two subclasses: Severe CVID enteropathy and Non-severe CVID enteropathy.

Figure 3. Macroscopic and microscopic gastrointestinal pathology and gut microbial dysbiosis in CVID. Gastrointestinal disease in CVID is associated with immune dysregulation, immunodeficiency and autoimmunity that effects the stomach, liver and large- and small intestine. The gut microbial composition in CVID is unhealthy and together with GI inflammation it allows gut leakage of microbial products into the blood stream to initiate/maintain an inflammatory process.

Figure 4. The future of CVID is personalized medicine. The heterogenous nature of CVID and the overlap between CVID enteropathy and inflammation/autoimmunity in other organs makes it logical to approach personalized therapy in CVID as a group. Data such as genomics, transcriptomics, metabolomics, and metagenomics including samples from blood, tissues and feces, are combined. Then statistical and mathematical integration methods for multiple omics datasets are applied to unravel the complexity of biological systems involved in CVID and to identify signatures that can stratify the patients further. This new knowledge can be used in: (i) Prevention, to detect patients at high risk of developing complications e.g. gastric cancer, liver failure or severe chronic enteropathy (ii) Correct diagnosis: to identify monogenic disease that enables individualized treatment strategy, and individuals that are wrongly categorized as CVID (iii) Targeted therapy: to predict which patients are more likely to respond to specific therapies e.g. biological therapy directed at specific mechanistic pathways, nutritional intervention e.g. high fiber diet, microbiome treatment e.g. probiotics, or a combination thereof.