Common variable immune deficiency (CVID) is a form of primary immune deficiency disease (PIDD). It presents most commonly with recurrent sino-pulmonary infections with the disease onset in twenties and thirties with estimated prevalence of 1 in 25,000 to 50,000. The various non-infectious complications of CVID presenting as different phenotypic variants like enteropathy/autoimmune/lymphoproliferative disorders likely represent the polygenic inheritance of the disease. The natural progression and treatment outcomes of these non-infectious complications varies considerably in comparison to patients with infectious complications of CVID.1
CVID enteropathy is a phenotypic variant presenting with chronic diarrhea and weight loss. We present herein a rare patient of CVID enteropathy without any history of recurrent sino-pulmonary infections.
Case Report
A 44-year-old male patient presented with complaints of chronic watery diarrhea and significant unintentional weight loss for last 18 months. Despite treatment with empirical antibiotics, anti protozoals and anti diarrhoeals, he continued to have 10-12 large volume stools per day. On examination, he had severe sarcopenia, loss of subcutaneous fat and oedema.
Investigations revealed anemia, leukocytosis, hypoprotenemia (both serum albumin and globulin levels were decreased), hypocalcaemia, decreased vitamin D levels and increased TSH (8.5 mIU/L). Stool miroscopy were normal. Viral markers were negative. Bone marrow examination showed reactive marrow with erythroid hyperplasia.
Upper GI Endoscopy revealed chronic Helicobacter Pylori related gastritis. Biopsy of second part of duodenum showed giardia with mixed inflammatory cells in lamina propria and mild decrease in villous length. As patient did not improve on metronidazole, colonoscopy was done which showed few rectal ulcers. Blind biopsy of terminal ileum showed diffuse inflammatory cell infiltrate comprising of both lymphocytes and plasma cells with one villi showing granulomatous foci (non-necrotizing) with epitheloid cells and giant cells (Figure 1 and 2). There was no significant increase in intra epithelial lymphocyte count. Double balloon enteroscopy (retrograde) and push enteroscopy (antegrade) did not show any small intestinal ulcers or strictures. CT enterography showed hypo dense lesions in segment VII of liver (? regenerative nodules) and mesenteric lymphadenopathy in mid abdomen and left hypochondrium. The absence of bloody diarrhea and of macroscopic lesions on endoscopy in spite of severe diarrhea and malabsorption made diagnosis of Crohn’s disease unlikely.
Patient did not have response to gluten free diet or fasting. Celiac profile showed decreased total IgA levels and IgA anti-tTG was negative. Presence of persistent giardiasis, granulomas and decreased globulin levels in serum indicated immune system abnormality. IPSID (immunoproliferative small intestinal disease) was suspected and serum protein electrophoresis did not show any alpha chain heavy bands.
Serum immunoglobulin levels were decreased (IgA 401 mg/dl, IgG<21mg/dl, IgM<11mg/dl). Absolute CD4 count was decreased (408/ul) and CD4/CD8 ratio was reversed (0.34). Antibody levels for diphtheria and pertussis were decreased (non-protective). A diagnosis of CVID was reached in accordance with revised European Society for Immunodeficiencies (ESID) 2019 diagnostic criteria (Table 1).2
Diagnosis of CVID related enteropathy was made and patient was suggested treatment with intravenous immunoglobulin (IVIG) and repeat vaccination with killed vaccines. Patient received IVIG monthly doses for two months, following which frequency of diarrhea decreased and edema subsided. Patient was subsequently lost to follow up.
Discussion
Common variable immune deficiency is a rare polygenic disease of late onset antibody failure (LOAF) usually presenting with recurrent acute and chronic infections, most commonly of sino pulmonary tract. In the past few decades, non-infectious complications of CVID have been increasingly recognized and efforts have been made to classify them into different phenotypes accordingly, which have diagnostic and therapeutic implications. It has been realized that these non-infectious complications often have increased mortality (mortality rate of 3.9 per 100 person-years for CVID with duodenal atrophy)3. This might be due to both delay in diagnosis and poor response to treatment.4
Gastrointestinal manifestations are common in CVID, most common features being recurrent/chronic diarrhea and malabsorption. Giardiasis has been commonly found (upto 50%) to be the cause in these patients. Other gastrointestinal manifestations include autoimmune/lymphoproliferative infiltration of intestine causing sprue like symptoms. Unlike celiac sprue, response to gluten free diet is not a feature. Unexplained lymphadenopathy and organomegaly (liver and spleen) are often present with enteropathy. Granulomas are often found in intestine. Regenerative nodules in liver represent focal nodular hyperplasia.
An attempt has been made to classify CVID according to different clinical phenotypes and study its relation to complications of the disease. Accordingly 5 major phenotypes described are - enteropathy; polyclonal lymphoproliferation; autoimmune cytopenias; OSAI: organ-specific autoimmune disease; IO: infection only.5 Patient can present with more than one phenotype having considerable overlap with varying dominance. Our patient had both infection (giardiasis) as well as inflammation of both duodenum and terminal ileum (inflammatory cell infiltrate in lamina propria and granuloma) indicating diffuse involvement of small bowel.
Our patient did not have history of recurrent lung infections, which are usually expected to be associated with CVID, contributing to delay in diagnosis. It has been suggested that deficiency of calcium, vitamin D and E along with iron deficiency are not common in other types of gastrointestinal tract involvement of CVID unlike in Enteropathy. This can be possibly used to confirm indirectly the presence of enteropathy apart from infection-related diarrheas in CVID. Although vitamin D deficiency has been observed in some patients of CVID without enteropathy.4
Malabsorption associated with CVID enteropathy can be particularly debilitating to the patient. Our patient had difficulty in walking and could not perform his daily activities without assistance. Associated anasarca contributed to frequent cellulitis in both lower limbs.
Other autoimmune manifestations like rheumatoid arthritis are common in CVID. Our patient had inflammatory pain of both knee joints and small joints of feet, though rheumatoid factor was negative. Mesenteric lymphadenopathy, either due to repeated infectious insults in the gut or due to abnormal immune response usually accompanies enteropathy, as evidenced in our patient.
Intravenous immunoglobulin replacement is the preferred treatment though response is usually less satisfactory in comparison to other phenotypes.6 Antibiotics have decreased the mortality associated with infectious complications. Steroids and immunomodulators like azathioprine have been tried to decrease gut inflammation in CVID enteropathy.4 Additional therapies like probiotics, fecal transplantation, or even dietary recommendations are being tried, though conducting trials would be difficult due to rarity of the cases and multiple phenotypes of CVID.7 Patients should receive repeat vaccinations with killed or subunit vaccines, though response is often suboptimal.8
Replenishment of vitamins, iron and calcium with oral or intravenous supplements should be considered when necessary.
Conclusion
Our case demonstrates that CVID enteropathy should be considered a differential in chronic diarrheas with malabsorption features not responding to routine therapies even in the absence of recurrent sinopulmonary infections. Early diagnosis and treatment can improve the prognosis of the patient.
References
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- Seidel MG, Kindle G, Gathmann B, Quinti I, Buckland M, van Montfrans J, et al. The European Society for Immunodeficiencies (ESID) Registry Working Definitions for the Clinical Diagnosis of Inborn Errors of Immunity. J Allergy Clin Immunol Pract 2019;7(6):1763–70.
- Pensieri MV, Pulvirenti F, Schiepatti A, Maimaris S, Lattanzio S, Quinti I, et al. The high mortality of patients with common variable immunodeficiency and small bowel villous atrophy. Scandinavian Journal of Gastroenterology 2019;54(2):164–8.
- Chapel H, Cunningham-Rundles C. Update in understanding common variable immunodeficiency disorders (CVIDs) and the management of patients with these conditions. British Journal of Haematology 2009;145(6):709–27.
- Bateman EAL, Ayers L, Sadler R, Lucas M, Roberts C, Woods A, et al. T cell phenotypes in patients with common variable immunodeficiency disorders: associations with clinical phenotypes in comparison with other groups with recurrent infections. Clin Exp Immunol 2012;170(2):202–11.
- Patel J, Kumar A, Agasti A, Choksey A, Phadke A, Sawant P. CVID Enteropathy- A Rare Cause of Chronic Diarrhea in a Child. The Indian Journal of Pediatrics 2012;79(10):1374–6.
- Gereige JD, Maglione PJ. Current Understanding and Recent Developments in Common Variable Immunodeficiency Associated Autoimmunity . Frontiers in Immunology 2019;10.
- Goldacker S, Draeger R, Warnatz K, Huzly D, Salzer U, Thiel J, et al. Active vaccination in patients with common variable immunodeficiency (CVID). Clinical immunology (Orlando, Fla) 2007;124(3):294–303.