|CASE BASED REVIEW
|Ahead of print publication
Common variable immunodeficiency: An uncommon cause of bronchiectasis, granulomatous disease, chronic liver disease, and enteropathy – Case report and review of literature
Veena Shamsudeen1, Arun Hegde2, Uday Bhanu Kovilapu3, Nisha Verma4, Anurag Jain5
1 Department of Internal Medicine, AFMC, Pune, Maharashtra, India
2 Department of Rheumatology, Command Hospital (Southern Command), Pune, Maharashtra, India
3 Department of Radiology, AFMC, Pune, Maharashtra, India
4 Department of Pathology, AFMC, Pune, Maharashtra, India
5 Department of Nuclear Medicine, Command Hospital (Southern Command), Pune, Maharashtra, India
|Date of Submission||18-Jun-2020|
|Date of Acceptance||31-Jul-2020|
Department of Rheumatology, Command Hospital, (Southern Command), Pune - 411 040, Maharashtra
Source of Support: None, Conflict of Interest: None
Common variable immune deficiency (CVID) is a primary immunodeficiency syndrome, characterized by a defective B cell function. Although there is no age or gender predilection, it is usually diagnosed between the second and fourth decades of life. The clinical features are diverse and include recurrent infections and autoimmune and granulomatous diseases, along with an increased risk of malignancies. Respiratory involvement occurs commonly in the form of recurrent upper and lower respiratory tract infections (LRTI), at times resulting in bronchiectasis. Gastrointestinal involvement may manifest either in the form of an infectious diarrhea due to parasites such as Giardia lamblia and bacteria such as Campylobacter jejuni, or as a noninfectious enteropathy resembling coeliac disease or inflammatory bowel disease. Some patients develop a granulomatous disease manifesting with noncaseating granulomas, especially of lymph nodes, skin, lung, spleen, and liver. Nearly 20%–25% of cases develop autoimmune complications such as autoimmune hemolytic anemia and immune thrombocytopenia. Hepatic involvement can occur in the form of abnormal biochemistry, nodular degenerative hyperplasia, and cirrhosis of liver. Treatment of infection, and replacement of immunoglobulins, remains the mainstay of management of CVID. Herein, we describe the case of a 48-year-old female, who initially presented to our hospital with recurrent bouts of upper and LRTI, along with small-bowel diarrhea, and progressively developed generalized lymphadenopathy and ascites, before being finally diagnosed by the rheumatologist, as a case of CVID, with associated CVID-related enteropathy, granulomatous disease, and chronic liver disease. She was managed with immunoglobulin replacement therapy, along with hydroxychloroquine and steroids with good response.
Keywords: Bronchiectasis, common variable immunodeficiency-related chronic liver disease, common variable immunodeficiency-related enteropathy, common variable immunodeficiency-related granulomatous disease, common variable immunodeficiency, intravenous immunoglobulin
|How to cite this URL:|
Shamsudeen V, Hegde A, Kovilapu UB, Verma N, Jain A. Common variable immunodeficiency: An uncommon cause of bronchiectasis, granulomatous disease, chronic liver disease, and enteropathy – Case report and review of literature. Indian J Rheumatol [Epub ahead of print] [cited 2020 Dec 4]. Available from: https://www.indianjrheumatol.com/preprintarticle.asp?id=299894
| Introduction|| |
Common variable immune deficiency (CVID) is one of the most frequently diagnosed primary immunodeficiency (PID) syndromes in adults, with an incidence of 1:25,000 (thus called common), and is characterized by an abnormal B cell differentiation, with resultant hypogammaglobulinemia. The degree of immune deficiency and clinical presentation is highly variable among patients, and hence the term, variable.
The European Society for immunodeficiencies and Pan-American Group for immunodeficiency suggest the following requirements, as essential, for a diagnosis – a history of chronic and recurrent infections, decreased levels of immunoglobulin G (IgG) and either immunoglobulin M (IgM) or immunoglobulin A (IgA) isotypes at least 2 standard deviations below the mean for age, and an age of onset ≥2, along with a poor response to vaccines. Other causes of PID and secondary causes of hypogammaglobulinemia such as drugs and malignancies are required to be ruled out, before considering a diagnosis. Although CVID can be diagnosed at any age, its onset is usually between 20 and 40 years of age, with a childhood-onset subtype, that peaks before the age of 10 years. Diagnosis in CVID is usually delayed by an average of 4–8 years from symptom onset.
CVID patients are prone to infections due to deficient antibody production. Respiratory infections are the most frequent, followed by involvement of the gastrointestinal (GI) tract. Herein, we, in our case report, emphasize the importance of considering CVID in any patient presenting with recurrent respiratory infections (maxillary sinusitis and tuberculosis, in our case), against a backdrop of noninfectious diarrhea, who progressively went on to develop CVID-related granulomatous disease (CVIDGD) and chronic liver disease. We also highlight the importance of aggressive management with replacement immunoglobulin therapy and steroids for disease control.
| Case Report|| |
A 48-year-old female, with a past history of pulmonary tuberculosis in 2001, and having completed 6 months of antitubercular treatment (ATT), presented to our hospital for the first time in 2008, with a history of recurrent episodes of small-bowel diarrhea (15–20 episodes/day without blood or mucus in stools) with associated weight loss of 20 kg over 10 months' duration. At presentation, her body mass index was 17.7 kg/m2. On evaluation, stool examination for Giardia was negative. Stool culture did not grow Salmonella More Details. Cytomegalovirus (CMV) IgG and IgM were also negative. Upper GI endoscopy and biopsy were suggestive of chronic gastritis, along with acute-on chronic duodenitis and villous atrophy. Serum IgA Tissue transglutaminase (TTG) levels were normal. Rectal biopsy was suggestive of a chronic inflammatory infiltrate in the lamina propria, with cryptitis and crypt abscess. She was provisionally managed as a case of coeliac disease with gluten-free diet with a partial response to therapy, in the form of decreased frequency of stools. However, there was no appreciable weight gain.
In December 2012, she became symptomatic with chronic cough and fever of 1-month duration. Clinical examination revealed cervical lymphadenopathy. Further evaluation in the form of noncontrast computed tomography (CT) chest revealed bronchiectasis [Figure 1]a, and the lymph node biopsy revealed follicular hyperplasia, without caseation. Mycobacterium (MTB) polymerase chain reaction (PCR) was positive. She was managed as a reactivation of pulmonary Kochs, with four-drug ATT for 6 months with symptomatic improvement. Between 2012 and 2015, she had recurrent episodes of sinusitis and lower respiratory tract infections (LRTI) requiring antibiotics.
|Figure 1: (a)Noncontrast computed tomography chest axial image showing cylindrical bronchiectatic changes in the right middle lobe and left lower lobe (black arrows)(b)Contrast-enhanced computed tomography abdomen axial image showing nodular liver surface (white arrow) with ascites, splenomegaly (bold black arrow), and enlarged portal vein (18 mm) (thin black arrow), suggestive of chronic liver disease. (c)Noncontrast computed tomography paranasal sinus showing bilateral maxillary sinusitis (white arrows)|
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In July 2015, she was again admitted with recurrent episodes of fever and was this time referred to a rheumatologist for the evaluation of pyrexia of unknown origin. In view of a history of recurrent respiratory infections, she was initially evaluated for secondary causes of immunodeficiency. Her blood sugar levels were within normal limits (fasting/postprandial – 90/124 mg/dL and glycated hemoglobin − 5.2), and human immunodeficiency virus was negative on enzyme immunoassay. Further evaluation for PID revealed reduced IgG (550 mg/dL, normal – 700–1600 mg/dL), IgM (<20 mg/dL, normal – 40–250 mg/dL), and IgA (<10 mg/dL, normal – 70–400 mg/dL). She was then diagnosed as a case of CVID and was started on intravenous immunoglobulin (IVIg) 400 mg/kg, once in 4 weeks, with effect from August 2015. With this line of management, the frequency of fever episodes, and cough, gradually reduced till 2019.
In January 2019, she once again became symptomatic with fever and cough. She also again developed increased frequency of stools. Clinical examination revealed cervical lymphadenopathy and mild ascites. She was reassessed for reactivation of Kochs. A contrast-enhanced CT of paranasal sinuses, chest, abdomen, and pelvis revealed features of chronic liver disease with portal hypertension and ascites [Figure 1]b, along with retroperitoneal, bilateral axillary and inguinal lymphadenopathy. There were also features of bilateral maxillary sinusitis [Figure 1]c and pulmonary parenchymal fibrotic changes and bronchiectasis. Fluorodeoxyglucose (FDG)-positron emission tomography (PET) whole-body scan revealed multiple FDG-avid nodules in the cervical, axillary, mediastinal, abdominal, pelvic, and inguinal regions [Figure 2], column 1]. Cervical lymph node biopsy was suggestive of chronic nonspecific lymphadenitis, with sinus hyperplasia, and ill-formed granulomas [Figure 3]a, [Figure 3]b, [Figure 3]c, [Figure 3]d. MTB PCR of lymph node biopsy was negative. Immunohistochemistry for Epstein–Barr virus latent membrane protein 1 was negative in the lymph node biopsy sample. QuantiFERON®-TB gold was negative, and serum angiotensin-converting enzyme levels and lactate dehydrogenase levels were normal. She was also assessed for a possibility of cirrhosis, and an upper GI endoscopy revealed evidence of portal hypertensive gastropathy. Viral markers for chronic liver disease in the form of hepatitis B surface antigen, anti-hepatitis C virus (HCV), and HCV RNA were negative. She was also investigated for autoimmune hepatitis, and anti-liver kidney microsome 1 antibody, anti-mitochondrial antibody, anti-smooth antibody, and anti-nuclear antibody by immunofluorescence, were all negative. Colonoscopy was normal. At this stage, her diagnosis was revised to CVID associated with CVID-related enteropathy (CVIE), CVIDGD, and chronic liver disease. The frequency of IVIg was increased to every 3 weeks. She was started on oral prednisolone, 20 mg daily, for granulomatous disease, along with hydroxychloroquine (HCQS), with steroids being tapered over the subsequent 9 months and stopped, as the lymphadenopathy and diarrhea resolved. A repeat FDG PET scan showed resolution of lymphadenopathy [Figure 2], column 2]. Presently, she remains symptom free on IVIg, 25 g once every 3 weeks, and HCQS. There has been no hospitalization in the past 6 months.
|Figure 2: Fluorodeoxyglucose positron emission tomographycomputed tomography axial section images showing axillary(3 d1 and 3d2) and retroperitoneal lymph nodes(3 a1,3 a2, 3b1,3b2,3c1,3 c2). Left column (column 1) showing pre therapy baseline scan and right column (column 2) showing posttherapy scan with decreased metabolic activity in the lymph nodes|
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|Figure 3: (a) Low-power photomicrograph of lymph node biopsy section showing thickened capsule (four-point star) and partial effacement of nodal architecture with poorly circumscribed small granulomas (blue arrows), (H and E, ×40). (b) Higher magnification of granuloma showing epithelioid histiocytes with abundant pink cytoplasm and slipper-shaped nuclei) (H and E, ×400,). (c) CD20 immunohistochemistry highlighting confluent germinal centers (four-point stars) (×100). (d) CD3 immunohistochemistry highlighting T cells in the paracortical location (blue arrows) of germinal center (four-point star) (×100)|
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| Discussion|| |
CVID is a primary disorder of the adaptive immune system, which is characterized by impaired production of immunoglobulin. It is characterized by an impaired differentiation of B cells into plasma cells and memory cells and a reduction in CD4 + T cells and T Regs, along with a decrease in the function and number of dendritic cells. It has sporadic inheritance, but in 5%–25% of patients, other family members are also affected. As it is primarily a B cell disorder, it is characterized by recurrent infections (mostly recurrent LRTI leading to bronchiectasis and recurrent paranasal sinus infections), autoimmune diseases, granulomas, and a predilection for malignancy.
CVID causes recurrent respiratory infections such as sinusitis, bronchitis, and pneumonia. Recurrent respiratory infections lead to the development of bronchiectasis which is seen in 17%–76% cases of CVID. High-resolution CT remains the main modality of diagnosis of bronchiectasis. Bronchiectasis usually affects the middle and lower lobes, and is usually bilateral. The upper lobe may be rarely affected. Patients with bronchiectasis need higher doses of IVIg replacement for response (500–600 mg/kg). Infective exacerbations have to be treated with parenteral antibiotics for a longer duration (10–14 days) to prevent relapse. Those with recurrent infections despite IVIg therapy may benefit from suppressive antibiotic therapy especially with azithromycin, given three times a week. Other useful therapies for bronchiectasis comprising bronchodilators, inhaled corticosteroids, and airway clearance techniques, may be required for optimal benefit.
Granulomatous disease is seen in 8%–22% of patients with CVID. Previously, granulomatous disease in CVID used to be interpreted as sarcoidosis. Granuloma in CVID involves many organs, with the most common site being lung. Granulomas in CVID are usually noncaseating. Other sites of granuloma formation are lymph node, spleen, skin, liver, bone marrow, kidney, and GI tract. Granuloma formation is triggered by recurrent infection. Treatment of granuloma requires immunosuppression. Steroids remain the mainstay of treatment of granuloma. If higher doses of steroids or a long duration of treatment is contemplated, additional agents such as HCQS or cyclosporine may be added as steroid-sparing agents. Hypercalcemia is a rare occurrence in granuloma associated with CVID, as compared to sarcoidosis and, if present, may respond to HCQS or steroids. Immunoglobulin replacement has little effect on granuloma. Mycophenolate mofetil can also be used in the management of granuloma, with the mechanism of action being a suppressive effect on T cells, inhibiting expression of adhesion molecules and nitric oxide production.
GI complications of CVID include both infectious and noninfectious complications. Acute or chronic infectious diarrhea is the most common complication. The most common organisms causing infective diarrhea are Giardia lamblia, followed by Campylobacter jejuni and Salmonella. Other organisms such as CMV and Clostridium difficile can also cause infective diarrhea. Recently, norovirus has also been implicated in infective diarrhea, in CVID, which can cause histopathological changes such as villous atrophy, which is reversible on treatment. Fungal infections caused by Microsporidia and Cryptosporidia can also occur in patients with greater degrees of T cell dysfunction. The incidence of Helicobacterpylori infection in CVID is same as that in the general population, but the risk of H. pylori-associated gastritis and gastric cancer is more in CVID, which might not resolve after H. pylori eradication. Chronic noninfectious enteropathy leading to chronic intermittent diarrhea, in turn leading to malabsorption, occurs in 10%–12% of CVID patients. This may resemble other chronic GI conditions such as Crohn's disease, ulcerative colitis, and coeliac disease. CVID is associated with a form of exudative enteropathy leading to depletion of immunoglobulins, thereby leading to an increased need for immunoglobulin replacement. Deficient immunoglobulins lead to chronic bacterial overgrowth (small intestinal bacterial overgrowth), villous atrophy, and inflammatory lymphocyte infiltration. Malamut et al., in a case series comprising fifty CVID patients, found 40% of patients with chronic GI symptoms. In a similar study by MaarschalkEller Broek et al., thirty patients with CVID underwent upper and lower GI endoscopy, with abnormal endoscopic findings being seen in 83% of patients, despite only 64% of patients having GIrelated symptoms. Lamina propria mononuclear cells of CVID patients produce increased amount of interleukin12 and interferongamma. Small-bowel villous atrophy is commonly associated with CVID. Coeliac disease is the first differential diagnosis considered after having ruled out infectious causes, and patients are usually initiated on a gluten-free diet. Nearly 20% of patients respond to a gluten-free diet. Immunoglobulin replacement has little role in the management of CVID-related enteropathy. Steroid remains the mainstay of treatment, and intestinal bacterial overgrowth can be managed by oral antibiotics. There is some evidence of the effectiveness of tumor necrosis factor inhibitors such as infliximab and adalimumab.
CVID is also associated with a higher incidence of liver disease. Liver disease in CVID can present with transaminitis, elevation of alkaline phosphatases, and thrombocytopenia. Almost 77% of cases are associated with abnormal liver imaging, such as heterogeneous echotexture. One of the most common radiological findings is nodular regenerative hyperplasia (NRH). A high index of suspicion is required to diagnose NRH on histopathology, even by an experienced pathologist. Presence of cirrhosis with portal hypertension in CVID is a poor prognostic marker. Theoretically, liver transplantation remains the only effective treatment of cirrhosis in CVID, however in practice, outcomes are poor due to disease recurrence. Hematopoietic stem cell transplantation (HSCT) alongside liver transplantation could be considered an option for CVID patients with liver disease as there is benefit seen in other primary immunodeficiencies. However, HSCT in CVID is associated with a significant risk of complications such as severe infections and graft versus host disease, with a mortality of 48%, and might not be a feasible treatment.
Our patient had low serum immunoglobulin levels, satisfying the European Society of Immunodeficiency criteria, for CVID; a history of recurrent upper respiratory tract infections in the form of maxillary sinusitis; and LRTI leading to bronchiectasis, requiring progressively increasing doses of immunoglobulin for infection control, which was in consonance with literature. She also had chronic noninfectious diarrhea, along with villous atrophy and crypt abscesses on rectal biopsy, with a resultant malabsorption syndrome, which was initially misinterpreted as celiac disease, in spite of having a negative IgA TTG, as described in literature. The diagnosis was later revised to CVID-related enteropathy, by the rheumatologist, and improved on management with steroids. She had features of chronic liver disease with portal hypertension, consistent with a diagnosis of CVIDrelated liver disease. She also had granulomatous lymphadenopathy with noncaseating granulomas, consistent with a diagnosis of CVIDGD, which resolved with HCQS and steroids.
| Conclusion|| |
CVID is a disease which presents with myriad manifestations, and the diagnosis is often missed in a busy clinic, due to limited time available for detailed history taking. GIT and respiratory tract are the common sites of infection. Prompt recognition and diligent treatment of infection, with timely replacement of correct dose of immunoglobulins, are the mainstays of therapy.
Written informed consent was taken from the patient.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient has given her consent for her images and other clinical information to be reported in the journal. The patient understands that her name and initial will not be published, and due efforts will be made to conceal identity, but anonymity cannot be guaranteed.
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Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3]