Common variable immunodeficiency syndrome in an adult

Abstract

In September, 2012, a 25-year-old woman came to our emergency department with a 3 week history of diarrhoea, generalised cramping abdominal pain, and low-grade fevers associated with an unintentional 9 kg weight loss. She had a history of immune thrombocytopenic purpura not needing treatment. On examina tion, the patient had a fever of 38·2°C and palpable axillary lymphadenopathy. CT of the chest, abdomen, and pelvis showed pulmonary nodules with patchy infi ltrates bilaterally, axillary and retroperitoneal lymphadenopathy (appendix), and splenomegaly (15·3 cm). Laboratory studies showed raised white blood cell count of 1·3 × 109/L (neutrophils 0·104 × 109/L), and platelets 104 × 109/L. Lymphoma was suspected, and the patient was admitted. Cefepime was started empirically for febrile neutropenia. Blood, urine, sputum, and stool cultures were all negative. HIV antibody and PCR tests were non-reactive. Monospot test and tests for Epstein-Barr virus and cytomegalovirus were negative for acute infection. Bronchoscopy was done because of CT fi ndings. Bronchoalveolar lavage was positive for herpes simplex type one, for which the patient was treated with valacyclovir. Diarrhoea resolved within 1 week of admission, abdominal pain at 2 weeks, and fever by 3 weeks, at which point the patient was discharged. Excisional biopsy of an axillary lymph node showed atypical follicular lymphoid hyperplasia without evidence of lymphoma. In-situ hybridisation study for Epstein-Barr virus showed rare positive cells. Focally increased numbers of Langerhans cells were seen without granulomata. The CD4/CD8 T-cell ratio was decreased (0·65 [normal range 1–4]); however, no T-cell immunophenotypic aberrancy was detected. Serum immunoglobulin concentrations showed low IgG (3·49 g/L), low IgA (<0·05 g/L), and normal IgM (0·62 g/L) (normal ranges 7·16–15·5 g/L, 0·45–2·59 g/L, and 0·71–3·77 g/L respectively). The combination of hypogammaglobulinaemia, viral infection, lymphadenopathy, splenomegaly, and gastrointestinal symptoms were suggestive of common variable immunodefi ciency syndrome (CVID). Functional antibodies to tetanus, Haemophilus infl uenzae B, and pneumo coccus were negative. The patient was vaccinated against all the above and repeat serological testing 2 months later showed no response, confi rming the diagnosis of CVID. She was last seen in December, 2013, and is well on monthly intravenous immunoglobulin infusions. Intermittent abdominal pain and diarrhoea is being followed up by gastroenterology. CVID is the most common primary immunodefi ciency, occurring in about 1:25 000 white people. The diagnostic criteria include low IgG (<4 g/L) and either low IgA or IgM, age greater than 2 years, poor response to vaccines, and the absence of other causes of hypogammaglobulinaemia. Most patients are diagnosed in adulthood (20–49 years), although there is usually a 6-year delay in diagnosis because of variation in symptoms. Infections are typically sinopulmonary with an overrepresentation for encapsulated or atypical organisms. 25% of patients have autoimmune conditions, with immune thrombocytopenia and autoimmune haemolytic anaemia being the most common. The main defect is a failure of B-cell diff erentiation into memory B cells and plasma cells. 50% of patients have reduced B-cell counts. Diminished antibody production results in increased susceptibility to recurrent bacterial infections. Intravenous immunoglobulin replacement reduces the frequency of recurrent bacterial infections, but does not prevent the development of chronic lung disease, granulomatous diseases, or malignancy. Half of CVID patients also have T-cell lymphocyte abnormalities leading to disseminated fungal and viral infections, in particular with the herpes viridae. Patients have reduced CD4 counts and regulatory T cells. By contrast, there is an expansion in the CD8 numbers leading to an inverted CD4/CD8 ratio. IVIg also provides suffi cient herpes simplex virus-specifi c IgG to neutralise or opsonise the virus. No established role of antimicrobial prophylaxis exists, but the annual infl uenza vaccine (inactivated) is recommended. CVID patients are at increased risk of developing cancer; however there are no current screening guidelines. This case is a reminder that CVID is not exclusively a paediatric disorder and should be included in the diff erential diagnosis of adults presenting with hypogammaglobulinaemia and recurrent or atypical infections, with or without diff use lymphadenopathy.