Common variable immunodeficiency: an update

Abstract

Common variable immunodeficiency (CVID) describes a heterogeneous subset of hypogammaglobulinemias of unknown etiology. Typically, patients present with recurrent bacterial infections of the respiratory and gastrointestinal tract. A significant proportion of CVID patients develops additional autoimmune, inflammatory or lymphoproliferative complications. CVID is the most frequent symptomatic primary immunodeficiency encountered in adults. Informative monogenetic defects have been found in single patients and families but in most cases the pathogenesis is still elusive. Numerous immunological studies have demonstrated phenotypic and functional abnormalities of T cells, B cells and antigen-presenting cells. A hallmark is the impaired memory B-cell formation that has been taken advantage of for classifying CVID patients. Clinical multi-center studies have demonstrated a correlation between immunological markers and clinical presentation. Long-term outcome is significantly influenced by delay of diagnosis and treatment and the presence of chronic inflammatory complications. While immunoglobulin replacement therapy plus antibiotics can control infections in most cases, patients with non-infectious inflammatory complications such as granulomatous inflammation, interstitial lung disease, inflammatory bowel disease, lymphoproliferation and developing malignancies still represent a therapeutic challenge. In this review we provide a systematic overview of the immunological, clinical, diagnostic and therapeutic aspects of CVID and highlight recent developments in these fields.

Figure 1

Oligoarthritis due to Mycoplasma salivarius as an early manifestation of common variable immunodeficiency. A male aged 36 years was healthy until he developed recurrent upper respiratory tract infections and a first bout of pneumonia 18 months prior to these images being taken. Five months later he presented with refractory right-sided gonarthritis to an orthopedic surgeon. Despite multiple sterile knee taps, arthroscopy and a Baker cyst resection, joint inflammation continued and extended to the right shoulder and the right ankle. He was referred to the Division of Rheumatology and Clinical Immunology at Freiburg University Hospital for further diagnosis and treatment of 'multifocal osteomyelitis and oligoarthritis of unknown origin'. On admission he presented with three tender and swollen joints (right knee, shoulder, ankle), moderately elevated C-reactive protein (CRP) levels (5 to 29 mg/dl) and severe hypogammaglobulinemia: IgG 1.7 g/L, IgA <0.6 g/L, IgM <0.3 g/L. Diagnosis of CVID was established and the patient was started on monthly intravenous immunoglobulin infusions (500 mg/kg) plus various ineffective antibiotic regimens (initially cefuroxime plus neomycin, then clarithromycin and metronidazol). A diagnostic puncture of the right shoulder eventually revealed Mycoplasma salivarius by multiplex PCR diagnostics. From that point on the patient was put on doxicycline (200 mg/daily orally) and the inflammatory process rapidly improved. Doxicycline was stopped after 4 weeks, whereas monthly intravenous immunoglobulin was continued. As of today, the patient has been back to work for 7 years and is clinically doing well. Magnetic resonance imaging follow-up (T2, TIRM sequences of the right knee) and laboratory parameters at three time points (A, B, C) nicely show the improvement of the severe arthritis and osteomyelitis of the right knee.