Clinical Presentation of Common Variable Immunodeficiency
Infections
Over 90% of CVID patients suffer from an increased susceptibility to bacterial pathogens affecting mucous membranes of the upper and lower airways and, to a lesser extent, of the gastrointestinal tract. Table 3 summarizes frequencies of specific infections and pathogens encountered in two consecutive studies on the Mount Sinai Hospital CVID cohort in New York and the French DEFI cohort study. In the DEFI cohort study, approximately two-thirds of the 252 patients presented with sinusitis or bronchitis and 50% had at least one bout of pneumonia during their life. About one-third of patients had developed bronchiectasis as a result of chronic and recurrent infections. Frequently detected pathogens were Streptococcus pneumoniae, Haemophilus influenzae, Staphylococcus aureus and Moraxella catharralis. Recurrent and chronic diarrhea was present in approximately 40% of patients and in about half of them pathogens like Giardia lamblia followed by Salmonella and Campylobacter jejuni were identified. Acute and chronic gastritis caused by Helicobacter pylori is frequently diagnosed in CVID patients. Up to 10% of CVID patients are described as suffering from increased rates of Herpes zoster infections. In contrast, typical opportunistic infections are quite unusual and evoke the possibility of an underlying combined immunodeficiency. A rare but typical complication of hypogammaglobulinemia is oligoarthritis due to Mycoplasma species (Figure 1). Clinically, the condition presents as reactive arthritis with synovial culture techniques being often negative; therefore, the microbiological diagnosis has to include multipathogen PCR in synovial fluid. In the differential diagnosis of hypogammaglobulinemic oligoarthritis, serological investigations are not helpful since most patients do not exhibit an adequate antibody response against the respective pathogens or the test results are influenced by intravenous immunoglobulin substitution therapy. In patients with suspected reactive arthritis, therefore, we recommend to initially determine IgG and IgA serum concentrations before proceeding to extensive and potentially meaningless antibacterial antibody responses.
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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.
Granulomatous Lesions
Approximately 10 to 20% of CVID patients develop granulomatous interstitial lung disease. Microbial testing of these lesions often reveals no specific pathogen; the reported detection of human herpes virus-8 in a US CVID cohort could not be confirmed in larger European patient groups (unpublished data), indicating that the underlying cause remains unknown and probably is multifactorial. Patients with granulomatous interstitial lung disease have a significantly poorer prognosis than other CVID patients. The granulomatous disease to some extent resembles sarcoidosis; in addition to lung and lymph nodes, also the liver, skin, spleen, bone marrow, gastrointestinal tract, brain and kidney (in decreasing frequency) may be affected.
Gastrointestinal Symptoms
Diarrhea is un-bloody if associated with a sprue-like disease and bloody when resulting from chronic inflammatory bowel disease. The sprue-like villous atrophy seen in CVID is often not gluten-sensitive and resembles more autoimmune enteropathy. The involvement of the colon in CVID is reminiscent of Crohn's disease and ulcerative colitis, but can be distinguished histologically. The nodular lymphoid hyperplasia that may occur both in the duodenum and ileum may be asymptomatic or associated with unformed stools.
Liver disease and abnormal liver function tests are found in 10% of CVID patients. The most common liver disease in CVID represents nodular regenerative hyperplasia of the liver tissue or seronegative, granulomatous hepatitis; autoimmune hepatitis is not a typical entity found in these patients. Usually, liver function in CVID patients is still preserved but portal hypertension may develop. Liver disease heralds a poorer prognosis. In any case of a suspected hepatopathy in CVID, seronegative hepatitis B and C as well as cytomegalovirus or Epstein Barr virus hepatitis must be ruled out by searching for hepatitis antigen or viral RNA, respectively.
Autoimmunity
Autoimmunity is present in about 30% of CVID patients. Table 4 summarizes frequencies of autoimmune disease encountered in two consecutive studies on the Mount Sinai Hospital CVID cohort in New York and the French DEFI cohort study.
Particularly common are autoimmune thrombocytopenia (10 to 12%) and autoimmune hemolytic anemia (5 to 7%), showing a significant correlation with splenomegaly. Cytopenias can manifest before, simultaneously with or after the diagnosis of immunodeficiency. Immunologically, autoimmune cytopenias are associated with low numbers of class-switched memory B cells, low numbers of regulatory T cells, expanded CD21 B cells, and nodular T-cell infiltrates of the bone marrow. Autoimmune thyroid disease, vitiligo, pernicious anemia, psoriasis, rheumatoid arthritis and systemic lupus erythematosus are observed in CVID cohorts at decreasing frequency (Table 4).
Lymphoproliferation and Malignancies
Benign lymphoproliferation is found in 40 to 50% of CVID patients, often as splenomegaly, and in approximately 10 to 20% as local or diffuse lymphadenopathy. Histologically, several subsets can be distinguished, with follicular hyperplasia and granulomatous inflammation being the most common ones. In conjunction with lymphoproliferation, CVID patients carry an increased risk of developing lymphoma. Most lymphomas are of the B-cell non-Hodgkin lymphoma type. In addition to lymphomas, stomach cancers represent an important malignant manifestation in CVID. The increased risk of cancer in CVID may result from impaired immunity to potentially carcinogenic pathogens (for example , Helicobacter pylori, Epstein-Barr virus) or impaired tumor cell surveillance. In this context it is notable that patients of a CVID subgroup exhibit increased radiosensitivity, known to be a risk factor for increased tumor incidence.