Lessons Learned From the Clinical Presentation of Common Variable Immunodeficiency Disorders: A Systematic Review and Meta-Analysis

Abstract

BackgroundDiagnostic delay in common variable immunodeficiency disorders (CVID) is considerable. There is no generally accepted symptom-recognition framework for its early detection.ObjectiveTo systematically review all existing data on the clinical presentation of CVID.MethodsPubMed, EMBASE and Cochrane were searched for cohort studies, published January/1999-December/2019, detailing the clinical manifestations before, at and after the CVID-diagnosis.ResultsIn 51 studies (n=8521 patients) 134 presenting and 270 total clinical manifestations were identified. Recurrent upper and/or lower respiratory infections were present at diagnosis in 75%. Many patients had suffered severe bacterial infections (osteomyelitis 4%, meningitis 6%, septicemia 8%, mastoiditis 8%). Bronchiectasis (28%), lymphadenopathy (27%), splenomegaly (13%), inflammatory bowel disease (11%), autoimmune cytopenia (10%) and idiopathic thrombocytopenia (6%) were also frequently reported. A bimodal sex distribution was found, with male predominance in children (62%) and female predominance in adults (58%). 25% of CVID-patients developed other manifestations besides infections in childhood, this percentage was much higher in adults (62%). Immune-dysregulation features, such as granulomatous-lymphocytic interstitial lung disease and inflammatory bowel disease, were more prominent in adults.ConclusionsThe shift from male predominance in childhood to female predominance in adults suggests differences in genetic and environmental etiology in CVID and has consequences for pathophysiologic studies. We confirm the high frequency of respiratory infections at presentation, but also show a high incidence of severe bacterial infections such as sepsis and meningitis, and immune dysregulation features including lymphoproliferative, gastrointestinal and autoimmune manifestations. Early detection of CVID may be improved by screening for antibody deficiency in patients with these manifestations.

Spectrum of Disease Manifestations in Patients with Selective Immunoglobulin E Deficiency

“…It is generally accepted that low levels of IgA, IgM, and IgG predispose to respiratory bacterial and viral infections. The high incidence of URI and pneumonia in our patients with SIgED is in keeping with that reported for CVID [ 8 , 9 , 29 ], SIgGD [ 8 ], IgGSD [ 9 , 10 ], SIgAD [ 11 , 12 ], and SIgMD [ 13 , 14 ]. The mechanism by which an SIgED may also predispose to lung infections remains to be elucidated.…”

“…It is generally assumed that in CVID patients, recurrent airway infections and persistent airway inflammation can lead to a vicious circle airway remodeling process resulting in bronchiectasis [ 43 ]. A recent analysis of existing data on the clinical presentation of CVID found that bronchiectasis was present in the CT scan in almost one-third of patients (28%, 95% CI 18–40) [ 29 ]. Bronchiectasis has been found in up to 14% of SIgAD patients and is more commonly reported when associated with IgG subclass deficiency [ 44 , 45 , 46 ].…”

“…Viral infections are a strong risk factor for developing asthma in children, and they are major contributors to exacerbations of asthma in both children and adults [ 47 ]. The link between viruses and upper (rhinitis) and lower respiratory diseases (asthma) might explain the high percentage of patients with CVID that are diagnosed with asthma (25%, 95% CI 17–35) and rhinitis (18%, 95% CI 8–31) [ 29 ]. What is not yet clear is the mechanism underlying this association.…”

“…CVID patients with asthma and rhinitis are often clinically characterized as allergic [ 29 , 43 ]. Interestingly, some of our patients reported nasal and bronchial allergic-like reactions—a few of the associated with seasonal exacerbations.…”

“…A substantial number of CVID patients (27%, 95% CI 22–32%) develop autoimmune manifestations [ 29 ]. Studies have shown that SIgGD [ 9 , 12 ] SIgMD [ 13 , 45 , 69 ], IgGSD [ 56 ], and SIgAD [ 11 , 12 , 44 , 55 ] are also associated with systemic and organ-specific autoimmune diseases.…”