CT screening for pulmonary pathology in common variable immunodeficiency disorders and the correlation with clinical and immunological parameters.

BACKGROUND: Pulmonary disease is common in patients with common variable immunodeficiency disorders (CVID) and involves infections, chronic airway disease and interstitial lung disease. Chronic pulmonary disease is associated with excess morbidity and early mortality and therefore early detection and monitoring of progression is essential. METHODS AND PURPOSE: Thin slice CT scan and pulmonary function were used to determine the prevalence and spectrum of chronic (pre-clinical) pulmonary disease in adult CVID patients regardless of symptoms. CT Scans were scored for airway abnormalities (AD) and interstitial lung disease (ILD). Other CVID related complications and B and T lymphocyte subsets were analyzed to identify patients at risk for pulmonary disease. RESULTS: Significant pulmonary abnormalities were detected in 24 of the 47 patients (51%) consisting of AD in 30% and ILD in 34% of cases. In only 7 (29%) of these 24 patients pulmonary function test proved abnormal. The presence of AD was correlated to (recurrent) lower respiratory tract infections despite IgG therapy. The presence of ILD was correlated to autoimmune disease and a reduction in the numbers of CD4 + T cells, naïve CD4 + T cells, naïve CD8 + T cells and memory B cells and lower IgG through levels over time. CONCLUSION: Preclinical signs of AD and ILD are common in CVID patients despite Ig therapy and do not correlate to pulmonary function testing. Patients at risk for ILD might be identified by the presence of autoimmunity or a deranged T cell pattern. Larger studies are needed to confirm these findings and to determine thresholds for the T lymphocyte subsets.

Outcome of screening endoscopy in common variable immunodeficiency disorder and X-linked agammaglobulinemia.

Gastrointestinal symptoms are common in patients with common variable immunodeficiency disorders (CVID) and less frequent in X-linked agammaglobulinemia (XLA) although the exact prevalence is not well established. In this study, endoscopic screening was performed in 30 patients with CVID and four patients with XLA. Endoscopic and/or histological abnormalities were detected in 25 of 30 patients with CVID (83 %), regardless of symptoms, and in nine of these patients the results prompted medical treatment. Helicobacter pylori-associated gastritis, adenomatous polyps, and lymphoid hyperplasia were most frequently encountered; no malignancies were detected. Adenomatous polyps were found in two of the four patients with XLA at a relative young age. In conclusion, gastrointestinal pathology is frequent in patients with CVID regardless of symptoms. Patients with XLA seem to be at risk for colorectal adenomas at a young age.

The spectrum of disease manifestations in patients with common variable immunodeficiency disorders and partial antibody deficiency in a university hospital.

BACKGROUND: Common variable immunodeficiency disorders (CVIDs) represents a heterogeneous disease spectrum that includes recurrent infections and complications such as autoimmunity, inflammatory organ disease and an increased risk of cancer. A diagnostic delay is common in CVIDs patients. PURPOSE: To determine the spectrum of clinical manifestations, immunological characteristics, and the time to diagnosis of 61 adult CVIDs and 18 patients with a partial antibody deficiency (SADNI and IgG subclass deficiency). METHODS: A retrospective cohort study was performed in patients who met the ESID/PAGID for CVIDs, IgG subclass deficiency and SADNI. Medical records were reviewed to obtain patient demographics, clinical and laboratory data. RESULTS: Infections were the main presentation of all antibody deficient patients and the number of patients with infections declined during IgG therapy. The development of bronchiectasis continued despite IgG therapy, as well as the development of autoinflammatory conditions. Non-infectious disease complications were present in 30% of CVIDs patients at the time of diagnosis and this increased to 51% during follow up despite IgG therapy. The most common complications were autoimmunity or lymphoproliferative disease. The median time to diagnosis was 10 years and in the patients with non-infectious complications the time to diagnosis was considerably longer when compared to the group of patients without complications (17.6 vs. 10.2 years, p = 0.026). CONCLUSION: In contrast to the partial antibody deficiencies we found a considerable delay in the diagnosis of CVIDs, especially in those patients who were dominated by non-infectious complications, and thus increased awareness would be beneficial. Pulmonary and other complications may continue despite adequate IgG replacement therapy suggesting other causes responsible for these complications.

T-cell response to viral antigens in adults and children with common variable immunodeficiency and specific antibody deficiency.

Several T cell abnormalities have been described in common variable immunodeficiency (CVID), a B cell disorder of mainly unknown origin. A subset of CVID patients suffers from frequent reactivations of herpes viruses. We studied T cell function in CVID [and in a subset of paediatric patients with specific antibody deficiency (SAD)] by measuring T cell proliferation and cytokine production in response to herpes virus-antigens in paediatric CVID patients (n=9) and paediatric SAD patients (n=5), in adult CVID patients (n=14) and in healthy controls. Paediatric CVID patients, but not SAD patients, displayed moderately increased CD8+ T cell proliferation in response to cytomegalovirus, human herpes virus type 6B (HHV6-B) and herpes simplex virus compared to controls. CD8+ T cell responses in adult CVID patients tended to be increased in response to cytomegalovirus and herpes simplex virus. In response to stimulation with herpes virus antigens, the proinflammatory cytokines interleukin (IL)-1beta, IL-6, tumour necrosis factor (TNF)-alpha and interferon inducible protein (IP)-10 were produced. Overall, no major differences were detected in cytokine production upon stimulation between patients and controls, although higher IL-10 and IL-12 production was detected in paediatric patients. In conclusion, cellular immunity against herpes virus antigens appears undisturbed in CVID patients, although defects in subpopulations of CVID patients cannot be excluded.

Immunoglobulin treatment in primary antibody deficiency.

The primary antibody deficiency syndromes are characterised by recurrent respiratory tract infections and the inability to produce effective immunoglobulin (Ig) responses. The best-known primary antibody deficiencies are common variable immunodeficiency (CVID), X-linked agammaglobulinaemia (XLA), immunoglobulin G (IgG) subclass deficiency, and selective antibody deficiency with normal immunoglobulins (SADNI). Therapy in these patients consists of prophylactic antibiotics and/or Ig replacement therapy. Diagnostic delay remains common owing to limited awareness of the presenting features and may result in increased morbidity and mortality. Replacement therapy with immunoglobulins increases life expectancy and reduces the frequency and severity of infections, but the effect on end-organ damage is still unknown. Both intravenous immunoglobulin (IVIg) and subcutaneous immunoglobulin (SCIg) treatment appear to be safe, with comparable efficacy. A starting dose of 300-400 mg/kg/month in IVIg and 100 mg/week for SCIg is recommended. IgG trough levels should be >5 g/L for patients with agammaglobulinaemia and 3 g/L greater than the initial IgG level for patients with CVID; however, the clinical response should be foremost in choosing the dose and trough level. Infusion-related adverse reactions are generally mild owing to improved manufacturing processes. In this paper, aspects of Ig replacement therapy in primary antibody-deficient patients will be addressed.