P218
Secondary immunodeficiency is associated with increased risk of infection, poor vaccine
responses and increased mortality in anti-neutrophil cytoplasm antibody associated vasculitis
Matthew Morgan1, Alex Richter1, Julia Flint1, Constantina Yiannakis1, Mark Drayson1, David
Goldblatt2, Lorraine Harper1.
1 University of Birmingham, Birmingham, UK
2 Institute of Child Health, University College London, London, UK
Introduction: Infection is a frequent complication in anti-neutrophil cytoplasm antibody associated
vasculitis (AAV) and is associated with increased morbidity and mortality. We investigated infection
rates, infection risk factors and vaccine responses in a cohort of patients under long term follow.
Methods: Clinical data was collected retrospectively from patient records. Patients received
pneumococcal (Pn; Prevnar 7), meningococcal (Men; MenA,C,W135,Y) and Men C with
haemophilus influenza type B (Hib; menitorix) vaccines. All patients were in established clinical
remission on a maximum maintenance immunosuppression regime of prednisolone 10mg daily with
either mycophenolate mofetil or azathioprine or no maintenance therapy. No patient had received
rituximab or cyclophosphamide within 6 months. Functional antibody titres were measured at
baseline, 4, 8 and 16 weeks and two years post vaccination. Target antibody titres post vaccination
were Pn >0.35 ug/ml, Men >2 ug/ml and Hib >1 International unit (IU) /ml. Anti-PN
opsonophagocytic assay (OPA) was done at 16 weeks. All participants gave informed consent.
Infections were classified as serious if they required hospital admission for treatment.
Results: 146 patients at a median of 4 (interquartile range 4-10) years since diagnosis participated in
the study giving a total of 1103 patients follow up. Overall rates were 0.69 infections/patient/year and
0.13 severe infections/patient/year. The commonest site of infection was the lower respiratory tract
followed by the upper respiratory tract, skin, dialysis catheters and urinary tract. Increased severe
infection rates were associated with worse renal function in remission, serum immunoglobulin G
(IgG) less than 6 g/L in remission and increased cumulative steroid exposure. 92 patients in
established remission underwent peripheral blood lymphocyte phenotyping and received vaccinations
as above. In these patients severe infections were additionally associated with reduced B and CD4+ T
cell counts. Serum IgG correlated with B cell count (cc=0.33; p=0.002), and CD4 count (cc=0.3;
p=0.005). B cell count correlated negatively with cumulative cyclophosphamide (cc=-0.29; p=0.012).
CD4 count correlated negatively with age (cc=-0.35; p=0.001). eGFR correlated with both B cell
(cc=0.25; p=0.022) and T cell (cc=0.35; p=0.001) count. Continued immunosuppression was
associated with lower B cell count and CD4 T cell counts and serum IgG concentrations. Achieving
target antibody titres following vaccination was associated with higher baseline serum IgG and B cell
count. There was a trend for patients on continued immunosuppression to have worse responses to
vaccination. Maintenance of target antibody titres at 2 years post vaccination was associated with
higher baseline B cell and CD4+ T cell counts and higher serum IgG concentration. OPA showed a
significant positive correlation with most anti-PN antibody titres tested suggesting that the antibodies
produced were functional. No increase in relapse was seen post-vaccination. At the most recent follow
up (median 3.6 years post vaccination) 15 patients had died at a median of 2.1 years post vaccination.
In multivariable survival analysis poor response to vaccination was an independent risk factor for
death (hazard ratio 0.64, 95% confidence interval 0.43-0.95; p<0.05) along with reduced eGFR.
Discussion: Patients with secondary immunodeficiency are at high risk of infection and do not mount
adequate vaccine responses. Immunodeficiency and poor vaccine responses are associated with
increased mortality. Better strategies are required to reduce the incidence of secondary
immunodeficiency, risk of infection and mortality in patients with ANCA vasculitis.