Managing Infection Risk in Primary Systemic Vasculitis Patients

Dr Matthew Morgan

University of Birmingham

The Problem

ANCA vasculitis causes lung and kidney damage

Treatment requires long term immunosuppression

Patient outcomes - EUVAS trials

535 patients from 4 EUVAS trials recruited 1995-2002

What are the risk factors for infection?

Direct drug side effects– Neutropenia– Steroids– Cyclophosphamide– Azathioprine/

Methotrexate/ Mycophenolate

Other factors? Lymphopenia? B-cell depletion? Hypogammaglobunaemia?

Birmingham Vasculitis Clinic Experience

– 89 PSV patients median follow up 5 years (2-22 years)

– 90% had at least 1 episode infection – 57% had severe infection requiring hospital

admission and IV antibiotics– Overall infection rate 1.5/patient/year – Severe infections 0.86/patient/year

Immunodeficiency is a risk for infection

IgG <5g/L increased risk of

All infections (p=0.03) Severe infections (p=0.01)

05

1015202530 Error bars indicate

mean95% CI

IgG

leve

l

Control group

Does vaccination improve infection risk?

92 patients in remission– Median age 51 (23-91)

On low dose/no immunosuppression

Received – Prevnar 7– Menitorix (Hib)– Men A, C, W135, Y

Antibody titres measured at weeks 0, 4, 8 &16

Serum IgG and lymphocyte subsets measured at baseline

Represents median

Vasculitis patients have low numbers of lymphocytes

Lymphocyte subset numbers in ANCA positive vasculitis patients

Ly

mp

hs

CD

3

CD

4

CD

8

CD

19

CD

16

/56

0

1000

2000

3000

Lym

ph

ocy

te n

um

ber

s ce

lls/

mm

3

Immunodeficiency 22% of patients had IgG <6.0 g/dL Correlates with

– CD19 B-cell count

(co-efficient 0.3; p=0.002)– CD4 T-Cell count

(co-efficient 0.3; p=0.005) Low IgG correlates with low anti-

Pneumococcal and Diphtheria antibodies Older age correlates with reduced CD19 and

CD4 cells

Response to Prevnar 7

Serotype

Percentage of patients with titre >0.35

P value Week 0 vs week16

Baseline Week 16

Pn4 23 46 <0.001

Pn6b 48 71 <0.001

Pn9v 55 83 <0.001

Pn14 55 74 <0.001

Pn18c 70 91 <0.001

Pn19f 59 76 <0.001

Pn23f 50 80 <0.001

Reponses to other vaccines

Patients with protective antibody titres

Vaccine Baseline Week 16Baseline vs week 16

HIb 24 26% 55 63%p<0.001

Men A 30 33% 62 71% p=0.001

Men C 8 9% 43 49% p=0.003

Men W135 2 2% 18 21% ns

Men Y 11 12% 44 51% p<0.001

Predictors of poor vaccine response

Low immune competence score predicts poor vaccine response (p=0.039)

Low IgG predicts poor vaccine response (p=0.017)

CD4 and CD19 counts do not predict response

p=0.039

Summary

Infection is a significant problem in systemic vasculitis

Low IgG is associated with increased infection

Most patients respond to vaccination Low IgG predicts a poor vaccination

response

Acknowledgements

Profs. Lorraine Harper & Mark Drayson Drs. Alex Richter, Julia Flint, Mark Cobbold Wellcome Trust Clinical Research Facility Staff Clinical Immunology – University of

Birmingham