Infections and immune factors in Guillain-Barré syndrome. 18 September 2000. Manuscript # 2000-00927 RDM Hadden et al. 1Supplemental data for www.neurology.org
Preceding infections, immune factors and outcome in Guillain-Barré syndrome
R.D.M. Hadden, MRCP,*1,2 H. Karch, PhD,3 H.-P. Hartung, MD,4,2 J. Zielasek, MD,2
B. Weißbrich, MD,5 J. Schubert, MD,5 A. Weishaupt, PhD,2 D.R. Cornblath, MD,6 A.V.
Swan, PhD,7 R.A.C. Hughes, FRCP,1 K.V. Toyka, MD,2 and the Plasma
Exchange/Sandoglobulin Guillain-Barré Syndrome Trial Group.
*1Department of Neuroimmunology, Guy’s King’s and St Thomas’ School of Medicine,
Hodgkin Building, Guy’s Hospital, St Thomas’ St, London SE1 9RT, UK.
Tel +44 20 7848 6122. Fax +44 20 7848 6123. [email protected] 2Department of Neurology, Julius Maximilians University, Würzburg, Germany. 3Institute for Hygiene and Microbiology, Julius Maximilians University, Würzburg,
Germany. 4Department of Neurology, Karl Franzens University, Graz, Austria. 5Institute for Virology and Immunobiology, Julius Maximilians University, Würzburg,
Germany.6Department of Neurology, Johns Hopkins University, Baltimore, MD, USA. 7Statistics Unit, Public Health Laboratory Service, London, UK.
*Corresponding author: Dr RDM Hadden, London. [email protected]
Infections and immune factors in Guillain-Barré syndrome. 18 September 2000. Manuscript # 2000-00927 RDM Hadden et al. 2Supplemental data for www.neurology.org
Table (T) E-1.
Preceding infections and neurophysiological type
Most patients had no identified preceding infection. Axonal neurophysiology and inexcitable nerves were relatively more common in
patients with C. jejuni infection, but most patients with C. jejuni infection had demyelinating neurophysiology.
GBS preceded by n (%) Demyelinating (%) Axonal (%) Inexcitable (%) Normal (%) Equivocal (%)
No identified infectiona 155 (68) 103a (66) 1 (1) 2 (1) 7 (5) 42 (27)
C. jejuni onlyb 52 (23) 29 (56) 5 (10)b 4 (8)b 0 14 (27)
Cytomegalovirus only 17 (7) 13 (77) 0 0 0 4 (24)
Epstein-Barr virus only 3 (1) 2 (67) 0 0 1 (33) 0
Two infections 2 (1) 1 (50) 0 1 (50) 0 0
Total 229 148 (65) 6 (3) 7 (3) 8 (3) 60 (26)
a Includes one patient with indeterminate CMV status.
bC. jejuni only vs. no infection: p=0.004 for axonal group, p=0.04 for inexcitable group
Infections and immune factors in Guillain-Barré syndrome. 18 September 2000. Manuscript # 2000-00927 RDM Hadden et al. 3Supplemental data for www.neurology.org
Table (T) E-2.
Preceding infections and raiseda pre-treatment serum concentrations of
adhesion molecules and sIL-2R.
Patients with CMV infection were more likely to have raised concentrations of these four
molecules, which are important in T cell activation and migration. Patients with C. jejuni
infection had similar concentrations to those with no identified infection.
GBS preceded by n sICAM-1
(%)
sVCAM-1
(%)
sL-selectin (%) sIL-2R
(%)
No infectionb 155 16 (10) 75 (49) 96 (62) 65 (42)
C. jejuni onlyc 52 8 (15) 27 (52) 31 (60) 29 (56)
CMV only 17 10 (59) 14 (82) 16 (94) 12 (71)
EBV only 3 1 (33) 3 (100) 3 (100) 2 (67)
Two infections 2 2 (100) 2 (100) 2 (100) 2 (100)
Total 229 37 (16) 121 (53) 148 (65) 110 (48)
p CMV vs. no infection <0.001 0.02 0.02 0.05
a Number (%) of patients with serum concentrations above the upper limit of normal
b Includes one patient with indeterminate CMV status with raised concentrations of sIL-2R
and sL-selectin.
cC. jejuni vs. no infection: not significant.
Infections and immune factors in Guillain-Barré syndrome. 18 September 2000. Manuscript # 2000-00927 RDM Hadden et al. 4Supplemental data for www.neurology.org
Table (T) E-3.
Preceding infections and mean (± SE) pre-treatment serum concentrations
(ng/ml) of adhesion molecules and sIL-2R.
This table shows the same relationships as the previous table, but gives the mean
concentrations instead of the proportions with raised concentrations. This data is shown
pictorially in figure 1. Patients with CMV infection had greater mean concentrations than
those with no infection. The three patients with EBV infection also had high concentrations
(not significant because of small numbers).
GBS preceded by n sICAM-1 sVCAM-1 sL-selectin sIL-2R
No infection 154 250 ±11 817 ±35 2050 ±116 4.5 ±0.2
C. jejuni only 52 293 ±26 980 ±101 2203 ±223 4.6 ±0.3
CMV only 17 603 ±78 1544 ±243 4383 ±466 6.8 ±1.5
EBV only 3 616 ±337 2633 ±1990 12713 ±6410 9.5 ±4.1
Two infections 2 744 ±105 2607 ±737 4093 ±1512 8.8 ±1.5
p ANOVA (all groups) <0.001 <0.001 <0.001 0.002
p CMV vs. no infection <0.001 0.009 <0.001 0.1
n (%)= number (%) of patients with serum concentrations above the upper limit of normal
One additional patient with indeterminate CMV status had raised levels of sIL-2R and sL-
selectin.
Infections and immune factors in Guillain-Barré syndrome. 18 September 2000. Manuscript # 2000-00927 RDM Hadden et al. 5Supplemental data for www.neurology.org
Table (T) E-4.
Mean (±SE) serum concentrations of cytokine receptors and sICAM-1 in
neurophysiological groups.
Patients with inexcitable nerves had the greatest mean concentrations of these molecules
associated with inflammation. This data is shown pictorially in figure 2. It is surprising that
patients with normal neurophysiology also had high concentrations of sICAM-1 and sIL-2R.
n sICAM-1 sTNF-R sIL-2R
Demyelinating 148 275 ±15 3.3 ±0.2 4.4 ±0.2
Axonal 6 245 ±36 2.4 ±0.5 4.4 ±0.6
Inexcitable 7 501 ±126 6.3 ±1.6 6.5a ±1.2
Normal 8 468 ±125 2.7 ±0.4 5.8 ±1.7
Equivocal 60 303 ±28 3.4 ±0.3 5.4 ±0.6
p ANOVA (all groups) 0.005 0.007 0.2
a sIL-2R: inexcitable vs. demyelinating (t-test): p=0.02
Infections and immune factors in Guillain-Barré syndrome. 18 September 2000. Manuscript # 2000-00927 RDM Hadden et al. 6Supplemental data for www.neurology.org
Table (T) E-5.
Proportion of GBS patients with recent Campylobacter jejuni infection in
each country.
C. jejuni was particularly frequent in Portuguese patients with GBS. The proportions of GBS
patients with C. jejuni infection were not significantly different between Europe and North
America.
Country n C. jejuni
infection
(%)
Belgium 16 6 (38)
Canada 49 9 (18)
Germany 44 12 (27)
Italy 4 2 (50)
Norway 4 0 (0)
Portugal 8 7 (88)
Switzerland 2 0 (0)
UK 77 14 (18)
USA 25 3 (12)
Total 229 53 (23)
Infections and immune factors in Guillain-Barré syndrome. 18 September 2000. Manuscript # 2000-00927 RDM Hadden et al. 7Supplemental data for www.neurology.org
Table (T) E-6.
Association of IgA Western blot antibodies to C. jejuni outer membrane proteins with neurophysiological type and IgA antibodies to ganglioside GM1.
This table and the following take four features associated with C. jejuni infection (i.e. axonal neurophysiology, anti-GM1 antibodies, pure motor GBS and poor outcome) and show whether these are particularly associated with antibodies to individual outer membrane proteins of two strains of C. jejuni. The 28, 29, 30, 31kD proteins are the PEB 1, 3, 2 and 4 molecules (probably involved in adhesion or transport), 42kD is porin (the major outer membrane protein), 55kD is flagellin and 70kD is a heat shock protein.All values shown are the percentages of each column group which had IgA antibodies to C. jejuni outer membrane proteins (e.g. of six patients with axonal neurophysiology, 50% had antibodies to a 28kD protein). However, the bottom row shows that the associations with overall C. jejuni infection (defined by ELISA/diarrhea) were stronger than those with any individual protein.
Strain, Protein kD
Axonal
n=6
Demyelin-ating
n=148
p GM1 IgA positive
n=33
GM1 IgA negativen=196
p
ATCC 4344628 50 10 0.02* 39 7 <0.001***29 33 6 0.06 27 3 <0.001***30 67 12 0.003** 46 8 <0.001***31 33 6 0.06 30 4 <0.001***42 67 51 0.7 82 46 <0.001***50 0 1 0 155 0 0 0 070 33 10 0.1 33 7 <0.001***92 17 2 0.2 3 2 1.0
LIO1128 50 9 0.02* 42 6 <0.001***29 33 5 0.05* 27 2 <0.001***30 50 15 0.06 49 10 <0.001***31 33 8 0.1 30 5 <0.001***42 67 47 0.4 91 40 <0.001***50 0 1 0 155 100 38 0.004** 82 30 <0.001***70 33 9 0.1 27 8 0.003**92 17 2 0.1 9 1 0.02*
Overall C. jejuni infection
83 20 0.002** 73 14 <0.001***
*,**,***= p<0.05, <0.01, <0.001: chi-squared or Fisher’s exact test.
Infections and immune factors in Guillain-Barré syndrome. 18 September 2000. Manuscript # 2000-00927 RDM Hadden et al. 8Supplemental data for www.neurology.org
Table (T) E-7.Association of Western blot antibodies to C. jejuni outer membrane proteins
with pure motor GBS or outcome.
All values shown are the percentages of each column group which had IgA antibodies to C.
jejuni outer membrane proteins (e.g. of 38 patients with pure motor GBS, 18% had
antibodies to a 28kD protein). However, the bottom row shows that the associations with
overall C. jejuni infection (defined by ELISA/diarrhea) were stronger than those with any
individual protein.
Strain, Protein kD
Pure motor GBSn=38
Motor-sensory
GBS n=161
p Poor outcome n=35
Able to walk at
48 weeks n=194
p
ATCC 4344628 18 10 0.1 26 9 0.008**29 13 5 0.1 23 4 <0.001***30 29 10 0.005** 31 10 0.002**31 16 6 0.04* 23 5 0.001***42 71 47 0.01** 63 50 0.250 0 1 3 1 0.355 0 0 0 070 16 12 0.3 14 10 0.692 3 2 0.6 0 2
LIO1128 21 9 0.04* 23 9 0.03*29 11 4 0.2 20 3 <0.001***30 32 12 0.008** 34 12 0.002**31 13 8 0.3 20 6 0.01**42 63 45 0.06 63 45 0.0850 3 0 0 1 1.055 61 34 0.005** 63 33 0.002**70 21 10 0.1 11 10 0.892 5 2 0.2 3 2 0.6
Overall C. jejuni infection
46 19 0.001*** 51 18 <0.001**
*,**,***= p<0.05, <0.01, <0.001: chi-squared or Fisher’s exact test.
Infections and immune factors in Guillain-Barré syndrome. 18 September 2000. Manuscript # 2000-00927 RDM Hadden et al. 9Supplemental data for www.neurology.org
Table (T) E-8.
Combinations of classes of antibodies to ganglioside GM1.
Antibodies to ganglioside GM1 of any class were detected in 89 patients (37%). Most
patients with IgA antibodies also had IgG antibodies, whereas most patients with IgM
antibodies did not have IgA or IgG antibodies.
Class of antibodies to
ganglioside GM1
n (%)
None 152 (63)
IgM alone 25 (10)
IgG alone 20 (8)
IgA alone 7 (3)
Both IgM + IgG 8 (3)
Both IgM + IgA 3 (1)
Both IgG + IgA 14 (6)
IgG + IgM + IgA 12 (5)
Total 241
Infections and immune factors in Guillain-Barré syndrome. 18 September 2000. Manuscript # 2000-00927 RDM Hadden et al. 10Supplemental data for www.neurology.org
Table (T) E-9.
Mean (±SE) cytokine receptor and adhesion molecule concentrations
before and after treatment.
Mean concentrations of sL-selectin fell following any treatment but more so after PE,
whereas concentrations of sVCAM-1 increased following any treatment but more so after
IVIg. Concentrations of sTNF-R increased similarly after any treatment.
Treatment ng/ml sL-selectin sVCAM-1 sTNF-R
IVIg Before 2466 ±220 912 ±61 3.6 ±0.3
n=66 After 2119 ±197 1321 ±77 4.5 ±0.9
% change -14* +45*** +25 NS
PE + IVIg Before 2562 ±408 977 ±102 3.3 ±0.3
n=65 After 1354 ±151 1630 ±138 4.1 ±0.4
% change -47*** +67*** +24**
PE Before 2193 ±193 901 ±81 3.1 ±.03
n=66 After 1373 ±103 1026 ±82 4.0 ±0.3
% change -37*** +14* +29***
Paired t-test: * p<0.05, ** p<0.01, *** p<0.0001
Infections and immune factors in Guillain-Barré syndrome. 18 September 2000. Manuscript # 2000-00927 RDM Hadden et al. 11Supplemental data for www.neurology.org
Table (T) E-10.
Prevalence of antiganglioside GM1 antibodies before and after treatment
The proportion of patients with IgM antibodies to ganglioside GM1 fell after treatment with
plasma exchange (with or without additional IVIg), but not after IVIg alone. The proportions
with IgG and IgA antibodies were not significantly affected by any treatment.
Treatment n IgG (%) IgM (%) IgA (%)
IVIg 66 Before 18 (27) 11 (17) 13 (20)
After 18 (27) 12 (18) 12 (18)
PE & IVIg 65 Before 14 (22) 14 (22) 8 (12)
After 13 (20) 6a (9) 5 (8)
PE 66 Before 14 (21) 15 (23) 10 (15)
After 8 (12) 5b (8) 7 (11)
aMcNemar’s test: p=0.04
bMcNemar’s test: p=0.002
Others not significant
Infections and immune factors in Guillain-Barré syndrome. 18 September 2000. Manuscript # 2000-00927 RDM Hadden et al. 12Supplemental data for www.neurology.org
Table (T) E-11. Subgroups in which outcome was affected by treatment type
After extensive searching, these were the only two subgroups in which outcome was significantly affected by treatment type. Patients
with pure motor GBS tended to have a better outcome after IVIg than PE, whereas patients with IgM antibodies to ganglioside GM1
tended to have a better outcome after PE than IVIg. In both subgroups, treatment with combined PE and IVIg gave the best outcome, but
there was no significant difference in paired comparisons between IVIg alone and PE alone. Results are barely significant and should be
interpreted with caution.
IVIg Both
PE & IVIg
PE p across three
treatments
p between two treatments
Pure motor GBS
poor outcome: n (%) 4/21 (19%) 2/22 (9%) 5/10a (50%) 0.03 0.03 (PE v both), 0.2 (IVIg v PE)
days (CI) until walkingc 41 (6-76) 24 (13-35) 220b 0.06 0.02 (Both v PE), 0.06 (IVIg v PE)
Motor and sensory GBS
poor outcome: n (%) 11/81 (14%) 12/83 (15%) 10/88 (11%) 0.8
IgM antibodies to ganglioside GM1
poor outcome: n (%) 3/13 (23%) 0/18 (0%) 1/16 (6%) 0.07
days (CI) until walkingc 57 (50-64) 17 (15-19) 41 (0-94) 0.02 0.01 (IVIg v both) , 0.04 (PE v both)aNote the small number of pure motor patients randomized to PE which may bias this comparison.bConfidence interval not calculable because half of these patients never walked within the follow up period of 336 days.cmedian (95% CI) days from randomization until first able to walk unaided.
IVIg = intravenous immunoglobulin, PE = plasma exchange
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