DTIC ADA271882: Role of Infection Due to Campylobacter jejuni in the Initiation of Guillain-Barre Syndrome

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22 December 1992 Reprint
Role of Infection Due to Campylobacter Jejuni Army Project Order
in the Initiation of Guillain-Barre Syndrome 90PP0820
Ban Mishu and Martin J. Blaser
93-26165
Veterans Administration Medical Center
Research Service
1310 24th Avenue South
Nashville, Tennessee 37212-2637
U.S. Army Medical Research & Development Command
Fort Detrick
Frederick, Maryland 21702-5012
Title of Project Order: Studies of the Outer Membrane Proteins of
Campylobacter Jejuni for Vaccine Development
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104
Role of Infection Due to Campylobacterjejunii n the Initiation of Guillain-Barre
Syndrome
Ban Mishu and Martin J. Blaser Fromi,t ie Division / In/eunous Diseases. Department o/ Medic'/no.
Vanderbilt I 'niversii v' SchoW (y Medicine: and ihe Medual Servi(e,
l)cpartient o/I eterans A/fifirs Medical C'enter. Nashville, 7T'nnessee
Recent reports suggest that infection with Campylobacterjejuni,a common enteric pathogen,
may cause Guillain-Barrk syndrome (GBS) by triggering demyelination of peripheral nerves.
GBS is preceded by an acute infectious illness (due to a variety of agents) in 50%-75% of cases;
the onset of neurological symptoms is preceded by diarrhea in 10%-30% of cases. In the last
decade, more than 20 published anecdotal reports and case series have described patients with C.
jejuni infection documented 1-3 weeks before onset of GBS. Cultures of fecal samples obtained
at the onset of neurological s) mptoms from patients with GBS have yielded C. jejuni in more
than 25% of cases. A relatively rare serotype, Penner type 019, is overrepresented among isolates
of C. jejuni from Japanese patients with GBS. Serological studies suggest that 20%-40% of
patients with GBS have evidence of recent C. jejuni infection. In summary, infection with C.
jejuni is a common antecedent to GBS and probably plays a role in initiating demyelination;
although several pathogenic mechanisms are possible, none has been proven.
Guillain-Barrý syndrome (GBS) is the most common ness and limb weakness and paralysis in 1892 [8]. Epidemio-
cause of acute neuromuscular paralysis in both adults and logical studies throughout the world have confirmed the asso-
children [ I, 2]. The annual incidence in the developed world ciation between GBS and preceding infectious illness [3,
is between I and 2 cases per 100,0O0 pupuiatiýrn [3, 4]. In 9-16]: 50%-75% of patients have such an illness in the weeks
recent years infection with Campyrlobacter jejuni has been preceding onset of GBS (table I). Specific infectious agents
identified as a potentially important precipitating factor for associated with GBS include Mvcoplasinap pwumoniae, hepa-
GBS. C jejuni is the most frequently identified bacterial titis B virus. cytomegalovirus, Epstein-Barr virus. varicella-
cause ofgastroenteritis in the United States and in other in- zoster virus, rubeola virus, and (most recently) human immu-
dustrialized countries [5]. Most infections with C.j ejuni pro- nodeficiency virus [1 7-2 1]. Although infections of the upper
duce an acute self-limited diarrheal illness [6]. Although ex- respiratory tract are also frequently described as antecedent
traintestinal complications of C. jejuni infection [71] suggest events, gastrointestinal infections including diarrheal illness
the involvement of immunopathogenic mechanisms, GBS precede GBS in 10%-307c/ of cases [3. 12. 16].
associated with C. jejuni infection has not been well recog-
nized. We review the existing evidence that infection due to
C. jejuni plays a role in the pathogenesis of GBS, and we Association of C. jejuni with GBS
discuss possible mechanisms for this association. In 1977. Skirrow reported that C. jejuni was a common
cause of acute diarrheal illness in England and established
methods that facilitated isolation of this organism [22]. Grad-
GBS as a Postinfectious Syndrome ually, this advance was incorporated into the routines of
Guillain-Barrý syndrome, sometimes called acute postin- many clinical microbiology laboratories. However, even at
fectious polyneuritis, often develops 1-3 weeks after an present, many laboratories attempt isolation of C.jejuni from
acute infection of the respiratory or gastrointestinal tract. fecal specimens only upon special request if at all, and few
Osler first noted the assc-ciation between acute infectious ill- laboratories utilize appropriate techniques for isolation of
all members of the rapidly expanding genus Camp vlobac-
ter (and now Arcobacter). Thus. any estimate of the role of
these organisms in the causation of human illness is likely to
Received 9 October 1992: revised 22 December 1992. be low.
Financial support: The Muscular Dystrophy Association and the In 1982, Rhodes and Tattersfield reported a case of GBS
Thrasher Research Fund.
Reprints or correspondence: Dr. Ban Mishu. Division of Infectious Dis- following enteric infection with C jejuni [23]. Because rou-
eases. A 3310 Medical Center North, Vanderbilt University Medical tine culture of stool specimens for campylobacters was so
Center. Nashville. Tennessee 37232. new, the authors suggested that previous cases of Campyrlo-
Clinical Infectious Diseases 1993;07:104-8 bacter-associated GBS may have gone unrecognized. Since
© 1993 by The University of Chicago. All rights reserved.
1058-4838/93/1701-0017S02.00 then, there have been 21 more reports of individual patients
(I ) 1993:17 (July) C. Iywum and (Guillain-Barrý Sndrome 105
Table I. Frequency of antecedent intections among patients with 019 133]. Since Penner lype 019 accounts for fewer than 2,
(.iuillain-Barr(cid:127) syndrome (BS). of('. jq/uni strains in Japan 1461, these studies suggest that an
Percentage with uncommon serotype of C. jeuni may be overrepresented
recognized among strains associated with GBS.
I o)cation antecedent Despite the brief duration of convalescent excretion of('.
oftstudy No. of patients inlfictious jejuni, serological tests may provide evidence of recent infec-
Irelerence] Year with GBS illness tion even after the bacteria can no longer be isolated from
Great Britain 1101 1964 52 69 stools. In both natural and experimental infections due to C.
Europe. United States 191 1966 1.100 58 jejuni, specific IgM and IgG antibody responses peak at 2
Nlinnesota [31 1978 40 70 weeks, but titers may remain elevated tor 4-6 weeks: levels
Norway I I11 1985 109 57 of IgA antibodies also peak at 2 weeks but fall to baseline
England 1121 1988 100 55 values within 4 weeks [471. Thus it may be possible to deter-
India 1131 1988 56 32
F~rance 1141 1989 71 50) mine serologically whether GBS patients have had anteced-
Spain 1151 1990 15 53 ent C.jejuni infection. Indeed, several investigators have doc-
Indonesia 1161 1990 28 75 umented high levels ofantibodies to C.jejuni in patients with
GBS orGBS-like illnesses [ 12, 28-30]. Although theantibod-
ies were assayed by a variety of techniques, most methods
found serological evidence of preceding C.jejuni infection in
and series of patients with GBS preceded by C.jejuni infec- 14%-409: of patients with GBS (table 3).
tion [ 12, 24-44]: data from reports that described patient Taken together, the anecdotal reports. the studies of series
characteristics are summarized in table 2. Although almost of GBS patients whose stools were cultured, and the serologi-
three times as many cases of C. jejuni-associated GBS have cal investigations suggest that C. f'juni infection may com-
been reported among male patients as among female pa- monly precede GBS. Nevertheless. GBS is a relatively rare
tients, it is uncertain whether this difference reflects demo- disease and is probably an uncommon manifestation of this
graphic reality or a selection bias in the reporting of cases. very frequent bacterial infection. The Centers for Disease
Initial reports indicated that patients with C. jejuni-asso- Control and Prevention estimates an annual incidence of
ciated GBS had severe disease, with extensive axonal dam- - 1.000 symptomatic infections with C. jejuni per 100.000
age and prolonged debilitation [23-25]. Subsequent reports. population-roughly 2 million cases-in the United States
however, have also described milder cases of GBS occurring [48]. The annual incidence of GBS in this country has been
in association with C jejuni infection [26, 27]. estimated at 1.7/100,000 population [3]. or 4.250 cases. IfC.
After the first anecdotal reports. some investigators began jejuni infection is an important antecedent event in only
to routinely culture the stools of patients with GBS for C. 10%-30% of GBS cases (the minimal estimate based upon
jejuni. However. because the duration of convalescent excre- serological surveys), then between 425 and 1.275 cases of
tion ofC. fjjuni is brief (mean, 16 days from onset of diar- GBS preceded by C jejuni infection occur in the United
rheal symptoms) [45] and because neurological symptoms in States each year (table 4). Therefore, on the basis of the esti-
C. jejuni-associated GBS usually develop 1-3 weeks after mated number of cases of GBS preceded by C.j ejuni ir.iec-
the onset of diarrhea [23-26]. cultures of fecal samples ob- tion and the total number of C. jejuni infections, it can be
tained at the onset of neurological symptoms may yield calculated that one in every 2,000-5,000 cases of C. jejuni
"false" negative results that are misleading. Despite this limi- infection is followed by GBS. These numbers illustrate that a
tation. Speed et al. isolated C. jejuni from stool cultures of common problem (C jejuni infection) with an uncommon
one of four patients with GBS [401. Ropper found that 13 manifestation (GBS) may represent a common cause of an
(12%) of 106 patients with GBS had diarrhea in the 10 days uncommon disease.
preceding the onset of neurological symptoms: stool was cul-
tured in nine of these cases, and C.jejuni was isolated in four Potential Mechanisms Involved in GBS Following
instances (44%) [31]. Kuroki et al. isolated C. jejuni from
seven (88%) of eight pediatric patients with GBS in Japan
[321. Because the patients were not related to one another The hallmark of GBS is segmental demyelination of pe-
and became ill in different years, it is not likely that these ripheral nerves, with mononuclear infiltrates and edema. My-
strains represented a common-source outbreak. Four of these elin destruction may be mediated by a direct toxic effect or
strains w(cid:127)c72 -f Pnner type 019: the remaining three isolates by an immunopathogenic mechanism: in the latter case. ei-
were not available. Other Japanese investigators serotyped ther humoral or cellular immune mechanisms could be oper-
four additional isolates of C. jejuni from patients with GBS alive,
and found that these four strains were also of Penner type Because of the extensive axonal damage noted in the earli-
106 Mishu and Blaser CID 1993:17 (July)
Table 2. Cases of*Guillain-Barrý syndrome (GBS) following infection with C. iiquii. as described in
published reports.
Location. )ear of
stud'v Ireferencel: Days from onset of
patient's age (y)/sex diarrhea to OBS Outcome
England. 1982 1231: 45/M 15 Wheelchair-hound at 8 mo
Finland. 1982 124): 42/M 9 Se\ ere deficits at 6 mo
England, 1983 125]: 34/F 10 Intubated: severe deficits at 6 mo
Australia. 1984 126]
34/M 23 Complete recos cr5 at 3 mo
22/F 21 Mild 6th-ner.e palks at 3 mo
England. 1984 127]: 16/M 10 Complete recoer, at 6 mo
England. 1985 1411: 27/M 7 Complete recoerry with minor delicits
Australia, 1986 [371: 2/F 9 Intubated: hospitalized at 4 mo:
complete recovers, at 6 mo
New York. 1987 1381: 69/M 13 Wheelchair-bound at 10%%
Swit/erland, 1988 1431: 19/M 13 Complete recover-, at 3 nio
Boston. 1988 [311
63/F 7 Wheelchair-bound at 6 mo
74/F I I Complete reco%cr at 6 mo
32/M 7 Complete reco.ers at 6 mo
19/M 10 Complete recover. at 2 mo
Switzerland. 1988 139]
38/M 6 Slow recoser over I
81/M I Complete recov.ery at 9 mo
6(/M 12 Complete recoers, at I
France. 1989 1421*
30/M 10 Complete recovers at 28 mo
62/M 8 Complete recoverv at 3 mo
74/M 4 Not described
Japan. 1990 135[*
25/M 14 Canes required for walking at 6 mo
83/F 7 Bedridden at 3 y
Japan. 1991 1321
7/M ? Complete recovery with minor deficits
9/M 6 Complete recovery with minor deficits
I O/F 15 Complete recovery
I I/M 5 Complete recovery with minor deficits
13/M 6 Complete recovery
14/M 6 Complete recovery
I 4/M 7 Improving at I mo
* Diagnosis of campylobacter infection made by serological tests: diagnoses in all other reports were culture
proven.
est cases, direct toxic damage to neural structures-perhaps had this antigen [36]. Previous studies of GBS patients had
attributable to a yet-unrecognized neurotoxin-has been not shown an association with a particular HLA type [51].
suggested [24]. However, the toxic activity of C. jejuni in (2) Perhaps only a few C. j(cid:127)juni strains are capable of trigger-
vitro [491 has not been demonstrated in vivo [50]. The tim- ing immunologically mediated myelin destruction. The asso-
ing of the onset of GBS (1-3 weeks after the peak of the ciation of Penner serotype 019 with the initiation of GBS
diarrheal illness) also argues against a direct toxic effect of C. [32. 33] suggests that these strains may represent a particu-
jejuni. larly virulent clone or that the 019 polysaccharide may be
Two distinct possibilities for mechanisms of immunologic either a virulence determinant per se or a marker for other
injury have been proposed. (I) Demyelination may result virulence factors.
from a specific genetic predisposition. A Japanese investiga- The neurological target fbr immunologic injury also is un-
tion showed that all of six patients with GBS who had ante- known. Serum from a patient with Cjejlni-associated GBS
cedent infection due to C.jjuni possessed the HLA-B35 an- reacted strongly with PO, a peripheral nerve myelin-specific
tigen, whereas only 14% of 3.090 healthy Japanese controls protein [34]I this observation suggested that C jejuni pos-
1I) 19 93:17 ()uhv ) ,wtin and (iuillain-Barrý Ssndrcrme 1o7
sesses antigens stimulating the production of'antibodies that Table 4. Estimated annual incidence,, of infection due to (
rweaich prpea L_e v ln n as iS inlr~ junm. (uillain-Barrý s~.ndrome (GBS). and (lBS preceded ký C. I,-
o'tngliosides found in m~elin may be the ultimate target o mfn'toni h nie tts
antibodies freinresponse to C. Jquni infection: OBS Aninual incidence
has followed the administration of' parenteral ganoliosides (ca~.ei 1( 10.)48)
152. 531. DesPopulation)
GBS ficlloswing C. /1//m infiection often is associated with Dsae [reference] I otal cases/V*
extensive axonal damage. a relatively severe clinical courseI 41 .0008
and a poor recovery [29]. 11no ne study5 the documentation of' (BS
high levels of' -gC antibodies recognizing GM Il in two pa All cases 1.7 131 4.2st0
tients with C. ftjitmi-associated GBS and extensive axonail Caises preceded hs
damage suuested the involvement of' increased levels of' ( ,i,,in inflection' 0,17-0.S] 42 5-1 .2 7
these antibodies in pathogenesis [351. In another investigat Based on estimated U.S. population of 25 0 million.
tion IgA antibodies to GM I vvere detected in 15 (28r) of'53 Estimated at I)0%-301, of all (iRS cases.
patients with CBS and in only 1( 41() of 26 controls: the (iBS
patients with antibodies to GM I had more extensive axonal
involvement and more severe clinical courses [541. Koski et routine cultures of' stool for (Thnpi~obacier species should
al. fiound that titers ot1gM antibodies to a neutral glveolipid beoeprofteitalvluinofainswthu-
in peripheral nerve myelin were elevated in all of' 12 patients pected GBS. Further studies must elucidate the role of' C.
with GBS but in none of 36 controls: the antibodies cross- Je.ju.itn in initiating CBS and illuminate the mechanisms in-
reacted with Forssman antigen as well as with eukaryotic cell volved in pathogenesis.
membranes [55]. However. earlier studies by Ilyas et al.
showed no increase in levels of antibodies to GM I in associa-
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