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Specific antibody secreting cell response to bacterial antigens in children with Kawasaki syndrome and healthy controls
6
SENSORINEURAL HEARING LOSS ASSOCIATED WITH KAWASAKI DISEASE J a n e C. B u m s . UCSD School of Medicine. S an Diego, CA for the U.S. Kawasaki Disease Multlcenter Hearing Loss Study Group. Recent reports from J a p a n and the U.S. have documented the association of sensorineural hearing loss (SNHL) and acute KD. To further characterize the nature and prevalence of this complication, we prospectively assessed the hearing of 75 unselected KD patients (pts) treated within the first 14 days of illness at 8 medical centers in North America. Standard audlometric procedures included visual reinforcement and play audlometry and tympanometry. Brainstem auditory evoked response (BAER) testing using click and tone pips (1-4KHz) was performed in pts with a b n o r m a l (abnl) or u n r e l i a b l e r e s u l t s on b e h a v i o r a l audiometry. S e r u m s a m p l e s were o b t a i n e d for determination of albumin, protein-bound and free salycIlate levels, and markers of systemic inflammation. Of t h e 75 pts, 25 h a d inconclusive h e a r i n g e v a l u a t i o n s due to abnl t y m p a n o g r a m s (10 pts), s u p r a t h r e s h o l d s c r e e n i n g procedures (8 pts), or unreliable behavioral testing without BAER testing (7 pts). Normal (rd) hearing was documented in 3 0 / 7 5 (40%) pts. Binaural or m o n o a u r a l mild SNHL (1525dBHL) was documented in 2 0 / 7 5 (26.7~ pis with recovery o f n l hearing (0.2mM/L) were documented in 1 pt with SNHL and 4 pts wlth nl hearing. W e c o n c l u d e that SNHL occurs in pts with KD and m ay be associated with markers of more severe inflammation. Audlologlc screening should be considered for all pts following acute KD.
PERIPHERAL GANGRENE ASSOCIATED WITH KAWASAKI DISEASE. Stanford T. Shulman, Shobun Tomita, Kyung Chung, Madeleen Mas, Samuel Giddlng. Children's Memorial, Northwestern Unlv, Chicago, IL; Kurume Unlv Japan; Univ of Miami; Unlv of California San Diego. Peripheral gangrene occurs very rarely in Kawasakl Disease (KD). We report three U.S. Infants with KD complicated by gangrene leading to necrosis of hands, feet or portions of digits. One child necrosed a hand, a foot, and a lower leg and foot. Eight patients have been reported previously, only one from Japan with >105,000 KD cases. These Ii patients were all < 7 months at onset of KD and predominantly non-Aslan in ethnlclty. At least 9/ii also had giant coronary aneurysms (~Smm) and 8/11 had peripheral arterial (usually axillary) aneurysms. In 8/11, diagnosis of KD was not established nor therapy instituted until at least 14 days after onset of illness. Peripheral ischemia initially manifested at 15-31 days after onset. Although the pathogenesls of this complication is poorly understood, it likely includes a combination of peripheral arterltls, arterlospasm, peripheral and/or more proximal thrombosis (as in an axillary aneurysm), and cardiogenlc shock. Aggressive management of these infants may include sallcylates and IVCG for their antl-lnflammatory effects, vasodilators such as POE 1 and/or sympathetic 51ockade, and thrombolytlc and/or anticoagulant agents in attempts to prevent or minimize potentially devastating progressive gangrene.
7 SPECIFIC ANTIBOOY SECRETING CELL RESPONSE TO BACTERIAL ANTIGENS IN CHILDREN WITH KAWASAKi SYNDR(~MEAND HEALTHY CONTROLS Mary P. Diode, Rose L. Brogden, John F. James, Diane L. L i n d f t o t t and James W. giggens, The chttdrenls Hospital and University of Colorado School of Medicine, Denver, CO
We measured specific antibc~/ secreting c e l l (AGO) response to a v a r i e t y of bacterial antigens in 8 children with Kawasaki Syndrome (KS) and 12 heatthy adult and pediatric controls. An enzyme linked immunosorbant essay was used (ELISPOT). Blood samples were obtained from Kg patients at a mean of 8.5 days post onset of fever (range 4-20 days). Total IgA, lgG or IBM ASC were not d i f f e r e n t between eases and controls. There were no differences between cases and controls in specific Ago to a v a r i e t y of d i f f e r e n t bacterial antigens, inctuding Haemophitus influenzae, Group G streptococcus, Streptococcus sanguis,
=-streptococcus or Arcanobacterium. significant below:
However, there were
differences in ASC number to the antigens listed
Geometric Mean No. ASC [ 106mononuclear celts
Ab
f
ANTIGEN
CLASS
KS PATIENTS
Or. 8 strep r strap
IBM |gM
Cr. A strep Or. A strep PEA~ Gr. A strep PEB~
IBM lgG IsM IgA
4].1 55.6 162.6 964.1 825.2
Or. A strep PECk_ Gr. A strep PE~ I 2 3 4
= = = =
i~M
(n:8) (n:8] (n=8) (n=4) (n=4)
236.3 (n=4) 469.0 (n=4)
CONTROLS
].B (n=12) 6.9 8.0 26.3 1.8 5.3 3.8
(n=lO) (n=12) (n=4) (n=4)
(n=4) (n=4)
P VALUE~ .03 .046 .0002
.03 .03 .04 .03
Or. A strep producing pyrogenic toxin A Cr. A strep producing pyrogenic toxin B Gr. A strep producing pyrogenic toxin C Witcoxan rank sum test
We conclude that tymphocytes frcx~patients with KS are producing antibody which reacts with streptococcal antigens. The highest response is seen with strains of Gr. A streptococcus that are producing pyrogenic exotoxins.
8
I~SSIBLE ROLE FOR GLUCAN PRODUCED BY STREFTOCOCCUS SANGUIS IN KAWASAKI DISEASE Kenshi Furusho, Tsuneo Hirota, Keiichi Hayase N'FF Kyushu Hospital, Kumamoto, Japan Streptococcus sanguis (SSH-83 and KIH-T strains) detected from throat swabs of children with KD was cultured in sucrose-and surface active agent (AOS or A B S ) - added medium, and glucan produced in culture fluid was assayed. In the medium containing both sucrose and AOS, the production of soluble glucan and insoluble glucan (ISG) by KIH-T strain remarkably increased. ISG.thus produced was isolated and its influence upon IL-1 and TNF production from human monocyte was studied- As a result, ISG was found to stimulate both IL-1 and TNF production at least as much as the positive controls(LPS). Anti-glucan IgG antibody was assayed by ELISA in serum from 71 normal healthy children and 28 children with KD. In 89% of children with KD it was much higher than normal range in convalescent phases of the disease and in most of them it increased in the convalescen phaseThe above findings suggest that an oral indigenous bacteria, Str. sanguis KIH-T, produces an immunoactivator, glucan, from sugar especially in the presence of AOS in the mouth- This interaction between this strain of bacteria and AOS seems to be a possible c a u s e - o f KD.
SENSORINEURAL HEARING LOSS ASSOCIATED WITH KAWASAKI DISEASE J a n e C. B u m s . UCSD School of Medicine. S an Diego, CA for the U.S. Kawasaki Disease Multlcenter Hearing Loss Study Group. Recent reports from J a p a n and the U.S. have documented the association of sensorineural hearing loss (SNHL) and acute KD. To further characterize the nature and prevalence of this complication, we prospectively assessed the hearing of 75 unselected KD patients (pts) treated within the first 14 days of illness at 8 medical centers in North America. Standard audlometric procedures included visual reinforcement and play audlometry and tympanometry. Brainstem auditory evoked response (BAER) testing using click and tone pips (1-4KHz) was performed in pts with a b n o r m a l (abnl) or u n r e l i a b l e r e s u l t s on b e h a v i o r a l audiometry. S e r u m s a m p l e s were o b t a i n e d for determination of albumin, protein-bound and free salycIlate levels, and markers of systemic inflammation. Of t h e 75 pts, 25 h a d inconclusive h e a r i n g e v a l u a t i o n s due to abnl t y m p a n o g r a m s (10 pts), s u p r a t h r e s h o l d s c r e e n i n g procedures (8 pts), or unreliable behavioral testing without BAER testing (7 pts). Normal (rd) hearing was documented in 3 0 / 7 5 (40%) pts. Binaural or m o n o a u r a l mild SNHL (1525dBHL) was documented in 2 0 / 7 5 (26.7~ pis with recovery o f n l hearing (0.2mM/L) were documented in 1 pt with SNHL and 4 pts wlth nl hearing. W e c o n c l u d e that SNHL occurs in pts with KD and m ay be associated with markers of more severe inflammation. Audlologlc screening should be considered for all pts following acute KD.
PERIPHERAL GANGRENE ASSOCIATED WITH KAWASAKI DISEASE. Stanford T. Shulman, Shobun Tomita, Kyung Chung, Madeleen Mas, Samuel Giddlng. Children's Memorial, Northwestern Unlv, Chicago, IL; Kurume Unlv Japan; Univ of Miami; Unlv of California San Diego. Peripheral gangrene occurs very rarely in Kawasakl Disease (KD). We report three U.S. Infants with KD complicated by gangrene leading to necrosis of hands, feet or portions of digits. One child necrosed a hand, a foot, and a lower leg and foot. Eight patients have been reported previously, only one from Japan with >105,000 KD cases. These Ii patients were all < 7 months at onset of KD and predominantly non-Aslan in ethnlclty. At least 9/ii also had giant coronary aneurysms (~Smm) and 8/11 had peripheral arterial (usually axillary) aneurysms. In 8/11, diagnosis of KD was not established nor therapy instituted until at least 14 days after onset of illness. Peripheral ischemia initially manifested at 15-31 days after onset. Although the pathogenesls of this complication is poorly understood, it likely includes a combination of peripheral arterltls, arterlospasm, peripheral and/or more proximal thrombosis (as in an axillary aneurysm), and cardiogenlc shock. Aggressive management of these infants may include sallcylates and IVCG for their antl-lnflammatory effects, vasodilators such as POE 1 and/or sympathetic 51ockade, and thrombolytlc and/or anticoagulant agents in attempts to prevent or minimize potentially devastating progressive gangrene.
7 SPECIFIC ANTIBOOY SECRETING CELL RESPONSE TO BACTERIAL ANTIGENS IN CHILDREN WITH KAWASAKi SYNDR(~MEAND HEALTHY CONTROLS Mary P. Diode, Rose L. Brogden, John F. James, Diane L. L i n d f t o t t and James W. giggens, The chttdrenls Hospital and University of Colorado School of Medicine, Denver, CO
We measured specific antibc~/ secreting c e l l (AGO) response to a v a r i e t y of bacterial antigens in 8 children with Kawasaki Syndrome (KS) and 12 heatthy adult and pediatric controls. An enzyme linked immunosorbant essay was used (ELISPOT). Blood samples were obtained from Kg patients at a mean of 8.5 days post onset of fever (range 4-20 days). Total IgA, lgG or IBM ASC were not d i f f e r e n t between eases and controls. There were no differences between cases and controls in specific Ago to a v a r i e t y of d i f f e r e n t bacterial antigens, inctuding Haemophitus influenzae, Group G streptococcus, Streptococcus sanguis,
=-streptococcus or Arcanobacterium. significant below:
However, there were
differences in ASC number to the antigens listed
Geometric Mean No. ASC [ 106mononuclear celts
Ab
f
ANTIGEN
CLASS
KS PATIENTS
Or. 8 strep r strap
IBM |gM
Cr. A strep Or. A strep PEA~ Gr. A strep PEB~
IBM lgG IsM IgA
4].1 55.6 162.6 964.1 825.2
Or. A strep PECk_ Gr. A strep PE~ I 2 3 4
= = = =
i~M
(n:8) (n:8] (n=8) (n=4) (n=4)
236.3 (n=4) 469.0 (n=4)
CONTROLS
].B (n=12) 6.9 8.0 26.3 1.8 5.3 3.8
(n=lO) (n=12) (n=4) (n=4)
(n=4) (n=4)
P VALUE~ .03 .046 .0002
.03 .03 .04 .03
Or. A strep producing pyrogenic toxin A Cr. A strep producing pyrogenic toxin B Gr. A strep producing pyrogenic toxin C Witcoxan rank sum test
We conclude that tymphocytes frcx~patients with KS are producing antibody which reacts with streptococcal antigens. The highest response is seen with strains of Gr. A streptococcus that are producing pyrogenic exotoxins.
8
I~SSIBLE ROLE FOR GLUCAN PRODUCED BY STREFTOCOCCUS SANGUIS IN KAWASAKI DISEASE Kenshi Furusho, Tsuneo Hirota, Keiichi Hayase N'FF Kyushu Hospital, Kumamoto, Japan Streptococcus sanguis (SSH-83 and KIH-T strains) detected from throat swabs of children with KD was cultured in sucrose-and surface active agent (AOS or A B S ) - added medium, and glucan produced in culture fluid was assayed. In the medium containing both sucrose and AOS, the production of soluble glucan and insoluble glucan (ISG) by KIH-T strain remarkably increased. ISG.thus produced was isolated and its influence upon IL-1 and TNF production from human monocyte was studied- As a result, ISG was found to stimulate both IL-1 and TNF production at least as much as the positive controls(LPS). Anti-glucan IgG antibody was assayed by ELISA in serum from 71 normal healthy children and 28 children with KD. In 89% of children with KD it was much higher than normal range in convalescent phases of the disease and in most of them it increased in the convalescen phaseThe above findings suggest that an oral indigenous bacteria, Str. sanguis KIH-T, produces an immunoactivator, glucan, from sugar especially in the presence of AOS in the mouth- This interaction between this strain of bacteria and AOS seems to be a possible c a u s e - o f KD.