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The Treatment of Diphtheria by Refined Diphtheria Antitoxin with Particular Reference to the Incidence of Serum Reactions

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"THE TREATMENT OP DIPHTHERIA BY REPINED
DIPHTHERIA
ANTITOXIN".
WITH PARTICULAR REFERENCE TO THE
INCIDENCE OP SERUM REACTIONS.
THESIS FOR DECREE OP M .D.,
ALEXANDER
PRESENTED BY:
HUTCHISON, M .B ., C h . B . , F . R . F . P . S . , D .P .H .
ProQ uest N u m b e r: 13849763
All rights reserved
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COH T E N T S
PAGE.
INTRODUCTION...................................................................................
Section 1 :
Methods u s e d t o c o n c e n t r a t e Serum:
(a)
V ariation o f S altC on centration ...
(b)
P r e c i p i t a t i o n w i t h A l c o h o l .........................
19.
(c)
A d s o r p t i o n .............................................................
22.
(d)
C atap horesis.
...............................................
23.
(e)
Enzymes....................................................................
24*
(f)
S p e c i f i c M e t h o d s . .............................................
30.
Summary
S46tlon 2 :
1.
5.
. • ...
34.
Serum R e a c t i o n s
D e f i n i t i o n and I n t r o d u c t i o n ...........................
37.
H i s t o r i c a l .....................................
Mechanism i n Animals and Man.
37.
...............
40.
Types o f R e a c t i o n ......................................
46.
F a c t o r s which i n f l u e n c e i n c i d e n c e ..............
47.
M anifestations. • • . • • • • • • • • • • • • • • •
55.
D e s e n s i t i s a t i o n ...........................................
P r e v e n t i o n and Treatment o f Serum
R e a c t i o n and Serum S h o c k . •• . . .
Summary and C o n c l u s i o n s ...............• • • • • • • •
68.
•
6 9.
73.
• 2*
CONTMTS (Contd. )
PAGE.
Present In v e s tig a tio n .
A n a l y s i s o f I n c i d e n c e and M a n i f e s t a t i o n s
o f Serum R e a c t i o n s o c c u r r i n g a f t e r t h e
Use o f C o n ce n tr a ted and R e f i n e d S e r a ...............
75#
Summary.............................................................................• • •
107.
S e c t i o n 3 : Treatment o f 1 , 0 0 0 Cases o f D i p h t h e r i a .
O b s e r v a t i o n s on P a t i e n t ............................................
111.
Treatment and General N u rs in g
.........................
112.
Treatment o f C o m p li c a t io n s due t o t o x i n
o f D i p h t h e r i a ...............
117.
Treatment o f C o m p li c a t io n s due t o S e r u m . . .
119.
P r e p a r a t i o n o f Media u s e d ............... ....
D ifferen tiation of C o lo n ies...
...
•
122.
.................
124.
B i o c h e m i c a l R e a c t i o n s o f t h e V ario us
S t r a i n s o f C. D i p h t h e r i a s ..........................
125.
Growth i n B roth o f V a r i o u s S t r a i n s
o f 0. D i p h t h e r i a s
...
125.
H a em oly tic T e s t s o f Various S t r a i n s
o f C. D i p h t h e r i a s . . ...................
125.
Animal P a t h o g e n i c i t y o f V a r io u s S t r a i n s
o f C.» D i p h t h e r i a s ................. . . .
126.
A n a l y s i s o f 1 , 0 0 0 C u l t u r e s ..................................
126.
C o n c l u s i o n s ..............................
126.
w- «
.3.
OOffEBffTS.
(C on td.)
PAGE,
General A n a l y s i s o f t h e 1 , 0 0 0 Oases T r e a t e d ,
A n a l y s i s o f Gases t r e a t e d by I n t r a v e n o u s
I n j e c t i o n .........
127,
140*
A n a l y s i s o f Gases t r e a t e d by I n t r a m u s c u l a r I n t r a v e n o u s I n j e c t i o n • • • •««
151,
A n a l y s i s o f Cases t r e a t e d by In t r a m u s c u l a r
I n j e c t i o n ....
162,
Comparison o f R e s u l t s o f Treatment by t h e
Three D i f f e r e n t Methods o f
a d m i n i s t e r i n g t h e serum.............
173,
Summary,
..............
176,
C o n c l u s i o n s ..................
Bibliography
179,
..........................................
oOo
181.
S i n c e 1 9 3 1 , when Anderson e t a l . p u b l i s h e d t h e i r a c c o u n t
o f th e t h r e e d i f f e r e n t t y p e s o f c . d i p h t h e r i a s , much work has been
done on t h i s s u b j e c t In B r i t a i n and a l s o i n o t h e r c o u n t r i e s i n th e
w orld.
I t was soon r e a l i z e d t h a t t h e p e r c e n t a g e i n c i d e n c e o f t h e
v a r i o u s t y p e s v a r i e d i n d i f f e r e n t p a r t s o f B r i t a i n in the same y e a r ,
and t h a t t h e y a l s o v a r i e d from y e a r t o y e a r .
Comparative f i g u r e s
f o r the same a r e a s i n d i f f e r e n t p a r t s o f the world were d i f f i c u l t t o
obtain.
Table showing D i f f e r e n t P e r c e n t a g e I n c i d e n c e i n th e Same y e a r in
, D i f f e r e n t Areas thro ug h out t h e World.
Area
Year
P ercentage
Percentage
Percentage
frravis
Intermedlus
M itls
Aberrant
5.8
65.1
24.1
4.96
6.0
54.2
39.8
50.0
26.0
24.0
50.9
19.9
27.8
63.2
21.7
10.5
91.3
78.2
3.7
8.8
3.7
9.2
6.3
1.8
91.9
9 .1
81.8
52.2
47.8
1.4
to
.
Glasgow ( C a r t e r 1935
1936)
Dundee (Murray)
1935
Liverpool
(P rivate
Communication) 1935
Manchester
(Robinson and
Marhhall) . . . 1 9 3 5
Romford
( T a n n a h i l l 1936) 1935
Cork (Cooper
e t 81.1936)1935
B erlin (
d o . ) 1935
Maryland, U . S .
( W h i t l e y ) ............ 1935
Iowa, U . S .
(Wright and
C h ristiso n )••..1935
A ustralia
(Andersop e t
a l .1936) . . .1935
Percentage
1.2
3.8
9.1
•2 «
Table showing D i f f e r e n t P e r c e n t a g e I n c i d e n c e i n th e Same Area i n
d if f e r e n t years*
Area
Year
Percentage
Glasgow ( C a r t e r
1933)
1933
Glasgow (Gartei?!
1935
M anchester (1^36)
(Robinson and
M arsh all)
1934
Manc he ster
(Robinson and
M arsh all)
1935
Liverpool
(Private
Communication)
1935
L i v e r p o o l (Do.)
1937
H u l l ( L e e t e e t a 1 )1 9 3 3
H u l l (M.O.H.
R e p o r t ) ................. 1938
Gravis
Percentage
Inkermedius
Percentage
I r i ti s
T
Percentage
Aberrant;
3.1
5.8
59.2
65.1
36.5
24.1
1.17
4.96
23.8
54.6
19.2
2.4
50.9
19.9
27.8
1.4
50.0
34.2
59.4
26.0
24.7
29.0
24.0
41.1
8.7
2.3
21.4
68.4
10.2
I t was a l s o r e c o g n i s e d t h a t t h e s e v e r i t y o f the c l i n i c a l
o a se d id no t a l w a y s o o i n c i d e w i t h t h e i s o l a t i o n o f t h e g r a v i s s t r a i n ,
a s had be en s u g g e s t e d by Anderson e t a l .
( 1 9 3 1 ) , though i n some a r e a s
t h i s was th e c a s e , w h i l e In o t h e r s t h e i n t e r m e d i a t e ty pe was
a s s o c i a t e d w i t h t h e more s e v e r e c l i n i c a l ty p e o f d i p h t h e r i a .
S e v e r i t y o f C l i n i c a l Type o f D i p h t h e r i a a s s e s s e d on P e r c e n t a g e
Death R a t e .
P e r c e n t a g e Death Rate
G r a v i s I n t e r m e d lu s M l f l s .
filasgow ( C a r t e r , 1933) ........................................
Dundee (Murray, 1 9 3 5 ) ........................ ...............
Manchester (Robinson and M arsh all 1934)
Hull (Leete e t a l . , 1 9 3 3 ) • • • • • * • • • • • •
Leeds (Cooper e t a l . 1 9 3 6 ) ........................
B e r l i n )(
do.
) . . . , . ..............
A u s t r a l i a (Anderson e t a l . , 1935) . . . .
P o r t E l i z a b e t h , S.A . (Emmerson, 1937)
-
13.8
19.4
6.3
13.2
26.0
11.1
7.8
11.1
15.7
5.7
4.9
9.4
7.5
3.4
2 .6
3 .8
1.4
100.0
7.9
2.3
In Glasgow, from the r e p o r t s by C a r t e r (1933 8nd 1936)
-
and
the M ed ic al O f f i c e r o f H e a l t h * s R e p o r t , 1935 (Knightswood H o s p i t a l ) ,
•3 •
i t was o b s e r v e d t h a t t h e p e r c e n t a g e i n c i d e n c e o f t h e g r a v i s s t r a i n
was i n c r e a s i n g in t h e Glasgow a r e a .
As t h e l i t e r a t u r e on t h e s e v e r i t y o f th e c l i n i o a l c a s e
c o r r e l a t e d w i t h the s t r a i n o f o . d i p h t h e r i a s
r e c o v e r e d from t h e c a s e
was not e x t e n s i v e , an i n v e s t i g a t i o n was commenced i n B e l v i d e r e F e v e r
H o s p i t a l , Glasgow, i n 1 9 3 7 , t o c o r r e l a t e t h e s t r a i n o f o . d i p h t h e r i a s
r e c o v e r e d from e a ch c l i n i c a l c a s e o f d i p h t h e r i a w i t h the c l i n i c a l
s e v e r i t y o f the c a s e .
At the same time a s th e i n v e s t i g a t i o n
commenced, M e s s r s . Burroughs Wellcome p l a c e d a t my d i s p o s a l a h i g h l y
c o n c e n t r a t e d d i p h t h e r i a a n t i t o x i n , w h ic h , t h e y c l a i m e d , g r e a t l y
red uc ed t h e i n c i d e n c e o f serum r e a c t i o n s when i t was a d m i n i s t e r e d .
T h is serum i s c a l l e d "R efined D i p h t h e r i a A n t i t o x i n " .
As t h i s a n t i t o x i c serum was c la i m e d t o c a u se no r e a c t i o n
a f t e r i t s a d m i n i s t r a t i o n , each c a s e was kept under o b s e r v a t i o n to
d eter m in e whether or not t h i s was th e c a s e , and t o ob s er v e t h e time
and type o f serum r e a c t i o n ( i f any) •
For com p a riso n, a s e r i e s o f
o a s e s o f d i p h t h e r i a t r e a t e d w i t h Burroughs Wellcome " c o n c e n t r a t e d "
(Banzhaf and G ib so n , 1 9 0 7 , and Ban zh af, 1912-13)
also in v estig a ted .
d i p h t h e r i a a n t i t o x i n wa
T h is i n v o l v e d an e x a m in a t io n o f t h e o a s e
r e o o r d s o f a l l c a s e s o f d i p h t h e r i a which had r e c e i v e d Burroughs
Wellcome c o n c e n t r a t e d d i p h t h e r i a a n t i d i p h t h e r l t i c serum between
t h e y e a r s 193 0-1 93 6 i n c l u s i v e .
From the c a s e r e c o r d t h e r e was
n oted t h e a g e , s e x , day o f d i s e a s e , the amount and r o u t e o f
a d m i n i s t r a t i o n o f the serum, the time taken f o r the serum r e a c t i o n ,
i f any, t o be m a n i f e s t , and the c l i n i o a l type o f serum r e a c t i o n .
1 , 0 0 0 o a s e s o f d i p h t h e r i a were t r e a t e d t o a c o n c l u s i o n .
150 r e c e i v e d t h e a n t i t o x i n by i n t r a v e n o u s i n j e c t i o n , 250 by combined
.4.
I n t r a m u s c u l a r and i n t r a v e n o u s t h e r a p y , and 600 by i n t r a m u s c u l a r
i n j e c t i o n alone*
P o u r - h o u r l y o b s e r v a t i o n s were made upon t h e
t e m p e r a t u r e , p u l s e and r e s p i r a t i o n s , t h e r a t e o f d i s a p p e a r a n c e o f
t o x a e m i a , membrane a n d / o r d i s c h a r g e s , and c o m p l i c a t i o n s *
The 1 , 0 0 0 c a s e s were swabbed by m y s e l f and t h e n i n o c u l a t e d
on L o e f f l e r ’ s medium, and on t o K er rin and Gaze (1936) media
p l a t e s , where t h e d i f f e r e n t c o l o n i e s were I d e n t i f i e d *
Prom t h e s e
c o l o n i e s the b i o o h e m i o a l and h a e m o l y t i o p r o p e r t i e s o f t h e d i f f e r e n t
t y p e s o f o* d i p h t h e r i a s were i n v e s t i g a t e d .
A l l the l a b o r a t o r y work, i n c l u d i n g t h e p r e p a r a t i o n o f t h e
m ed ia, was done by me.
T h is t h e s i s i s p r e s e n t e d i n t h r e e s e c t i o n s : (1)
A s u rv e y o f the methods used t o c o n c e n t r a t e
diphtheria a n t i t o x i n .
(2)
Serum r e a c t i o n s :
T h e i r i n c i d e n c e and m a n i f e s t a t i o n s ,
t o g e t h e r w i t h a comparison o f t h e i r o c c u r r e n c e and
c l i n i o a l f i n d i n g s f o l l o w i n g th e i n j e c t i o n o f
c o n c e n t r a t e d and r e f i n e d d i p h t h e r i a a n t i t o x i n *
(3)
An a n a l y s i s o f the r e s u l t s o f t r e a t m e n t o f 1 , 0 0 0
oases o f c l i n i c a l diphtheria tr e a te d with r e fin e d
diphtheria a n t i t o x i n .
~•- r
F'. O
-
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t. U& -I“?>S'.V--I t S ti 0 - V V V 3 -- rO :
v?
SECTION
I*
A Survey o f t h e methods used
to oonoentrate dip hth eria a n tito x in *
i-
i;?gSV
VO-v
F o - =v 3-0 F > B F 5 ; -
' " FoF-vF ;.i:? F : FrOOov
■ I;vwv
off
VVFr V
-j.'-ri’ d
V
? /•• /• \
f : v -'
F^^.i ••• '• ;• r v - ~ e - F ■;
bfeF "'Or: •-; Ffvfof: :- ..
- o o s !mal? Ffe-
. 5.
S i n c e t h e i n t r o d u c t i o n o f a n t i - D i p h t h e r i t i c serum by
Behrin g
and K i t a s a t o (1890) r e p e a t e d e f f o r t s have been made t o reduoe t o a
minimum t h e c o n t e n t o f n o n - s p e c i f i c s u b s t a n c e *
The e a r l y w o rkers
i n i n t h i s f i e l d o f m ed ic in e hoped t o produce a pure a n t i b o d y *
In
v i e w o f the c l e a r e r u n d e r s t a n d in g r e a c h e d on t h e natu re o f a n t i b o d i e s
th e work done has been t o reduce t h e r a t i o o f the a n t i b o d y t i t r e
to
th e p r o t e i n c o n c e n t r a t i o n o f th e r e s u l t a n t produ ot*
The methods employed have b e e n : (1) N o n - S p e c i f i c - f r a c t i o n a l p r e o i p i t a t i o n o f t h e serum and
adsorption*
(2)
S p e c i f i c methods depend ing upon th e p r e o i p i t a t i o n o f th e
a n t i b o d y by the s p e c i f i c a n t i g e n and e x t r a c t i n g t h e
compound*
(1)
N o n - S p e o i f i o methods are d i v i d e d i n t o t h e f o l l o w i n g g r o u p s : (^) V a r i a t i o n o f t h e s a l t c o n c e n t r a t i o n *
(b) P r e c i p i t a t i o n w i t h a l c o h o l *
(c) A d s o r p t i o n .
(d) C a t a p h o r e s i s .
(e) Enzymes*
(a)
B r i e g e r and E h r l i c h ( 1 8 9 3 ) •
They used a 2 7 - 3 0 p e r c e n t ,
s o l u t i o n o f Ammonium S u lph a te and t h e i r e x p e r i m e n t s were done upon
m ilk from cows which had been immunized*
Prom t h e i r r e s u l t s t h e y
oonolude d t h a t Ammonium Su lph ate in c o n c e n t r a t i o n s between 2 7 - 3 0 per
o e n t* p r e c i p i t a t e d most o f the a n t i t o x i n from the m i l k , and o f t h e
o t h e r s a l t s t h e y t r i a d , Magnesium S u lph a te came n e x t i n e f f i o a c y to
Ammonium Su lph ate i n p r e c i p i t a t i n g th e a n t i t o x i n .
The p r e c i p i t a t e
o b t a i n e d was d i s s o l v e d i n w a t e r , d i a l y s e d a g a i n s t f l o w i n g w a t e r ,
f i l t e r e d and f i n a l l y d r i e d *
The powder t h e y o b t a i n e d by t h i s method
had , w e i g h t f o r w e i g h t , 400 - 600 t i m e s t h e a n t i t o x i c s t r e n g t h o f the
o r i g i n a l milk*
B r o d l e . 1897*
He was t h e f i r s t t o prove t h a t D i p h t h e r i a a n t i t o x i n was
p r e c i p i t a t e d from an a n t i - D i p h t h e r i t i c serum by any means t h a t
c o m p l e t e l y p r e c i p i t a t e d t h e G l o b u l i n s i n t h e serum.
He made
f r a c t i o n a l p r e c i p i t a t i o n s o f t h e serum, u s i n g as h i s p r e c i p i t a n t
Ammonium S u lp h a t e *
He found f o u r d i f f e r e n t p o r t i o n s in th e serum,
a l l o f which c o n t a i n e d a n t i t o x i n in e q u a l q u a n t i t i e s *
Freund and S t e r n b e r g , 1 8 9 9 .
They found t h a t by a dd ing o n e - t h i r d In volume o f a 5 p e r
o e n t P o t a s h alum s o l u t i o n t o one volume o f serum t h s t a l l t h e
a n t i t o x i n remained in the f i l t r a t e - t h e albumin was p r e c i p i t a t e d and
the f i l t r a t e c o n t a i n i n g o n l y th e g l o b u l i n s c o n t a i n e d a l l th e
antitoxin*
The g l o b u l i n was the n p r e c i p i t a t e d by Ammonium S u lp h a t e
and so a c o n c e n t r a t e d a n t i t o x i n was produced*
F uld and S p i r o , 1 90 0 .
From e x p e r i m e n t s t h e y determ ined t h a t t h e r e were two
g l o b u l i n f r a c t i o n s - (1)
one which was p r e o i p i t a t e d by a 2 8 - 3 3 p e r
c e n t , s o l u t i o n o f Ammonium S u l p h a t e , and t h i s t h e y c a l l e d
" E u g lo b u l i n " , and (2) one which was p r e c i p i t a t e d by a 3 4 - 4 6 p e r c e n t ,
s o l u t i o n o f Ammonium Su lphate*
They c a l l e d t h i s f r a c t i o n
"Pseudoglobulin” •
H i s s and A t k i n s o n . 1901*
They e s t i m a t e d th e g l o b u l i n c o n t e n t o f the seruiji
o f h o r s e s a t v a r i o u s s t a g e s du rin g t h e i r immunization a g a i n s t
D iphtheria*
The p r e c i p i t a n t u s ed was Ammonium S u lp h a t e *
They
o b t a i n e d t h e t o t a l p r o t e i n c o n t e n t o f t h e serum by b o a t i n g and t h e
albumin c o n t e n t was e s t i m a t e d by t h e d i f f e r e n c e *
They found t h a t
t h e g l o b u l i n c o n t e n t o f th e serum i n c r e a s e d during im munization
a g a i n s t d i p h t h e r i a , and t h a t t h e albumin f r a c t i o n d i m i n i s h e d *
In
10 c . c ’ s o f a normal h o r s e * s serum t h e y found t h e g l o b u l i n o o n t e n t
t o be .3 2 3 5 gramme*
When t h i s same h o r se had been Immunized
a g a i n s t d i p h t h e r i a so t h a t 10 c . c ! s o f serum c o n t a i n e d 120 a n t l d i p h t h e r i t i o u n i t s , t h e g l o b u l i n c o n t e n t had r i s e n t o *8987 gramme*
P ic k , 1902:
From numerous e x p e r i m e n t s he c o n c lu d e d t h a t t h e a n t i t o x i n
was a s s o c i a t e d w i t h th e p s u e d o g l o b u l l n s , but not w i t h t h e e u g l o b u l i n s
T h i s was t h e c a s e when h o r s e s were immunized, but n o t f o r g o a t s ,
where th e c o n d i t i o n s were the r e v e r s e *
G ib s o n , 1905-6>
He p u b l i s h e d a
method whereby t h e p r o t e i n o o n t e n t o f a
serum c o u l d be g r e a t l y
r e d u c e d , and he c la im e d t h a t he c o u l d
c o n c e n t r a t e a serum t o
a t l e a s t double i t s o r i g i n a l a n t i t o x i c
strength*
was:-
(1)
H is method
P r e o i p i t a t i o n o f the g l o b u l i n s w i t h an e q u a l volume o f
s a t u r a t e d ammonium s u l p h a t e s o l u t i o n .
(2)
F iltra tio n .
(3)
E x t r a c t i o n o f the r e s i d u e w i t h s a t u r a t e d sodium c h l o r i d e
s o l u t i o n , so r e - d i s s o l v i n g th e p s e u d o g l o b u l i n w i t h the
antitoxin.
• 8*
(4)
F iltration #
(5)
P r e o i p i t a t i o n w i t h h a l f s a t u r a t i o n o f ammonium s u l p h a t e *
(6)
Drying o f t h e p r e c i p i t a t e and d i a l y s i n g i n parchment*
(7)
S t e r i l i z a t i o n o f the r e s u l t a n t s o l u t i o n by double f i l t r a t i o n
through B e r k e f e l d f i l t e r s .
(8)
A d d i t i o n o f *25 t o . 5 p er c e n t* s o liu m c h l o r i d e and a
preservative•
LedIngham* 1 9 0 7 t
He found t h a t i n a h o r se where the serum was lo w i n a n t i t o x i o v a l u e t h e t o t a l p r o t e i n c o n t e n t showed no te n d e n c y t o i n o r e a s e
d u r in g immunization*
The s l i g h t i n o r e a s e found was due t o a r i s e in
the albumin c o n t e n t *
During th e immunization o f a h o r s e whioh
produced a h i g h grade a n t i t o x i o serum, the p e r c e n t a g e g l o b u l i n o o n t e n t
o f the t o t a l p r o t e i n i n c r e a s e d p r o g r e s s i v e l y *
F in d i n g t h a t t h e
e u g l o b u l i n was more a f f e c t e d than th e p s e u d o g l o b u l i n , he c o n c lu d e d
t h a t the p s e u d o g l o b u l i n c o n t a i n s m o st , i f not a l l , th e a n t i t o x i n ,
but t h a t i t seemed p r oba b le t h a t t h i s r e l a t i o n s h i p o n l y h e l d good
when t h e a n t i t o x i c o o n t e n t o f the serum was s t e a d i l y r i s i n g *
Ledlngham a l s o found t h a t i n g o a t s the a n t i t o x i o o o n t e n t o f t h e
e u g l o b u l i n and p s e u d o g l o b u l i n f r a c t i o n s may va r y a t d i f f e r e n t p e r i o d s
in t h e c o u r s e o f immunization*
Gibson and C o l l i n s , 1 9 0 7 >
E xp erim enting w i t h r a b b i t s , g o a t s and h o r s e s , and u s i n g
v a r i o u s organism s such a s B* d i p h t h e r i a , F l e x n e r manila d y s e n t e r y ,
S h i g a s d y s e n t e r y , e t c . , a s a n t i g e n s t h e y found t h a t t h e r e was g r e a t
d i s t r i b u t i o n o f the a n t i b o d i e s i n t h e d i f f e r e n t f r a c t i o n s o f a serum
and t h a t t h e d i s t r i b u t i o n o f a n t i b o d i e s v a r i e d from time t o time i n
.9 .
t h e same anim al#
They us ed ammonium s u l p h a t e t o p r e c i p i t a t e
t h e v a r i o u s f r a c t i o n s and o f ammonium s u l p h a t e t h e y s a i d t h a t i t
was not a r e l i a b l e means o f d i f f e r e n t l y c l a s s i f y i n g p r o t e l d s , th e
p r e c i p i t a t i o n c h a r a c t e r s o f which a r e not w i d e l y s e p a r a t e d *
Banzhaf and Gibson# 1 9 0 7 :
They produced a serum which was c o n c e n t r a t e d about 4 - 5
tim es i t s o r ig i n a l a n t it o x io str e n g th .
The f o l l o w i n g method was
used t o s e p a r a t e th e p s e u d o g l o b u l i n - a n t i t o x i n c o m b in a t io n from t h e
o t h e r serum p r o t e i n s .
(1)
The serum was d i l u t e d w i t h o n e - t h i r d i t s volume by w a t e r ,
and t h e n h e a t e d t o a tem perature o f 57° C. f o r 15 hou rs
or t o a tem per at ure o f 58° C. f o r 7 h o u r s .
Ammonium
s u l p h a t e was then added u n t i l i t s c o n c e n t r a t i o n was 3 0 $
o f t h e whole volume o f l i q u i d .
The p r e c i p i t a t e formed
( F r a c t i o n 1) was o b t a i n e d by f i l t r a t i o n .
(2) F r a c t i o n 1 was suspended in a s a t u r a t e d s o l u t i o n o f b r i n e .
The s o l u t i o n was f i l t e r e d and t h e f i l t r a t e c o n t a i n i n g
the s o l u b l e p s e u d o g l o b u l i n p l u s a n t i t o x i n , which had
been p r e s e n t i n f r a c t i o n 1 , was made . 2 5 $ a c i d w i t h
G lacial a cetic acid .
The e n s u i n g p r e c i p i t a t e was
f i l t e r e d , p r e s s e d and d i a l y s e d .
(3) To the f i l t r a t e from f r a c t i o n 1 was added ammonium
s u l p h a t e u n t i l i t was i n a c o n c e n t r a t i o n o f 54$ and t h e
p r e c i p i t a t e th u s formed was f i l t e r e d , p r e s s e d and
d ialysed.
The r e s i d u e from th e d i a l y s i s o f th e second f r a c t i o n
10.
p r e c i p i t a t e was t h e more p o t e n t , but t h e r e s i d u e from b o t h
d i a l y s e s from f r a c t i o n s 1 and 2 was mixed and t h e r e q u i s i t e
amount o f sodium c h l o r i d e and p r e s e r v a t i v e added*
The
f i n i s h e d f r o d u c t had a p r o t e i n c o n t e n t o f about 1 8 - 2 0 $ ,
and was c o n c e n t r a t e d t o about 4 - 5 t i m e s t h a t o f t h e o r i g i n a l
serum*
B a n z h a f , 1 9 1 2 -1 5 :
F o l l o w i n g th e p r i n c i p l e i n the l a s t method, he produced a
,fone f r a c t i o n method” #
The c o n c e n t r a t e d serum he produced had
4 - 5 t i m e s t h e a n t i t o x i c s t r e n g t h , and a p r o t e i n o o n t e n t about 2 0 $ o f
t h e o r i g i n a l serum.
(1)
The method w a s ; -
The serum was d i l u t e d by o n e - h a l f o f i t s volume by w a t e r ,
and the whole made up t o 30$ o f s a t u r a t i o n w i t h
ammonium su lp h a te *
(2)
The mixture was h e a t e d t o 60°C. and k e p t a t t h a t
tem perature f o r a few m i n u t e s .
(3)
The hot serum was f i l t e r e d .
(4)
The p r e c i p i t a t e o f e u g l o b u l i n was washed w i t h 33 $
ammonium s u l p h a t e .
The w a s h in g s were f i l t e r e d and
were added t o t h e main b u lk o f t h e f i l t r a t e , which
was then made up t o 50$ s a t u r a t i o n w i t h ammonium
sulphate.
(5)
The p r e c i p i t a t e was f i l t e r e d , p r e s s e d and d i a l y s e d *
The d i a l y s e d r e s i d u e s were t r e a t e d a s i n t h e Ban zh afGibson method*
T h is method, Banzhaf c l a i m e d , was q u i c k e r t h a t t h e
#11.
p r e v i o u s method, a s t h e time taken t o e x t r a c t t h e f i r s t f r a c t i o n
w i t h b r i n e was n o t r e q u i r e d *
I t was a c h e a p e r method b e c a u se l e s s
m a t e r i a l s were u s e d .
The drawback
however was t h a t th e p r o d u c t i o n o f a r e a d i l y
f i l t e r a b l e end p r o d u ct depended a g r e a t d e a l upon t h e c o n d i t i o n o f
t h e serum m i x t u r e s a f t e r t h e p r e l i m i n a r y h e a t i n g *
I f th e l a t t e r had
n o t f i l t e r e d r e a d i l y th e end p r o d u ct was found t o be u n s a t i s f a c t o r y *
Homer, 19161
The d i s a d v a n t a g e o f the Banzhaf one f r a c t i o n method was t h a t
the f i n a l
p ro du ct might be o p a l e s c e n t due t o a s u s p e n s i o n o f e u g l o b u l i n
and which
was d i f f i c u l t t o g e t r i d o f by f i l t r a t i o n .
From her
e x p e r i m e n t s Homer found t h a t the s u c c e s s f u l p r e p a r a t i o n o f an e a s i l y
f i l t e r a b l e end product depended upon the i n i t i a l h e a t i n g o f t h e
mixtures*
The a dv a n ta g es o f u s in g sodium o h l o r i d e in serum m i x t u r e s
weres(a)
During t h e h e a t i n g o f t h e m i x t u r e s , i f t h e tem perature was
kept a t 6 3 - 6 5 ° C . , t h e a d d i t i o n o f 1 . 5 $ sodium o h l o r i d e
d i d not change the amount o f p r o t e i n rem a ining in s o l u t i o n
but i f t h e tem perat ure were r a i s e d t o 6 7 ° C . , t h e n a
change took p l a c e .
(b)
I f a s o l u t i o n o f p s e u d o g l o b u l i n and e u g l o b u l i n i n s a t u r a t e d
brine
was heated t o 61°C. and k ept a t t h a t tem perature
for a
few m i n u t e s , 60$ o f the s o l u b l e g l o b u l i n was
c o n v e r t e d i n t o I n s o l u b l e g l o b u l i n , and t h e r e was a l o s s
of a n tito x in .
(c) The h e a t i n g o f the serum w i t h sodium o h l o r i d e d e n a t u r a t e d
the p r o t e i n and made I t more e a s i l y p r e c i p i t a t e d w i t h
•12.
sodium o h l o r i d e or 30# o f s a t u r a t i o n o f ammonium s u l p h a t e .
The sodium c h l o r i d e had a f a v o u r a b l e i n f l u e n c e on
f i l t r a t i o n by r e - a d j u s t i n g t h e pH v a lu e o f the serum m i x t u r e s .
Homer (1916^) .
F o l l o w i n g the g e n e r a l p r i n c i p l e s o f t h e Banzhaf and Gibson
and the Banzhaf methods, she produced a serum w h ic h she c l a i m e d was
8 - 9 t i m e s the s t r e n g t h and which c o n t a i n e d 1 7 - 1 9 # o f t h e t o t a l
p r o t e i n o f th e o r i g i n a l a n t i t o x i c serum.
(1)
Her method w a s : -
The serum was d i l u t e d w i t h 1 / 5 t o 1 / 3 i t s volume by w a t e r ,
and t h e n made 1 . 5 - 2 . 0 # w i t h sodium c h l o r i d e .
(2)
The mixture was toeated t o 5 6 - 5 7 ° C . f o r 15 hours or 5 7 - 5 8 ° C .
f o r 8 hours.
(3)
The h eated serum was then made 30# s a t u r a t e d w i t h ammonium
o
s u l p h a t e and the mixture h e a t e d t o 61 C. and kept a t t h a t
tem peratur e f o r a few m i n u t e s .
(4)
A f t e r i t had c o o l e d t o 4 0 -4 5 ° C . t h e m ixture was f i l t e r e d .
(5)
The p r e c i p i t a t e was t h e n washed w i t h a 33# s o l u t i o n o f
ammonium s u l p h a t e , and t h e w a s h in g s were added t o the main
bulk o f the f i l t r a t e which was then made up t o 50#
s a t u r a t i o n o f ammonium s u l p h a t e .
(6)
The p r e c i p i t a t e was f i l t e r e d , p r e s s e d and d i a l y s e d .
(7)
T h is was now t r e a t e d w ith the n e c e s s a r y amount o f sodium
c h l o r i d e and p r e s e r v a t i v e .
Th is method was an improvement on the G ib so n-Banzhaf
method f o r the f o l l o w i n g r e a s o n s : (1)
There was o n l y one f r a c t i o n , and the e x t r a c t i o n w i t h b r i n e
was u n n e c e s s a r y , so t i m e , l a b o u r and expense were s a v e d .
.1 3 .
(2)
The h e a t i n g o f the serum wade up t o 3 0 # s a t u r a t i o n w i t h
ammonium s u l p h a t e s e r v e d t o a g g l u t i n a t e t h e s u s p e n s o i d
p a r t i c l e s o f p r o t e i n i n t o c o n g l o m e r a t e s l a r g e enough t o
be r e t a i n e d i n the f i l t e r p a p e r .
In the G ib s o n - B a n z h s f
p r o c e s s i t was o f t e n n e c e s s a r y t o i n o r e a s e t h e p e r c e n t a g e
o f ammonium s u l p h a t e t o 35 t o e n s u r e the r e t e n t i o n o f th e
p a rticles.
(3) The p o t e n c y o f t h e serum was much g r e a t e r and the p r o t e i n
c o n t e n t much l e s s .
(4) The t o t a l l o s s o f a n t i t o x i c u n i t s was n o t g r e a t e r than 1 0 # .
Over th e Banzhaf p r o c e s s i t s a d v a n t a g e s w e r e : (1) As more p r o t e i n was removed a s a r e s u l t o f h e a t d e n a t u r a t i o n
o f serum p r o t e i n s and t h e i r i n c r e a s e d p r e c i p i t a b i l i t y by
30# s a t u r a t i o n o f ammonium s u l p h a t e t h e r e was l e s s chance
of f i l t r a t i o n d i f f i c u l t i e s .
(2) By the a d d i t i o n o f 1 . 5 - 2 . 0 # sodium c h l o r i d e th e r e a c t i o n
o f t h e medium ten ded t o be more s u i t a b l e f o r c o m p le t e
p r e c i p i t a t i o n o f the p r o t e i n s thrown out o f t h e e m u l s o i d
s o l u t i o n by t h e 30 # s a t u r a t i o n o f ammonium s u l p h a t e .
(3) The f i n i s h e d p r o d u ct was n e a r l y double the a n t i t o x i c
s t r e n g t h o f the Banzhaf p r o d u c t .
Homer 1916^.
Ex p er im e nting w i t h e l e c t r o l y t e s she found t h a t , i f a
serum i s h e a t e d w it h an e l e c t r o l y t e , much s t r o n g e r c o n c e n t r a t i o n s
p e r gramme o f p r o t e i n can be o b t a i n e d , bu t t h a t t h e r e i s a l s o a
l i m i t t o which a serum can be c o n c e n t r a t e d .
She used sodium o h l o r i d e
•14#
and ammonium s u l p h a t e i n c o n c e n t r a t i o n s o f 1 0 - 2 0 $ and 3 0$
resp ectively.
The s t r o n g e s t serum she produced c o n t a i n e d 2 2 , 5 0 0
u n i t s p e r gramme o f p r o t e i n .
Homer, 191V1 .
In a f u r t h e r i n v e s t i g a t i o n i n t o the f a c t o r s i n f l u e n c i n g
t h e p r o d u c t i o n o f c o n c e n t r a t e d s e r a , Homer found t h a t t h e pH o f
t h e serum was o f g r e a t importance and t h a t the b e s t r e s u l t s were
o b t a i n e d when the pH o f th e serum - ammonium s u l p h a t e m ixture - was
a d j u s t e d t o between 5 . 3 - 5 . 0 .
F u r t h e r , th e f i l t r a t i o n o f t h e
m i x t u r e s c o u ld be improved by th e a d d i t i o n o f 2 $ sodium o h l o r i d e
t o t h e m i x t u r e s , and th e improvement was due to a s p e c i f i c a c t i o n
by the sodium c h l o r i d e upon the g l o b u l i n s .
I f t h e serum was
h e a t e d f o r some h o u r s , up t o 8 , at a t em p erature o f 5 7 - 5 8 ° C . , t h e r e
was a g r e a t e r p r e c i p i t a t i o n o f p r o t e i n s by t h e ammonium s u l p h a t e .
She a l s o found t h a t by the a d d i t i o n o f p h e n o l . 3 5 -
. 5 $ t h e r e was
an a l t e r a t i o n in t h e s u r f a c e t e n s i o n o f t h e p r o t e l n s i n c o l l o i d a l
s o l u t i o n and an i n c r e a s e i n t h e i r p r e c i p i t a t i o n .
Homer 19172 .
In a f u r t h e r i n v e s t i g a t i o n she found t h a t i f 2 $ sodium
c h l o r i d e and . 3 -
. 3 5 $ c r e s y l i o a c i d were added t o the serum p r i o r
t o the h e a t i n g o f the plasma - ammonium s u l p h a t e m ixtu r e - t h e
t e n d e n c y o f th e end p r o d u c t s t o be c l o u d y was d i m i n i s h e d .
There
was no d e s t r u c t i o n o f a n t i t o x i n p r o v i d e d t h s t th e 2 $ sodium
c h l o r i d e was added, and t h a t the serum - ammonium s u l p h a t e mixture was n o t h e a t e d t o above 60°C. and was not a l l o w e d t o remain a t
t h a t tem perature f o r more than 2 h o u r s .
3
Homer, 1917 *
.It* •
She found t h a t f o r a serum whose pH v a l u e i s above
7 t h e serum must be h e a t e d t o a t em p erature o f 5 7 . 5 ° C . f o r not
l e s s than 4 and not more than 5 hours f o r the maximum p r e o i p i t a t i o n
t o be o b t a i n e d , i f 3Q$ s a t u r a t e d ammonium s u l p h a t e were u s e d .
Homer a l s o found t h a t , i f she i n c l u d e d in the second f r a c t i o n the
p r o t e i n p r e c i p i t a t e d by v a r y in g c o n c e n t r a t i o n s between 30 - 44$
o f s a t u r a t i o n w i t h ammonium s u l p h a t e i n s t e a d o f 30 - 5 0 $ , the
amount o f albumin which appeared in the f i n a l f r a c t i o n was much
reduced.
F i n a l l y , the serum produced was c l e a r e r i n c o l o u r ,
c o n t a i n e d l e s s p r o t e i n and was more c o n c e n t r a t e d than t h a t produced
when 30 - 50$ o f s a t u r a t i o n o f ammonium s u l p h a t e was u s e d .
Homer 1 9 1 8.
In 1918 she s u g g e s t e d a new m o d i f i c a t i o n o f her p r e v i o u s
method f o r c o n c e n t r a t i o n o f a n t i - d i p h t h e r i t i c
sera.
The t e c h n i q u e
w ass(1) P o o le d b a t c h e s o f u n d i l u t e d o x a l a t e d or c i t r a t e d plasma
were t r e a t e d i n the f o l l o w i n g manner (a) The pH was a d j u s t e d t o 8 .
(b) I f t h i s c o u ld not be done, between . 2 5 -
.3$
o r e s y l l c a c i d or t r i k r e s o l was added t o the plasma*
(c) 2$ sodium c h l o r i d e was added .
The plasma thus t r e a t e d was h e a t e d i n two s t a g e s ;
(1) The plasma was h e a t e d in j a r s a t a tem perat ure
o f 57*5°C. f o r 4 h o u r s .
( i i ) T h e plasma was then made 30$ o f s a t u r a t i o n with
ammonium s u l p h a t e and the temperat ur e r a i s e d t o
• 16 .
58°C# and t h e n c o o l e d t o 45°C*
The m i x t u r e s were
constan tly stirred*
(2) The m ix tu r e was f i l t e r e d and F r a c t i o n 1 o b t a i n e d *
T h is
f i r s t fr a c tio n p r e c ip it a t e , c o n sistin g of euglobu lin,
h e a t d e n a t u r a t e d p r o t e i n and pseu do g l o b u l i n , was now
washed w i t h 30 $ s a t u r a t i o n o f ammonium s u l p h a t e - about
o n e - h a l f volume o f ammonium s u l p h a t e to one volume o f
plasma*
The w a s h i n g s were now added t o the main b u lk
o f the f i l t r a t e s , and then t o t h e main b u lk was added a
s a t u r a t e d s o l u t i o n o f ammonium s u l p h a t e t o b r i n g th e
ammonium s u l p h a t e c o n t e n t up t o 46$ o f s a t u r a t i o n *
The
p r e c i p i t a t e produced was now f i l t e r e d , p r e s s e d and
d i a l y s e d u n t i l i t was f r e e o f s u l p h a t e *
To t h e r e s i d u e
was added *85$ sodium c h l o r i d e and . 3 5 $ c r e s y l i c a c i d *
About 18$ o f a n t i t o x i n was l o s t *
To a v o i d t h i s 18$
l o s s o f a n t i t o x i n the f o l l o w i n g method was employed;
a f t e r t h e f i r s t p r e c i p i t a t e s had been washed w i t h 3 0 $
o f s a t u r a t i o n ammonium s u l p h a t e , th e y were put i n t o ca nvas
bags and t h e s e were p l s c e d i n a s a t u r a t e d s o l u t i o n o f
brine*
The f i r s t p r e c i p i t a t e s o f many p la s m a s were added
to the brine tu b .
T h is was c l o s e d a t room tem perature
f o r some time and th e n the b r i n e d e x t r a c t o f a l l t h e
p r e c i p i t a t e s was f i l t e r e d *
To t h e f i l t r a t e was added
. 3 $ g l a c i a l a c e t i c a c i d and t h e p r e c i p i t a t e produced was
f i l t e r e d , p r e s s e d and d i a l y s e d a f t e r 3$ washing soda had
been added t o the c o n t e n t s o f each d i a l y s i n g bag*
The
d i a l y s i n g was c o n t i n u e d u n t i l th e c o n t e n t s o f the bags
t !? •
were f r e e from s a l t *
To t h e s e r e s i d u e s were added *85$
s o l i d sodium o h l o r i d e and * 3 5 $ o r e s y l i c a c i d *
T h i s method had the f o l l o w i n g a d v a n t a g e s : (!)• The ad ju stm e n t o f t h e u n d i l u t e d plasma removed t h e
d i f f i c u l t i e s experienced in the f i l t r a t i o n o f the hot
plasma-ammonium s u l p h a t e mixture*
(2) The two s t a g e s c o u l d be oom pleted in 7 hours*
(3) By p r e c i p i t a t i o n w i t h 40$ and no t 50$ s a t u r a t i o n ammonium
s u l p h a t e the h e a t d e n a t u r a t e d albumin In t h e f i n a l
p r o d u ct was l e s s and th e serum was c l e a r e r *
(4) The l o s s o f a n t i t o x i n was reduc ed t o 2 *5 $ .
Homer 1919^ *
From f u r t h e r i n v e s t i g a t i o n s upon the c o n c e n t r a t i o n o f
a n t i t o x i n s , she con c lu d e d t h a t where a serum showed a 35 $ or
l e s s , h e a t d e n a t u r a t i o n , t h e secon d f r a c t i o n must be p r e c i p i t a t e d
by ammonium s u l p h a t e between 30 - 45$ o f s a t u r a t i o n *
I f ammonium
s u l p h a t e o f l e s s than 45$ o f s a t u r a t i o n was n o t u s e d , then some
o f t h e a n t i t o x i n was d i s c a r d e d w i t h the albumin f i l t r a t e s *
F u r t h e r , i f t h e lo w er f i g u r e o f 30 $ was r a i s e d , some o f the
a n t i t o x i n was a g a in l o s t b eca use i t was p r e c i p i t a t e d w i t h t h e
f i r s t f r a c t i o n and i n such a form t h a t i t was i n s o l u b l e i n b r i n e .
Homer a l s o c onclu ded t h a t where the h e a t d e n a t u r a t i o n was 35$
or l e s s the a n t i t o x i n was p r e c i p i t a t e d w i t h s a t u r a t i o n s o f
ammonium s u l p h a t e v a r y in g between 36 - 45$*
From her o b s e r v a t i o n s
she thought t h a t t o i s o l a t e a n t i t o x i n s c o m p l e t e l y , o t h e r means
than f r a c t i o n a l p r e c i p i t a t i o n would have t o be used*
Homer 19192 *
I n v e s t i g a t i n g f u r t h e r i n t o th e c o n o e n t r a t i o n o f
a n t i t o x i n , Homer showed t h a t th e i n o r e a s e d p r e c i p i t a b l l i t y o f
p s e u d o g l o b u l i n by s a t u r a t i o n s o f ammonium s u l p h a t e v a r y i n g
between 20 - 47$ depended upon t h e h e a t i n g o f t h e serum*
She
a l s o d e m o n s tra te d t h a t t h e r e was no need t o have a p r e l i m i n a r y
h e a t i n g o f the serum*
When ammonium s u l p h a t e was used In
s a t u r a t i o n s v a r y in g between 30 - 44$ w i t h h e a t e d serum, t h e same
r e s u l t s c o u l d be o b t a i n e d u s i n g ammonium s u l p h a t e in s a t u r a t i o n s
o f 36 - 6 0 $ , and unhe at ed serum*
The h e a t i n g o f the serum,
how ever, red uced t h e t o x i c i t y o f the c r e s y l i c a c i d - p r o t e i n
complex.
Homer 1919^.
Comparing the u s e s o f sodium s u l p h a t e and ammonium
s u l p h a t e a s p r e o i p i t a n t s o f a n t i t o x i n , Homer found t h a t t h e r e were
no o r i t i c a l p o i n t s which marked out t h e p r e c i p i t a t i o n l i m i t s o f
the i n d i v i d u a l p r o t e i n s , and t h a t t h e c o n c e n t r a t i o n s o f sodium
s u l p h a t e and ammonium s u l p h a t e v a r i e d w i t h t h e pH v a l u e o f the sera*
They a l s o v a r i e d depending upon whether or not the serum had been
t r e a t e d w i t h c r e s y l i c a c id *
She s t a t e d t h a t when sera are b e i n g
h e a t e d p r i o r t o p r e c i p i t a t i o n , th e use o f c r e s y l i c a c i d I s
b e n e f i c i a l , but w i t h unheated serum i t must not be used*
When
sodium s u l p h a t e was used t h e a g g l u t i n a t i o n o f the p a r t i c l e s o f
p r e c i p i t a t e d p r o t e i n i n t h e e u g l o b u l i n and p s e u d o g l o b u l i n zone
was b e t t e r than I f ammonium s u l p h a t e was u s e d .
The r e a so n f o r
t h i s i s t h a t the sodium s u l p h a t e d o e s not hydrolyse in s o l u t i o n ,
•1 9 .
but ammonium s u l p h a t e d o e s , and so the sodium s u l p h a t e f i r s t
f r a c t i o n s c o u l d be h e a t e d f o r 4 - 5
l o s i n g any o f the a n t i t o x i n .
hours a t 58°C• w i t h o u t
The end pr odu ct was c l e a r e r t han
t h a t produced by the t w o - s t a g e ammonium s u l p h a t e method.
Barr, Glenny and P op e , 1 9 5 1 .
For g r e a t e r a c c u r a c y , t h e y conc lu d e d s o l i d ammonium
s u l p h a t e s h o u ld be used i n p r e c i p i t a t i o n , as the s o l u b i l i t y o f
s a l t s v a r i e s w i t h the t e m p e r a t u r e .
When a s o l u t i o n - o f
ammonium s u l p h a t e was added t o a serum, the p r o t e i n f i l t r a t e
became d i l u t e d w i t h each a d d i t i o n o f the ammonium s u l p h a t e
solu tion .
The
q u a n t i t i e s o f ammonium s u l p h a t e should be
e x p r e s s e d i n grammes p e r l i t r e o f the serum, and not a s a
p e r c e n t a g e o f s a t u r a t i o n as t h i s v a r i e s w i t h t h e t e m p e r a t u r e .
They found t h a t i f albumin were added t o a serum a
g r e a t e r q u a n t i t y o f ammonium s u l p h a t e was r e q u i r e d t o p r e c i p i t a t e
t h e a n t i t o x i n , and t h a t t h e amount r e q u i r e d i n c r e a s e d a s t h e y
i n c r e a s e d t h e amount o f albumin.
F u r t h e r , they found t h a t i f two a n t i s e r 8 , which
showed d i f f e r e n c e s i n a n t i t o x i n d i s t r i b u t i o n a s determ ined by
s a l t i n g - o u t methods, were mixed, some r e d i s t r i b u t i o n o f
a n t i b o d i e s took p l a c e .
(b) P r e o i p i t a t i o n by A l c o h o l .
M ella n b y , 1 908.
He found t h a t , working a t room t e m p e r a t u r e s , the
g r e a t e r p r o p o r t i o n o f th e a n t i t o x i n was p r e c i p i t a t e d by a
•20 •
c o n c e n t r a t i o n o f a l c o h o l between 35 - 4b%»
When w orking a t
a tem p er atu r e o f 2°C. he found t h a t most o f th e a n t i t o x i n was
p r e c i p i t a t e d by a c o n c e n t r a t i o n o f a l c o h o l between 16 - 2 8 ^ .
The advantage o f the c o l d method was t h a t t h e t o t a l p r o t e i n
p r e c i p i t a t e d was s o l u b l e and so t h e whole o f the a n t i t o x i n c o u l d
be r e c o v e r e d .
At the h i g h e r t e m p e r a t u r e , some o f t h e a n t i t o x i n
was l o s t through c o a g u l a t i o n o f the p r o t e i n .
Mellanby a l s o found t h a t i f a l c o h o l was added t o an
a n t i t o x i c serum, i t d id not d e s t r o y th e a n t i t o x i n s so l o n g a s
none o f the p r o t e i n s were c o a g u l a t e d .
When c o a g u l a t i o n o f t h e
p r o t e i n s to o k p l a c e , d e s t r u c t i o n o f a n t i b o d y a l s o oc cu rr ed *
He
conc lu d e d t h a t , so f a r as the c o a g u l a t i n g a c t i o n o f a l c o h o l was
c o n c e r n e d , t h e r e i s no p h y s i c a l d i f f e r e n c e between d i p h t h e r i a
a n t i t o x i n and p r o t e i n s from normal serum.
Hardy and G a r d in e r , 1 9 1 0 .
They p r e c i p i t a t e d the p r o t e i n s in a n t i s e r a by
a b s o l u t e a l c o h o l or a c e t o n e a t 0°C*
was a w h ite powder.
The p r o d u c t t h e y o b t a i n e d
o
T h i s was washed w i t h e t h e r a t 0 C* t o
remove the a l c o h o l or a c e t o n e .
The p r e c i p i t a t e was t h e n e x t r a c t e d
w i t h b o i l i n g e t h e r , f i l t e r e d and d r i e d i n vacuo w i t h s u l p h u r i c
acid .
T h is p r e c i p i t a t e l a s t e d i n d e f i n i t e l y , and when
r e d i s s o l v e d showed the a n t i t o x i n t o be p r e s e n t undamaged.
Moloney and T a y l o r , 1 9 2 8 .
Usin g v a r i o u s c o n c e n t r a t i o n s o f a l c o h o l a t v a r i o u s
pH v a l u e s , t h e y found t h e optimum c o n c e n t r a t i o n f a c t o r t o be
about 3 0 $ .
They t r e a t e d a c l t r a t e d plasma whose pH v a l u e was
.2 1 .
5*3 w i t h 14$ a l c o h o l a t a t em p era ture o f 40°C*
They a l s o found
t h a t t h e same c o n c e n t r a t i o n f a c t o r c o u l d be o b t a i n e d working
a t room t em p era ture i f t h e y used c i t r a t e d p la sm a, pH 5*3 bu t
27$ a l c o h o l *
Using t h e serum t h e y o b t a i n e d in i n t r a d e r m a l t e s t s upon
known serum s e n s i t i v e p a t i e n t s , t h e y fo und t h a t t h e i r a l c o h o l
produced serum c au se d l e s s r e a c t i o n than t h a t produced by t h e
use o f ammonium s u l p h a t e *
M e r r i l l and F l e i s h e r , 1 9 32 .
They used a s p r e c i p i t a n t s f o r the a n t i t o x i n m e t h y l ,
e t h y l and p r o p y l a l c o h o l in v a r y i n g s t r e n g t h s , a t v a r i o u s
tem p e r a t u r e s and a t v a r y in g pH c o n c e n t r a t i o n s *
They found
that (1) Between 70 - 75$ c o n c e n t r a t i o n t h e r e was c o m p lete
p r e c i p i t a t i o n o f p r o t e i n s , but t h a t th e p r e c i p i t a t e
was alm o st a l l i n s o l u b l e in w a t e r .
(2) With h i g h e r c o n c e n t r a t i o n s o f a l c o h o l , p r o t e i n
p r e c i p i t a t i o n was a l s o c o m p l e t e , bu t t h a t t h e
p r e c i p i t a t e was r e a d i l y s o l u b l e i n water*
^
(3) The l o s s o f a g g l u t i n i n s was a l m o s t p a r a l l e l w i t h the
lo ss of so lu b ility *
(4) I f th e tem perat ure o f the serum was r a i s e d the
so lu b ility
o f t h e p r e c i p i t a t e d i m i n i s h e d e v en when
a l c o h o l i c c o n c e n t r a t i o n s o f 90$ were used*
/ \
(5)
0
At low t e m p er a tu r es - 5 C* - a l l p r e c i p i t a t e s , no m a tter
what c o n c e n t r a t i o n o f a l c o h o l had been u s e d , were
solu b le in w ater.
(6) The pH v a l u e f o r maximum p r e o i p i t a t i o n i s 6 , and
p r e o l p i t a t i o n i s l e s s , above and b e lo w t h i s v a l u e .
(7) The g r e a t e r t h e o o n o e n t r a t i o n o f t h e serum, t h e g r e a t e r
t h e amount o f p r o t e i n p r e c i p i t a t e d by any g i v e n
oonoentration of a lo o h o l.
T h e i r method f o r p r o d u cin g an immune serum i n a d r y s t a t e
was 2 (1) They added one volume o f serum t o 10 o f a o e t o n e .
(2) The p r e c i p i t a t e was washed w i t h a c e t o n e and then t h r e e
t i m e s w i t h anhydrous e t h e r *
(3) The w h i t e powder was p l a c e d i n an i n c u b a t o r f o r one hour
a t 37°C.
(4) The powder was r e d i s s o l v e d in d i s t i l l e d w a t e r or
•85$ sodium c h l o r i d e *
They found t h a t t h e r e was no l o s s o f a n t i b o d y i f t h i s
method was c a r r i e d out at a tem perat ure o f 20 - 2 5 ° C • and i f t h e
i n c u b a t i o n d i d not e x c e e d one h o u r.
(c)
A dsorption.
Muoh o f t h e e x p e r i m e n t a l work has been done on
a n t i b o d i e s o t h e r than d i p h t h e r i a a n t i b o d i e s .
E l s l e r and S p i e g e l - A d o l f , 1 9 2 9 .
have s t u d i e d t h e a d s o r p t i o n
o f t y p h o i d a n t i b o d i e s w i t h aluminium hyd rox id e and e l u t i o n w i t h
N/10 sodium h y d r o x i d e .
They s u cc ee d e d i n c o n c e n t r a t i n g the
serum t o a s l i g h t e x t e n t .
When S p i e g e l - A d o lf (1932) a t t e m p t e d
t o p u r i f y o t h e r a n t i s e r a by the same method, he had no s u c c e s s .
.2 3 .
F r a n k e l , 1952
A d opting t h e method d e s c r i b e d by O l i t z k l and
FrSTnkel (1931) he p r e p a r ed
e l u t e s from d i p h t h e r i a
se ra whioh
c o n t a i n e d 12 - 2 4 $ o f the
o r i g i n a l a n t i b o d y , bu t t h i s was l a t e r
d i s p r o v e d by Pope and Marrack.
(d)
Cataphoresis*
M e lla n b y , 1 9 0 8 .
He p a s s e d a c o n s t a n t c u r r e n t o f
100 v o l t s through
z i n c s u l p h a t e e l e c t r o d e s i n t o an a n t i t o x i c
serum f o r 3 hours*
o b t a i n e d a d e p o s i t o f i n s o l u b l e p r o t e i n on
th e anode*
a n t i t o x i c v a l u e o f the rem a ining serum was
found t o have remained
constant*
He
The
The a n t i t o x i n had n e i t h e r accum ulate d nor d i m i n i s h e d
i n t h e rem ain in g serum.
He c o n c lu d e d t h a t d i p h t h e r i a a n t i t o x i n
p o s s e s s e d the same p r o p e r t i e s a s normal p r o t e i n s when t e s t e d by
an e l e c t r i c c u r r e n t p a s s i n g th rough i t .
When the i n s o l u b l e mass o f p r o t e i n a t t h e anode was
r e d i s s o l v e d in sodium h y d r o x i d e , i t was found t o
v a l u e p r o p o r t i o n a l t o the
have an a n t i t o x i c
amount o f p r o t e i n d i s s o l v e d - t h a t i s ,
the p r e c i p i t a t e p o s s e s s e d t h e a n t i t o x i c V8lue o f t h e o r i g i n a l
protein.
P a u l i , 1924
1 &2
He used a t h r e e chambered c e l l c o n t a i n i n g t h e serum
i n th e middle compartment, which was s e p a r a t e d from the o t h e r
two chambers by two semi-permeable membranes*
The two end
compartments c o n t a i n e d p la tinu m e l e c t r o d e s p l a c e d i n f l o w i n g
d i s t i l l e d water.
When a c u r r e n t was p a s s e d the i o n s o f t h e
•24.
serum p a s s e d t o the e l e c t r o d e s , t h e e q u i l i b r i u m be tween th e
e l e c t r o l y t e s and t h e p r o t e i n s was d i s t u r b e d and t h e g l o b u l i n s
were p r e c i p i t a t e d .
The e u g l o b u l i n s e p a r a t e d f i r s t and a f t e r
p r o l o n g e d e l e c t r o d i a l y s i s t h e p s e u d o g l o b u l i n was a l s o
p r e c i p i t a t e d , and so a g l o b u l i n f r e e s o l u t i o n o f albumin was
obtained.
A d o lf, 1924.
U sin g the same method, she found t h a t t h e
p r e c i p i t a t e s produced l a s t in e l e o t r o d i a l y s l s c o n t a i n e d l i t t l e
a n t i t o x i n , but t h a t t h e amount o f a n t i t o x i n i n c r e a s e d a s
p r e c ip it a t io n increased#
She c l a i m e d by h e r method t o be a b l e
t o remove a l l the a n t i t o x i n .
W ern ic ke, 1 9 2 5 .
He used the same method a s A d o l f , but was unable t o
p r e c i p i t a t e a l l the a n t i t o x i n .
(e) Enzymes.
M ella n b y , 1 9 0 8 *
He found t h a t i f 0 . 2 $ h y d r o c h l o r i c a c i d were added
t o a serum i t d i d not d e s t r o y t h e a n t i t o x i n , bu t i f p e p s i n were
a l s o added, t h e a n t i t o x i n was r a p i d l y d e s t r o y e d .
had t h i s e f f e c t , but a c t e d more s l o w l y .
Trypsin a l s o
He e x p e r im e n t e d w i t h
t r y p s i n and found t h a t t h e d i m i n u t io n o f the amount of p r o t e i n
p r e c i p i t a t e d by ammonium s u l p h a t e a f t e r d i g e s t i o n w i t h t r y p s i n
was c o n s t a n t f o r a l l c o n c e n t r a t i o n s o f ammonium s u l p h a t e .
Pope 1 9 5 8 .
He o b t a i n e d two p s e u d o g l o b u l i n s o l u t i o n s from one
•25 •
o r i g i n a l a n t i - s e r u m by the f o l l o w i n g method:He o b t a i n e d a p r e c i p i t a t e , whioh c o n s i s t e d o f f i b r i n ,
e u g l o b u l i n and some p s e u d o g l o b u l i n , by p r e c i p i t a t i o n o f
th e d i p h t h e r i a plasma by 30$ s a t u r a t i o n w i t h ammonium
sulphate*
The a n t i t o x i c p s e u d o g l o b u l i n was e x t r a c t e d by
s o l u t i o n and r e p r e c i p i t a t i o n w i t h ammonium s u l p h a t e *
When t h i s had been d i l u t e d t o a p p r o x i m a t e l y 2 $ p r o t e i n and
when 5$ sodium c h l o r i d e had been a dd ed , s o l u t i o n s o f
v a r y i n g pH v a l u e were o b t a i n e d and h e a t e d a t v a r i o u s
t e m p e r a t u r e s to d e n a t u r a t e th e p r o t e i n s *
The t e m p e r a t u r e s
o
v a r i e d between 58 and 65 0 . , depend ing upon the pH v a l u e o f
th e s o l u t i o n *
The a n t i t o x i c c o n t e n t was measured
th e f l o c c u l a t i o n method and t h e p r o t e i n by the Z e i s s
d i p p i n g R e f ra c t o m et e r*
I t was found t h a t where t h e pH v a l u e had been a d j u s t e d t o
around 4*0 and c e r t a i n t e m p e r a t u r e s had been u s e d , th e
d e s t r u c t i o n o f a n t i t o x i n was much l e s s than t h e
d e n a t u r a t i o n and l o s s o f s o l u b i l i t y o f p r o t e i n *
A fter
f i l t r a t i o n , the r e s i d u a l a n t i t o x i n and p r o t e i n were found*
The number o f a n t i t o x i c u n i t s p e r gramme o f p r o t e i n was
a s much a s f i v e t i m e s a s many, per gramme o f p r o t e i n o f
the o r i g i n a l s o l u t i o n .
When a s i m i l a r experim en t was c a r r i e d out on a n o t h e r
p s e u d o g l o b u l i n s o l u t i o n o b t a i n e d by f r a c t i o n a t i o n by
ammonium s u l p h a t e i n v a r y i n g c o n c e n t r a t i o n s between 30 and
5 0 $ , t h e r e was no i n c r e a s e in a n t i t o x i c u n i t s p e r gramme o f
•26.
protein*
The d i f f e r e n o e betw een th e two p s e u d o g l o b u l i n s o l u t i o n s
was t h a t i n one c a s e t h e p s e u d o g l o b u l i n had been a c t e d upon by
the enzyme f i b r i n o l y s i n , w h i l s t In t h e o t h e r i t had n o t *
The
d i f f e r e n c e In t h e r e s u l t s o b t a i n e d was in no way dependent upon
the p s e u d o g l o b u l i n b e c a u se when f i b r o l y s i n was added t o the
second s o l u t i o n , I t behaved in t h e same manner a s th e f i r s t *
He v i s u a l i z e d the i n t a c t a n t i t o x i c p s e u d o g l o b u l i n
m o l e c u l e a s ha v in g two comp onents, one n o n - a n t l t o x i c w i t h a low
h e a t d e n a t u r a t i o n tem peratu re and the o t h e r b e a r i n g a n t i t o x i c
p r o p e r t i e s and l e s s e a s i l y d e n a t u r a t e d *
Under c e r t a i n
c o n d i t i o n s c r i t i c a l d e n a t u r a t i o n , d e n a t u r a t e s t h e f i r s t o f t h e s e and
r e n d e r s the whole m o lec u le I n s o l u b l e , but by means o f enzyme a c t i o n
the u n dena tu ra ted p r o t e i n may be s p l i t o f f a s a s o l u b l e p r o t e i n ,
s t i l l having i t s s p e c i f i c a n t i t o x i c a c t i v i t y *
I f t h e p r o t e o l y t i c enzyme i s a l lo w e d t o a c t o n l y on th e
u n de na tu ra te d p r o t e i n t h e n , f o r a de gree o f h y d r o l y s i s which
cannot be d e t e c t e d a s a change i n t h e t o t a l p r o t e i n c o n t e n t , a
change i s produced which a l l o w s the e a s i l y d e n t a u r a b l e p o r t i o n
t o become i n s o l u b l e w i t h o u t I n t e r f e r e n c e w i t h t h e o t h e r
a n t i t o x i n bearing fr a c tio n *
Pope found a l l p r o t e o l y t i c enzymes t o g i v e t h e same
r e s u l t s a s f l b r i n o l y s i n when employed under c o r r e c t c o n d i t i o n s *
Pope, 1939 (1)
He used v a r i o u s p r o t e o l y t i c enzymes such as p e p s i n
(BP 1 / 2 0 0 0 - 1 / 1 0 , 0 0 0 ) , T r yp sin and a c t i v a t e d papain t o d i g e s t
.2 7 .
the n o n - a n t i t o x i c p r o t e i n i n serum and so I n c r e a s e t h e
p u r i t y o f the a n t i t o x i n .
He d e f i n e d t r u e d i g e s t i o n o f
p r o t e i n a s flI t s c o n v e r s i o n i n t o a form no l o n g e r o o a g u l a b l e
by h e a t a t t h e i s o e l e c t r i c p o i n t o f the p r o t e i n ( i n t h e
presence of a s u ita b le e l e c t r o l y t e )
”.
He found t h e f a c t o r s t o be o b s er v ed when t r u e d i g e s t i o n
i s being considered were:(1) Where t h e tem per at ure was 2 0 ° C . , t h e r e a c t i o n o f t h e
s o l u t i o n may be pH 3 , b u t where t h e tem p er a tur e was
35 - 4 0 ° C . , the pH must be h i g h e r than 4 .
I f not,
th e r e was marked l o s s o f a n t i t o x i n .
(2) Where th e r e a c t i o n o f the s o l u t i o n was pH 4 th e r a t i o
o f p e p s i n t o p r o t e i n must be kept h i g h - ^/10
( P e p s i n 5 . P . 1 / 1 0 , 0 0 0 ) , i f n o t , a p r e c i p i t a t e was
formed and t h i s c a r r i e d out the enzyme w i t h i t *
At
lower pH v a l u e s t h i s p r e c i p i t a t e was not formed, and
so l o w e r p e p s i n - p r o t e i n r a t i o s c o u l d be u s e d .
(3) During th e d i g e s t i o n by enzymes, p r o t e o s e s were formed,
8nd so pure a n t i t o x i n c o u l d not be o b t a i n e d by s a l t i n g
out methods, as t h e s e p r o t e o s e s were a l s o p r e c i p i t a t e d
with a n t i t o x i n .
He found t h a t not more than 90$ o f t h e o r i g i n a l
p r o t e i n could be d i g e s t e d w i t h o u t much o f the a n t i t o x i n b e i n g
lo st.
He a l s o fo u n d , from a st u d y o f t h e plasma from i n d i v i d u a l
h o r s e s t h a t p r o t e i n d i g e s t i o n and a n t i t o x i n s t a b i l i t y v a r i e d
g r e a t l y , even a l t h o u g h the c o n d i t i o n s o f t h e p e p t i c d i g e s t i o n were
4
28
•
k ept as n e a r l y I d e n t i c a l a s p o s s i b l e #
Some p la s m a s showed
marked a n t i t o x i c l o s s f o r th e d i g e s t i o n o f t h e f i r s t p o r t i o n s
o f p r o t e i n w h i l e o t h e r s showed an a n t i t o x i n l o s s w h ic h was
c o n s t a n t i n terms o f " u n i t s p er gram p r o t e i n l o s s , p e r gram o f
p r o t e i n d i g e s t e d ” u n t i l most o f t h e p r o t e i n had been d i g e s t e d #
Serum from h o r s e s which had been immunized r a p i d l y t o a h ig h
t i t r e gave th e b e s t r e s u l t s w i t h a sim ple d i g e s t i o n method#
The a n t i t o x i n m o l e c u l e , when a l t e r e d by enzyme a o t i o n ,
was more s t a b l e t o p h en o l than t h a t p r e p ar ed by o t h e r methods#
Fope c o n c lu d e d t h a t t h e p u r i f i c a t i o n o f a n t i b o d i e s by
enzyme a c t i o n had l i t t l e
advantage o ver s a l t i n g out methods
u n l e s s i t was f o l l o w e d by t h e use o f a d s o r p t i o n p r o c e d u r e s t o
remove th e i n e r t p r o t e i n s .
P o p e , 1939^#
E x p er im e n tin g f u r t h e r w i t h enzymes he t r i e d the e f f e o t
of:
(1) H ea ting th e plasma b e f o r e t r e a t m e n t w i t h t h e enzyme
(2) A f t e r s l i g h t enzyme a c t i o n , h e a t i n g t h e serum and
s e p a r a t i n g the p r o t e i n s by c r i t i c a l h e a t d e n a t u r a t i o n #
The second was th e b e t t e r method#
Prom h i s f u r t h e r e x p e r i m e n t s he s u b s t a n t i a t e d h i s
t h e o r y t h a t t h e a n t i t o x i c g l o b u l i n i s a complex moleoul© which
i s composed o f two p r o t e i n components, one o f which i s non­
a n t i t o x i c and i s e a s i l y d e n a t u r s t e d i n a c i d s o l u t i o n s and t h e
o t h e r which i s a n t i t o x i c and i s l e s s e a s i l y d e n a t u r a t e d .
The
a n t i t o x i c g l o b u l i n can e a s i l y be d i s a g g r e g a t e d i n t o i t s two
•29 •
components by enzyme a c t i o n *
The second p o r t i o n i s , however, d e n a t u r a t e d by a l c o h o l ,
a o e to n e or urea#
Pope a l s o found t h a t i f the o r i g i n a l a n t i t o x i c
s o l u t i o n or the s e p a r a t e d a n t i t o x i c p o r t i o n was h e a t e d t o e x o e s s ,
or h e a t e d i n a s o l u t i o n whose pH v a lu e was 3 or l e s s , t h e
a n t i t o x i c p r o p e r t y was perm a n en tly l o s t *
H is e x p e r i m e n t s showed t h a t the d i s a g g r e g a t i o n o f
the a n t i t o x i c m o l e c u l e i n t o i t s two component p a r t s c o u l d be
a c c o m p l i s h e d by a v e ry s m a l l amount o f enzyme i n a v e r y s h o r t
time •
His method f o r c o n c e n t r a t i n g a n t i t o x i n on a l a r g e
scale i s The o r i g i n a l plasma c o n t a i n i n g #4$ t r i c r e s y l i s d i l u t e d w i t h
volumes o f w a t e r b e f o r e the pH i s a d j u s t e d , and b e f o r e the
p e p s i n i s added*
I f t o l u o l i s added p r i o r t o h e a t i n g , t h e
l i p o i d s i n t h e serum come out w i t h t h e c o a g u l a t e d p r o t e i n
when t h e mixture i s h e a t e d t o 55°C* f o r two hours#
The
enzyme i s added, and i t i s arranged t h a t a t r u e d i g e s t i o n
w i l l n o t t a k e p l a c e , as t h i s would (1) produce p r o t e o s e s
which would be s a l t e d - o u t l a t e r in the p r o c e s s , and (2) make
i t im possible for
d i f f e r e n t i a l h e a t i n g t o be employed t o
separate the p r o t e i n s .
A d i s a g g r e g a t i o n i s made t o ta k e
p l a c e , and the c o n d i t i o n s f o r t h i s vary w i t h t h e enzyme
chosen*
For p e p s i n i t i s a pH o f 3*2 and a tem per atur e
o f 20 - 23°C* f o r 30 minutes*
The enzyme a c t i o n i s then stopped by c hangin g t h e
•30 •
pH o f t h e s o l u t i o n from 3 . 2 t o 4 . 1 , u s i n g sodium h y d r o x i d e and
adding a h i g h c o n c e n t r a t i o n o f an e l e o t r o l y t e
sulphate)
( s a t u r a t e d ammonium
t o p r e c i p i t a t e some p r o t e i n and th e enzyme*
The
m ixtur e i s now h e a t e d to the tem p erature which c o a g u l a t e s the
non-antitoxic p ro tein .
The pH o f t h e f i l t r a t e
i s adjusted to
7 and t h e a n t i t o x i n i s p r e c i p i t a t e d by 30 - 3 2$ ammonium
sulphate.
The p r e c i p i t a t e i s p r e s s e d and d l a l y s e d *
The f i n a l
p r o d u c t has a p r o t e i n c o n t e n t o f 10$ and an i n c r e a s e o f
a n t i t o x i c u n i t s p e r m i l l i l i t r e o f 8 - 12 t i m e s .
i s about 60$ o f th e o r i g i n a l t o t a l .
The a n t i t o x i n
T h is i s c a l l e d ’’R e f i n e d
serum” .
(2)
S p e c i f i c Methods.
The a c t i v e immunization o f human b e i n g s a g a i n s t
d i p h t h e r i a by the use o f s l i g h t l y n t o x i c m i x t u r e s o f t o x i n and
a n t i t o x i n was f o r many y e a r s a t t e n d e d by u n p l e a s a n t r e a c t i o n s
in the p a t i e n t .
These r e a c t i o n s were i n t h e main due t o the
p r e s e n c e o f n o n - s p e c i f i c p o i s o n o u s s u b s t a n c e s a r i s i n g m a in ly from
t h e c u l t u r e medium used f o r t h e p r o d u c t i o n o f t h e t o x i n , the
p r o d u c t s o f b a c t e r i a l growth o t h e r than t o x i n , b a c t e r i a l p r o t e i n
and h o r s e serum.
These u n d e s i r a b l e c o n s t i t u e n t s o f d i p h t h e r i a
p r o p h y l a c t i c s have been d i f f i c u l t t o remove.
I t was Ramon (1922)
who f i r s t s u g g e s t e d t h a t f l o o c u l e s which form when n e u t r a l or
n e a r l y n e u t r a l m i x t u r e s of t o x i n and a n t i t o x i n are l e f t a t room
temperature f o r some time might be used t o c o n c e n t r a t e
an ti-d ip h th eritic sera.
t h e s e l i n e s has e v o l v e d .
Prom t h i s e x perim en t much work alo n g
.3 1 .
Ramon, G. 1 9 2 5 .
To 500 c . c f s o f f r e s h d i p h t h e r i a t o x i n he added
40 c . c f s o f a n t i t o x i n c o n t a i n i n g 200 u n i t s p e r c . c .
He
s e p a r a t e d t h e p r e o i p i t a t e o f t o x i n - a n t i t o x i n f l o o c u l e s by
c e n t r i f u g i n g , and t h e n t h e f l o c c u l e s were was he d, f i r s t w i t h
p h y s i o l o g i c a l s a l t s o l u t i o n , and then w i t h d i s t i l l e d w a t e r .
The p r e p a r a t i o n was n e x t d i s s o l v e d i n 75 o . c 1s o f N/ 1 0 0
a c e t i c a c i d , and t h e mixture h e a t e d f o r one hour a t a
o
tem perature o f 58 - 60 C.
I t was e s t i m a t e d to c o n t a i n a
c o n c e n t r a t i o n o f 6 0 , 0 0 0 u n i t s p e r gram o f d r i e d f l o c c u l e and
t o r e p r e s e n t a r e c o v e r y o f 75$ o f th e o r i g i n a l t i t r e .
H a r t l e y , 1925.
He prepared f l o o c u l e s in which th e a n t i t o x i n was in
e x ce ss of the t o x i n .
These f l o c c u l e s were i n s o l u b l e in s a l i n e ,
and a f t e r r e p e a t e d w a s h i n g s c o n t a i n e d l e s s t ha n 1$ o f t h e
n i t r o g e n compounds o f th e o r i g i n a l m i x t u r e .
These f l o c c u l e s
caused no r e a c t i o n when i n j e c t e d i n t o guin ea p i g s , even in
large do ses.
When gu in ea p i g s were i n j e c t e d w i t h a q u a n t i t y o f the
em u lsion o f t h e f l o c c u l e s which c o n t a i n e d l e s s than a
hundredth o f a milligramme o f f l o c c u l e , t h e y became immune t o
diphtheria t o x in .
H a r t l e y found t h a t the v a l u e o f the f l o c c u l e s v a r i e d
w i t h th e o r i g i n a l t o x i n - a n t i t o x i n m i x t u r e .
I f the a n t i t o x i n
had been much in e x c e s s o f the t o x i n , t h e f l o c c u l e s d i d not
induce a h i g h degree o f immunity i n the guinea p i g s .
I f the
.3 2 .
a n t i t o x i n were o n l y s l i g h t l y i n e x c e s s , t h e n th e f l o c c u l e s
produced good immunity.
I f the t o x i n was v e r y s l i g h t l y i n
e x c e s s o f th e a n t i t o x i n , t h e f l o c c u l e s produced th e h i g h e s t
de g r ee o f immunity o f t h e s e t h r e e t y p e s o f f l o o c u l e s .
H a r t l e y 1926*
He s u b s t a n t i a t e d h i s f i n d i n g s on t h e a n t i g e n i c
p r o p e r t i e s o f th e t h r e e d i f f e r e n t t y p e s o f f l o c c u l e and he
o b s er v ed t h a t the f l o o c u l e s formed i n e x c e s s o f t o x i n t o o k
longest to p r e c ip it a t e .
He a l s o found t h a t t h e s o l u t i o n
which remained when n e u t r a l f l o c c u l e s had been o b t a i n e d , was
a l s o a b l e t o produce a s l i g h t immunity.
The f l o c c u l e s c o n t a i n e d l e s s than 1.0/6 o f the t o t a l
n i t r o g e n i n the m i x t u r e s from which t h e y s e p a r a t e d .
The
most a c t i v e p r e p a r a t i o n in h i s s e r i e s c o n t a i n e d o n l y 0 . 0 2 $
o f t h e t o t a l n i t r o g e n o c c u r r i n g In the mixture from which I t
was d e r i v e d .
He had some e v i d e n c e t h a t the l a r g e amount o f
e x t r a n e o u s n i t r o g e n o u s compounds which t o x i n - a n t i t o x i n m ix t u r e s
c o n t a in , i n t e r f e r e s w ith the production o f a n t i t o x i n .
I f the
f l o c c u l e s were r e p e a t e d l y washed w i t h normal s a l i n e s o l u t i o n s ,
t h e r e was l i t t l e
a l t e r a t i o n In t h e i r n i t r o g e n c o n t e n t and t h e i r
antigenic a c t i v i t y .
A n tito x in production fo llo w ed the i n j e c t i o n o f small
amounts o f f l o c o u l e s which s e p a r a t e i n n e u t r a l or t o x i c m i x t u r e s .
Thus th e i n j e c t i o n o f amounts o f f l o c c u l e s from a n e u t r a l
m ixture c o n t a i n i n g
4 , 0 0 0 o f a mmgr. o f n i t r o g e n produced 0 . 0 2 -
0 . 1 u n i t s o f a n t i t o x i n p er c . o . o f serum In s i x guinea p i g s .
.3 3 .
Doses a hundred t i m e s a s l a r g e produced 0 . 1 - 0 . 6 u n i t s .
f l o c c u l e s from a t o x i c mixture were e v e n more a c t i v e .
The
Doses
c o n t a i n i n g l e s s than •*“/ ! ( } , 0 0 0 o f a mmgr. o f n i t r o g e n produced
from 0 . 0 2 - 0 . 1 u n i t s o f a n t i t o x i n p e r c . o . o f serum in
I n o c u l a t e d a n i m a l s and d o s e s t e n t i m e s as l a r g e , produced
from 0 . 2 - 1 . 3 u n i t s o f a n t i t o x i n per c . o .
Marrack and Sm ith , 1 9 3 0 .
They th o u g h t t h a t the f l o c c u l e s o b t a i n e d from an
a n t i t o x i n - t o x i n mixture rese m bled v e r y o l o s e l y p s e u d o g l o b u l i n ,
a s the u l t r a - v i o l e t a b s o r p t i o n c u r v e s of th e f l o o c u l e s and o f
p s e u d o g l o b u l i n are I d e n t i c a l .
They found a l s o t h a t f l o c c u l e s
c o n t a i n e d a v e r y s m a l l amount o f l i p o i d m a t e r i a l .
They f i n a l l y
c o n c lu d e d t h a t f l o c c u l e s c o n s i s t e d m a inly o f a n t i t o x i n , and t h a t
a n t i t o x i n was not p r e c i p i t a t e d w i t h the p s e u d o g l o b u l i n f r a c t i o n
o f a serum, bu t t h a t a n t i t o x i n i s a c t u a l l y p s e u d o g l o b u l i n .
•34
•
S U M M A R Y *
The n o n - s p e c i f i c methods o f c o n c e n t r a t i n g serum have
been more f u l l y i n v e s t i g a t e d than th e s p e c i f i c m eth ods.
The e a r l y I n v e s t i g a t o r s used f r a c t i o n a t i o n w ith a
r e v e r s i b l e p r e c i p i t a n t such a s ammonium s u l p h a t e or sodium
s u l p h a t e which removed from the serum, f i b r i n o g e n , p a r t o f
t h e e u g l o b u l i n and th e a lbu m in .
I t was soon r e a l i z e d
however, t h a t t h i s method d id not produce a pure a n t i t o x i n
but a produ ct which a s w e l l s s c o n t a i n i n g a n t i b o d i e s , a l s o
o o n t a i n e d l i p o i d s , e u g l o b u l i n and alb u m in .
Further, t h i s
preparation d e te r io r a te d with age.
Further i n v e s t i g a t i o n s le d to rep eated f r a c t i o n a t i o n
w i t h ammonium s u l p h a t e or d i a l y s i s t o a s a l t f r e e c o n d i t i o n which
was f o l l o w e d by d i l u t i o n and a d ju stm e n t o f th e pH o f the serum
t o th e i s o - e l e c t r i c p o i n t o f the w a t e r I n s o l u b l e p r o t e i n - l i p o i d
co mplex .
None o f t h e methods us ed produced a v e r y c o n c e n t r a t e d
serum when c o n s i d e r e d i n terms o f u n i t s o f a n t i t o x i n p e r gramme
of p r o te in .
The c o n c e n t r a t e d se ra produced by t h e s e methods
c o n t a i n e d about 15^ o f p s e u d o g l o b u l i n but much o f t h i s was
no n -sp ecific.
The e a r l y i n v e s t i g a t i o n s o f th e use o f enzymes t o
p u r i f y a n t i t o x i n s did not g i v e p r o m isin g r e s u l t s .
were handicapped by two main r e a s o n s (a)
The a t t e m p t s
lack o f co n tro l fa c to r s
such a s t h e r e a c t i o n (pH) o f the d i g e s t i o n m i x t u r e s ; and (b)
•35 •
l a c k o f a sim ple method f o r e s t i m a t i n g th e a n t i t o x i c c o n t e n t
during d i g e s t i o n and i s o l a t i o n o f f r a c t i o n s .
The i n t r o d u c t i o n
o f an i n v i t r o method by Ramon has l e d t o an i n c r e a s e in the
amount o f e x p e r i m e n t a l work c a r r i e d out on d i p h t h e r i a t o x i n
and a n t i t o x i n .
Pope d e s c r i b e d a method f o r c o n c e n t r a t i n g a n t i s e r a
whereby he s l i g h t l y a l t e r e d th e a n t i t o x i c p s e u d o g l o b u l i n o f t h e
a n t i s e r u m by the a c t i o n o f enzymes.
T h is was f o l l o w e d by
c r i t i c a l h e a t d e n a t u r a t i o n o f the n o n - a n t i t o x l c p r o t e i n s .
H is c o n c e p t i o n o f t h e a n t i t o x i c g l o b u l i n was t h a t i t i s
composed o f a complex m o l e c u l e , one p o r t i o n o f which i s
n o n - a n t i t o x i c w i t h a low heat d e n a t u r a t i o n tem p erature and th e
o t h e r a n t i t o x i c and l e s s e a s i l y d e n a t u r a t e d .
By t h e use o f c e r t a i n p r o t e o l y t i c enzymes, under o e r t a i n
s p e c i f i e d c o n d i t i o n s , he a t t e m p t e d t o d i g e s t t h e n o n - a n t i t o x i c
p r o t e i n and so i n o r e a s e t h e p u r i t y o f the a n t i t o x i n *
In t h i s p r o c e s s however p r o t e o s e s were formed which
r educed the i n c r e a s e o f p u r i t y o f the a n t i t o x i n .
To remove t h e s e
p r o t e o s e s a d s o r p t i o n methods were n e c e s s a r y .
He found t h a t t h e r e was a l i m i t t o which d i g e s t i o n c o u l d
be a l l o w e d to p r o g r e s s , a f t e r whioh d e s t r u c t i o n
of antitoxin
too k p l a c e .
The serum he o b t a i n e d had a p r o t e i n c o n t e n t o f 16 # and an
i n c r e a s e d value in u n i t s p e r m l. o f 8 - 12 t i m e s t h e o r i g i n a l
serum.
S p e o i f i c Methods:
The use o f f l o c c u l e s which
*36 •
p r e c i p i t a t e when d i p h t h e r i a t o x i n and a n t i t o x i n a r e mixed,
t o induce immunity, have produced good r e s u l t s *
Very
s m a ll amounts o f t h e s e f l o c c u l e s were a b l e t o induce a
h i g h de gree o f immunity i n a n i m a l s immunized by t h i s method*
The t h r e e d i f f e r e n t t y p e s o f f l o c c u l e s have been i n v e s t i g a t e d
a s t o t h e i r e f f i c a c y in pro d u cin g a n t i b o d i e s and t h e ,ft o x i c ,!
f l o c c u l e s have been found t o g i v e the b e s t r e s u l t s *
c l o s e l y resem ble p s e u d o g l o b u l i n , which i s ,
F loccu les
in the opinion
o f Marrack and Smith (1930), a c t u a l l y a n t i t o x i n .
SECTION
11.
Serum R e a c t i o n s :
T h e i r i n c i d e n c e and m a n i f e s t a t i o n s ,
t o g e t h e r w i t h a comparison o f t h e i r
o c c u r r e n c e and c l i n i c a l f i n d i n g s
f o l l o w i n g th e i n j e c t i o n o f
c o n c e n t r a t e d and r e f i n e d d i p h t h e r i a
a n titoxin .
.3 7 .
SERUM
D efin ition -
REACTIONS
Serum r e a c t i o n I s the r e a c t i o n o f the human body
to the p a r e n te r a l i n j e c t i o n o f f o r e ig n p r o t e i n s con ta in e d in
anim al serum.
people.
The degree o f t h i s r e a c t i o n v a r i e s i n d i f f e r e n t
In some t h e r e may o n l y be a few u r t i c a r i a l w h e a l s ,
w h i l s t i n o t h e r s who are serum s e n s i t i v e , t h e r e may be a
s e v e r e r e a c t i o n , accompanied w i t h c y a n o s i s , oedema, p a i n s i n
t h e j o i n t s and an u r t i c a r i a c o v e r i n g most o f t h e b o d y .
incub ation period v a r i e s .
The
In t h e serum s e n s i t i v e i n d i v i d u a l
i t may come on i m m e d ia t e ly , but the a v e ra g e f o r t h e n o n - s e n s i t i v e
p a t i e n t i s 8 - 10 d a y s .
The s e n s i t i v e p a t i e n t may have been
s e n s i t i s e d by a p r e v i o u s i n j e c t i o n o f serum, by c o n t a c t w i t h
animal p r o t e i n or he may be n a t u r a l l y a l l e r g i c t o serum
protein s.
I t i s u s u a l l y in t h e serum s e n s i t i v e p e o p l e t h a t
the f a t a l c a se s are recorded.
The sudden and immediate r e a c t i o n s are very o f t e n
termed a n a p h y l a c t i c r e a c t i o n s , as t h e y are comparable t o the
anaphylaxis o f s e n s i t i s e d anim als.
H isto rica l.
The f i r s t o b s e r v a t i o n s on serum r e a c t i o n s were
made by D a l l e r a in 1 8 7 4 , who o b s er v ed u r t i c a r i a l r a s h e s
in p a t i e n t s f o l l o w i n g t r a n s f u s i o n w i t h lambs* b l o o d .
r a s h e s appeared 7 - 1 0
These
days a f t e r the t r a n s f u s i o n .
S h o r t l y a f t e r the I n t r o d u c t i o n o f a n t i - d i p h t h e r i t i c
serum by Behring and K i t a s a t o in 18 9 0 , and more so a f t e r
.3 8 .
i t s t h e r a p e u t i c v a l u e had been r e p o r t e d upon by Em ile Roux
a t the I n t e r n a t i o n a l Congress o f Hygiene a t Budapest ( 1 8 9 4 ) ,
serum:
r e a c t i o n s were o b s e r v e d i n p a t i e n t s f o l l o w i n g i t s
parenteral adm in istration.
These r e a c t i o n s were no t new
c o m p l i c a t i o n s o f the d i s e a s e , but c o m p l i c a t i o n s d i r e c t l y due
t o t h e serum.
L u b l ln s k y (1894)
f i r s t o b s er v ed the symptom complex o f
f e v e r , J o i n t p a i n s and r a s h e s which o c c u r r e d some d ay s a f t e r
i n j e c t i o n o f the serum.
Heubner and Bokay (1895)
said that
th e symptom complex was due t o the n o n - a n t i t o x i o p r o t e i n s
p r e s e n t in the serum, and t h e i r v ie w was c o n f ir m e d by
Johannessen and Heubner ( 1 8 9 5 ) , who
dem onstrated t h a t serum
r e a c t i o n s t o o k p l a o e a f t e r the i n j e c t i o n o f norms! h o r se
serum and so the r e a c t i o n s c o u l d no t be a t t r i b u t e d t o the
a n t i b o d i e s p r e s e n t in th e serum.
1
Hartnung (L896 ) p u b l i s h e d the f i r s t s t a t i s t i c s on
serum r e a c t i o n s .
The p e r c e n t a g e v a r i e d from 8 - 1 1 , and o f
serum r a s h e s t h e r e were f o u r t y p e s (a) U r t i c a r i a l ,
(b) M o r b i l l i f o r m ,
(c) Polymorphus or c i r c i n a t e , and
(d) S c a r l a t i n i f o r m .
He a l s o r ec ord ed two c a s e s o f abnormal
r e a c t i o n s a f t e r a second i n j e c t i o n o f serum ( 1 8 9 6 ^ ) .
Sim ilar
r e a c t i o n s were r e p o r t e d by Denys and L e c l e f (1896) and
G o o d all ( 1 8 9 8 ) .
The f i r s t f a t a l i t y a f t e r serum a d m i n i s t r a t i o n
was r ec o r d e d in 1 8 9 6 .
The c h i l d was an a l l e r g i c i n d i v i d u a l
who had had no p r e v i o u s i n j e c t i o n o f serum, but was g i v e n a
p r o p h y l a c t i c dose o f d i p h t h e r i a a n t i t o x i n .
The c a se was
•39 •
r e p o r t e d by P r o f e s s o r Lan gerhans.
The term serum s i c k n e s s or serum d i s e a s e was f i r s t
used by Von P i r q u e t and S c h i c k i n 1903*
i n v e s t i g a t o r s p u b l i s h e d t h e i r book
In 1905 t h e s e two
"Die Serurakrankheit",
wh ich c o n t a i n e d a f u l l a c co u n t o f the e t i o l o g y , t y p e s and
symptoms o f serum r e a c t i o n s in man.
2 . Mechanism o f Serum R e a c t i o n s .
Attem pts t o de m onstrate t h a t t h e c o u r s e o f serum
r e a c t i o n s i s due t o an a n t i g e n - a n t i b o d y r e a o t i o n have r e s u l t e d
in many e x p e r i m e n t s b e i n g c a r r i e d o u t .
The f i r s t im porta nt
work in t h i s f i e l d was done by Von P i r q u e t and S c h i c k (1903 1911)•
Most o f the work done s i n c e th en has been towards
v e r i f i c a t i o n o f t h e i r f i n d i n g s , which were m ainly the
r e l a t i o n s h i p between the appearance i n t h e b l o o d - s t r e a m o f
p r e c i p i t i n s and the o n s e t o f serum r e a c t i o n .
p r e o i p i t i n s appear in th e blo o d 6 - 9
These
days a f t e r serum
i n j e c t i o n and ne ver b e f o r e t h e symptoms o f serum d i s e a s e .
Von P i r q u e t (1911)
conclu ded t h a t normal serum r e a c t i o n s
i n man o c c u r r i n g 8 - 1 2
days a f t e r i n j e c t i o n were a n a l a g o u s
t o a n a p h y l a x i s in a n i m a l s , b e c a u se r a b b i t s and g u in e a p i g s
became s e n s i t i s e d and a n t i b o d i e s app eared i n th e b l o o d - s t r e a m
a ft e r a sim ilar in te r v a l.
He a l s o s t a t e d t h a t a serum
i n j e c t i o n r e p e a t e d w h i l e s p e c i f i o a n t i b o d i e s are s t i l l
p r e s e n t in the body c a u s e s an immediate r e a c t i o n .
A fter a
l o n g e r i n t e r v a l a n t i b o d i e s may n o t s t i l l be p r e s e n t , but
the body h a s been s e n s i t i s e d t o produce a n t i b o d i e s more
•40*
r a p i d l y , c a u s i n g an a c c e l e r a t e d r e a c t i o n a f t e r 4 - 7
days*
Animal E xp eriments*
As our knowledge o f the mechanism o f serum
r e a c t i o n s has been g r e a t l y enhanced by t h e i n j e o t i o n o f
a n i m a l s w i t h serum, the r e s u l t s r e c o r d e d by t h r e e o b s e r v e r s
w i l l be quoted t o i l l u s t r a t e t h e v a l u e o f anim al
experim ents•
(a)
F l e i s c h e r and Jones (1 9 3 1 - 1 9 3 4 ) working w i t h
a l b i n o r a b b i t s , found t h a t serum r e a c t i o n c h a r a c t e r i z e d by
erythema and oedema was apparent in the e a r s o f 68 *9$ o f
rabbits, 3 - 9
o f h o r s e serum*
days su bseq uent t o the su b s o a p u la r i n j e c t i o n
They c o u l d not d i s c o v e r any e v i d e n c e t h a t
the oc cu rr en ce o f serum r e a c t i o n was d i r e c t l y a s s o c i a t e d w i t h
th e p r o d u c t i o n or appearance o f p r e c i p i t i n s .
There was no
d i f f e r e n c e in the p r e c i p i t i n c u r v e s o f i n j e c t e d r a b b i t s who
did or did n o t d e v e lo p serum r e a c t i o n .
The v a r i a t i o n in
i n c i d e n c e o f serum r e a c t i o n u s i n g serum from d i f f e r e n t h o r s e s
was 24 - 93 p e r c e n t , and t h e y c o n c lu d e d t h a t the a c t i v e
f a c t o r i s p r e s e n t in a l l s e r a , the im porta nt f a c t o r in
p r o d u c t i o n o f serum r e a c t i o n s b e i n g the r e a c t i v i t y o f t h e
in d ividu al r a b b its.
In r e a c t i o n s a f t e r a second i n j e c t i o n t h e time
between the f i r s t and second i n j e c t i o n i s th e im p o r ta n t
f a c t o r , up t o 12 days a normal r e a c t i o n o c c u r r e d , between
2 - 4
weeks r e a o t i o n s were o f the a c c e l e r a t e d t y p e , from
5 - 7
weeks t h e r e were both immediate and a c c e l e r a t e d
r e a c t i o n s , and from 3 - 5
occu rred *
months o n l y immediate r e a c t i o n s
A f t e r 6 months r e a c t i o n s ten d e d t o r e v e r t t o
the normal t y p e .
"These r e a c t i o n s in r a b b i t s are e s s e n t i a l l y a n a l a g o u s
t o r e a o t i o n s ap p ea r in g in man su bseq ue nt t o second
i n j e c t i o n s o f serum."
F r a c t i o n a l p r e c i p i t a t i o n o f serum w i t h ammonium
s u l p h a t e proved t h a t t h e p s e u d o g l o b u l i n was p r i m a r i l y
concerned w i t h t h e cause o f serum r e a c t i o n , e u g l o b u l i n o n l y
when i t was i n j e c t e d i n l a r g e q u a n t i t i e s and albumin n o t a t
a ll.
Abnormal r e a o t i o n s a f t e r se cond i n j e c t i o n were e q u a l l y
f r e q u e n t w ith p s e u d o g l o b u l i n and e u g l o b u l i n , r a r e w i t h
a lb u m in •
1 &2
(b) Kahn (1933
) a l s o e x p e r i m e n t in g w i t h a l b i n o r a b b i t s
found t h a t f o l l o w i n g the i n j e o t i o n o f w h i t e o f egg or h o r se
serum, sk i n s e n s i t i v i t y r e a c t i o n s and serum p r e o i p i t i n s
were p a r a l l e l f o r some w e ek s, w h i l e a month or more l a t e r
sk i n s e n s i t i v i t y r e a c t i o n s were s t i l l p r e s e n t in th e ab sen ce
o f serum p r e c i p i t i n s .
Mechanism o f Serum R e a c t i o n s i n Man.
To s u b s t a n t i a t e the a ssum p tio n t h a t serum r e a c t i o n s
i n man are due t o an a n t i b o d y - a n t i g e n r e a c t i o n , i t must be
proved t h a t (a) f o l l o w i n g the p a r e n t e r a l a d m i n i s t r a t i o n o f
a n t i s e r a , a s p e c i f i c a n t i g e n appears in th e b lo o d plasma
(b) where serum r e a c t i o n s f o l l o w s p e c i f i c a n t i b o d i e s appear
i n the b l o o d - s t r e a m
(c) where no serum r e a o t i o n s f o l l o w ,
A2.
no a n t i b o d i e s are e l a b o r a t e d or i f t h e y a r e , t h e i r p r e s e n c e
cannot be d e t e c t e d i n th e b l o o d - s t r e a m .
(a) P r e s e n c e o f a S p e c i f i c A n t ig e n in th e B l o o d - S t r e a m .
Longoope and Raokemann, 1 9 1 8 ,
c o n c lu d e d t h a t d u rin g
the i n c u b a t i o n p e r i o d o f serum d i s e a s e the amount o f a n t i g e n
p r e s e n t i n t h e b l o o d - s t r e a m remains c o n s t a n t and i s depe nd ent
upon th e amount o f serum
adm inistered •
Mackenzie and Leake, 19 2 1 ,
u s i n g serum from r a b b i t s
which had been immunized a g a i n s t ho rse serum, p r e c i p i t a t e d out
o f human serum the h o r se serum p r e s e n t in i t , a f t e r the
p a t i e n t had r e c e i v e d a n t i - s e r u m d e r i v e d from h o r s e s .
In
e l e v e n o f the p a t i e n t s who d e v e lo p ed s e v e r e serum r e a c t i o n s ,
t h e h o r s e serum ( p r e c i p i t i n o g e n )
d i s a p p e a r e d from th e human
serum when the symptoms o f the serum r e a c t i o n were p a s s i n g o f f .
Where t h e p a t i e n t s d e v e lo p e d no r e a c t i o n , t h e p r e c i p i t i n o g e n
remained in th e bloo d f o r a s l o n g a s the o b s e r v a t i o n s were
c a r r i e d out (two months) •
Mackenzie and Hangar, 1 9 5 0 , proved t h a t h o r s e serum
can be found in t h e b l o o d - s t r e a m f o r 2 - 3
weeks f o l l o w i n g
a d m i n i s t r a t i o n , but i f a serum r e a c t i o n o c c u r r e d , i t r a p i d l y
disappeared.
(b) P r e s e n c e o f A n t i b o d i e s .
W e l l s , 1 9 1 5 , dem onstrated the p r e s e n c e o f p r e c i p i t i n s
in t h e b loo d plasma 4 - 5
antiserum .
days a f t e r t h e a d m i n i s t r a t i o n o f
He thought t h a t the c o n c e n t r a t i o n o f t h e
p r e c i p i t i n s i n c r e a s e d w i t h the amount o f a n t lse r u m g i v e n and
.4 3 .
t h a t th e symptoms o f serum r e a c t i o n s d i s a p p e a r e d when t h e
p r e c i p i t i n s were l i b e r a t e d .
Longcope and Raokemann, 1 9 1 8 , were o f the o p i n i o n
t h a t serum r e a c t i o n s were not due t o t h e appearance o f
a n t i b o d i e s in the blo o d pla s m a , but t h a t the a n t i b o d i e s
n e u t r a l i z e d the a n t i g e n and so t h e p a t i e n t r e o o v e r e d from
h i s serum r e a c t i o n .
Mackenzie and Leake, 1 9 2 1 , t e s t e d f o r p r e c i p i t i n s
by adding an e q u a l volume o f normal s a l i n e t o a q u a n t i t y o f
patients*
serum and p r e c i p i t a t e d the p r e c i p i t i n s by v a r i o u s
d i l u t i o n s o f h o r se serum.
In e l e v e n p a t i e n t s who had s e v e r e
serum r e a c t i o n s t h e y found a h ig h c o n c e n t r a t i o n o f p r e c i p i t i n s
and t h i s c o n c e n t r a t i o n r o s e near t h e time when the symptoms
were p a s s i n g o f f .
In f o u r p a t i e n t s who had m ild serum
r e a c t i o n s the c o n c e n t r a t i o n o f the p r e c i p i t i n s was v e r y low
or a b s e n t .
Wyard, 1 9 2 2 .
From 35 o a s e s he found by p r e c i p i t a t i o n
w it h h o r s e serum, s p e c i f i c a n t i b o d i e s in 24 c a s e s .
He was o f
t h e o p i n i o n t h a t a l t h o u g h p r e c i p i t i n s may be found in the
p a t i e n t * s serum, serum r e a c t i o n s have no r e l a t i o n s h i p w i t h them.
Tuft and R a m s d e ll, 1 9 2 9 , conducted many e x p e r i m e n t s
f o r the p r e s e n c e o f a n t i b o d i e s by p r e c i p i t a t i o n and p a s s i v e
transfer.
They o b t a i n e d bloo d from p a t i e n t s a t d i f f e r e n t
i n t e r v a l s f o l l o w i n g i n j e c t i o n or a n t i t o x i c and Immune h o r s e
serum.
T h eir r e s u l t s showed t h a t , where r e a c t i o n s o c c u r r e d ,
a n t i b o d i e s were dem onstra ble in many o f t h e p a t i e n t s *
sera by
.4 4 .
means o f t h e P r a u s n l t z - Kus tner r e a c t i o n , and a l s o t h a t
p a s s i v e s e n s i t i s a t i o n o f g u in e a p i g s * e a r s k i n c o u l d be
produced#
Mackenzie and Hangar, 1 9 3 0 , dem onstr ated t h e p r e s e n o e
o f p r e c i p i t i n s in human sera from n o n - s e n s i t i v e p a t i e n t s
9 - 2 1
days a f t e r the i n j e c t i o n o f the a n t i - s e r u m .
They
th o u g ht t h a t s h o r t l y a f t e r the i n j e c t i o n o f serum the o e l l s
o f the body began t o produce p r e c i p i t i n s which remained
intracellu lar*
At the end o f the i n c u b a t i o n p e r i o d , t h e
c o n c e n t r a t i o n o f th e p r e c i p i t i n s was su ch t h a t i t r e a c t e d w i t h
t h e h o r s e serum i n the b l o o d - s t r e a m *
Where serum r e a c t i o n
too k p l a c e , the p r e c i p i t i n s were i n e x c e s s in the p a t i e n t f s
serum.
( c) Absence o f A n t i b o d i e s where no Serum R e a c t i o n o c c u r s .
Longoope and Rackemann, 1 9 1 8 y c o n s i d e r e d t h a t i t was
i m p o s s i b l e f o r serum r e a c t i o n t o oc cur i f no a n t i b o d i e s c o u l d
be found in t h e p a t i e n t ’ s serum.
Mackenzie and Leake, 1 9 2 1 , in f o u r c a s e s where no
serum r e a c t i o n o c c u r r e d , were unable t o de m onstra te p r e c i p i t i n s
i n the b l o o d - s t r e a m .
Prom
the o b s e r v a t i o n s made above i t w i l l be s e e n
t h a t t h e r e i s c o n s i d e r a b l e e x p e r i m e n t a l p r o o f t h a t serum
r e a c t i o n s are dependent upon an a n t i b o d y - a n t i g e n r e a c t i o n *
Coca, 19 3 1 , h a s , however, been a b l e t o d e m onstrate the p r e sen o e
o f p r e c i p i t i n s in the blood b e f o r e and a f t e r the o c c u rr en ce o f
symptoms and a l s o i n the a bsen ce o f r e a c t i o n s *
He a l s o has
.4 5 .
shown t h a t symptoms c o u l d o ccu r w i t h o u t p r e c i p i t i n s b e i n g
present.
I t might be t h a t t h e e l a b o r a t i o n o f a n t i b o d i e s depends
more on th e i n d i v i d u a l than on t h e serum i n j e c t e d , b u t t h e r e i s
no doubt t h a t a n t i b o d i e s do appear i n the p a t i e n t ! s serum*
The
p r e s e n c e or absence o f dem onstra b le a n t i b o d i e s must depend a
g r e a t d e a l upon the p a t i e n t *
In one p a t i e n t , who shows serum
r e a c t i o n , the a b t i b o d i e s might o n l y be in s l i g h t e x c e s s and so
t h e i r p r e s e n c e might not be d e t e c t a b l e ; i n a n o t h e r w i t h no
serum r e a c t i o n , the a n t i b o d i e s might be i n g r e a t e x c e s s and
e a s i l y dem onstrable•
C onclusions.
F o l l o w i n g upon the p a r e n t e r a l a d m i n i s t r a t i o n o f
\
f o r e i g n serum in man, a n t i g e n s can be de m o nstrate d i n t h e blood*
During t h e i n c u b a t i o n p e r i o d t h e r e i s a g r a d u a l f o r m a t i o n o f
s p e c i f i c a n t i b o d i e s in t h e s p e c i a l c e l l s o f the body
( r e t i c u l o - e n d o t h e l i a l sy s tem , s k i n , e t c . ) .
The p r o o e s s may
end t h e r e , but in c e r t a i n c a s e s , f o r no appare nt r e a s o n , a
r e a c t i o n t a k e s p l a c e between the a n t i g e n and the s p e c i f i c
a n t i b o d y , h i s t a m i n e i s l i b e r a t e d i n the t i s s u e s and t h e o n s e t
o f t h e serum r e a c t i o n o c c u r s .
The a n t i b o d i e s e x tr u d e d i n
e x c e s s from th e c e l l s i n t o the b l o o d n e u t r a l i z e th e a n t i g e n
and so the symptoms o f the r e a c t i o n d im in ish *
remains i n th e c e l l s f o r a p r o l o n g e d p e r io d *
demonstrated by sk in s e n s i t i v i t y t e s t s *
Some a n t i b o d y
T h is can be
When a second
i n j e c t i o n o f serum i s g i v e n , the i n c u b a t i o n p e r i o d i s reduoed
*46 m
b e c a u se t h e r e I s some a n t i b o d y a l r e a d y p r e s e n t i n th e t i s s u e
cells*
3*
Serum R e a c t i o n s i n Man*
A*
Types b f R e a c t i o n (Von P l r q u e t and S o h i c k , 1905)
(i)
Normal:
A f t e r primary i n j e c t i o n and a l a t e n t
p e r i o d o f 7 - 15 d a y s .
(ii)
Aooelerated:
In which the l a t e n t p e r i o d i s
reduced to l e s s than 7 days*
T h is ty p e
u s u a l l y f o l l o w s t h e r e i n j e c t i o n o f serum
a f t e r a p e r i o d o f s e v e r a l months ( 7 months
t o 7§ y e a r s in Von P i r q u e t ! s s e r i e s o f c a s e s ) .
(iii)
Immediate:
Occurs w i t h i n 24 hours from t h e time
o f a d m i n i s t r a t i o n and o c c u r s u s u a l l y where a
p r e v i o u s i n j e c t i o n o f serum has been r e c e i v e d
from 2 weeks t o 6 months p r e v i o u s l y *
(12 - 50
days in Von P i r q u e t * s s e r i e s ) .
The l a t t e r two groups may be termed abnormal r e a c t i o n s *
Coca, 1 9 3 1 , d i f f e r e n t i a t e s t h e immediate type o f
r e a c t i o n which o c c u r s i n s e n s i t i v e p a t i e n t s a f t e r a pr im ary
i n j e c t i o n o f sm all q u a n t i t i e s o f serum i n t o two c l a s s e s : (i)
Where the r e a c t i o n o c c u r s w i t h i n a few hours and
where th e symptoms ar e s i m i l a r t o t h o s e
d e v e l o p i n g i n the normal r e i n j e c t e d patfent.
(ii)
The s e v e r e and o c c a s i o n a l l y f a t a l immediate r e a c t i o n
which o c cu rs w i t h i n a few m i n u t e s , c h a r a c t e r i z e d
by dyspn oea, c y a n o s i s , v om itin g e t c .
#47#
B.
F a c t o r s w h ic h i n f l u e n c e t h e I n c i d e n c e o f Serum R e a c t i o n s ,
(i)
Age:
There i s d i f f e r e n c e o f o p i n i o n on t h i s
subject.
Coca (1922)
s t a t e s t h a t th e i n c i d e n c e o f
serum r e a c t i o n s v a r i e s l i t t l e
G o o d a l l (1928)
at d i f f e r e n t a g e s .
i s o f the o p i n io n t h a t the r a t e i s
h i g h e s t in young p e o p l e .
Hunt (1932) foun d the
i n c i d e n c e h i g h e s t in the 10 - 20 age g r o u p .
Hecks he r (1926)
rec o rd ed t h a t w i t h l a r g e d o s e s o f
serum the i n c i d e n c e and s e v e r i t y o f serum r e a c t i o n s
In creases with age.
(ii)
Sex:
G o o d a l l (1928)
in c a s e s t r e a t e d w i t h
u n c o n c e n t r a t e d d i p h t h e r i a a n t i t o x i n found a
h i g h e r p r o p o r t i o n o f r e a c t i o n s in f e m a l e s than
m ales.
With r e f i n e d serum, the r e v e r s e was
observed.
The g e n e r a l c o n c e n s u s o f o p i n i o n i s ,
however, t h a t se x has no i n f l u e n c e on the i n c i d e n c e ,
(ill)
Race:
Mackenzie and Hangar (1930)
found a low
i n c i d e n c e o f serum r e a c t i o n s i n n e g r o e s and North
American I n d i a n s .
C o c a , D e l b e r t and Menger (1922)
o b s er v ed i n a s e r i e s o f c a s e s t h a t 46$ o f American
I n d i a n s and 75$ Whites d e v e lo p ed serum r e a c t i o n s .
The I n d i a n s had a m i l d e r r e a c t i o n than the
( i v ) Amount o f Serum i n j e c t e d :
W hites,
B roa dly s p e a k i n g , the
i n c i d e n c e o f serum r e a c t i o n s i s d i r e c t l y
p r o p o r t i o n a l t o t h e amount o f serum i n j e c t e d . T h is
f a c t i s s u b s t a n t i a t e d by th e r e s u l t s o f
^48 4
Sturtevant
( 1 9 1 6 ) , G o o d a ll (1928)
and Hunt ( 1 9 3 2 ) *
H untf s
f i g u r e s f o r d i p h t h e r i a serum were - under 10 c * o f s
o f serum i n j e c t e d , t h e i n c i d e n c e was 1 4 . 5 # ; where
o ver 100 o . c f s were i n j e c t e d , the i n c i d e n c e r o s e
to 6 1 .7 $ .
(v) Type o f Serum:
(a) Whole and c o n c e n t r a t e d *
As has been dem onstra ted a b o v e , a n t i t o x i n i s
mainly a s s o c i a t e d w i t h t h e p s e u d o g l o b u l i n f r a c t i o n
o f serum p r o t e i n *
The v a r i o u s methods us ed t o
i s o l a t e t h i s have been d e s c r i b e d *
With
c o n c e n t r a t e d serum the b u lk o f serum i n j e c t e d i s
diminished as
more u n i t s o f a n t i t o x i n are p r e s e n t
in eaoh c u b i c
c e n t i m e t r e o f a n t i t o x i c serum.
Toomey and August (1930)
r e p o r t e d on a l a r g e s e r i e s o f
c a s e s t r e a t e d between 1924 - 1 9 2 9 .
With
u n c o n c e n t r a t e d serum t h e p e r c e n t a g e was 1 0 . 6 and
w it h c o n c e n t r a t e d serum i t was 1 6 . 6 .
The h i g h e r
dosage employed i n r e c e n t y e a r s may a c c o u n t f o r
this*
A
f u l l i n v e s t i g a t i o n i n t o th e i n c i d e n c e o f serum
r e a c t i o n s f o l l o w i n g the a d m i n i s t r a t i o n o f
u n c o n c e n t r a t e d and c o n c e n t r a t e d serum was
p u b l i s h e d in the M.A*B. r e p o r t o f 1928 - 1929*
During 1926 - 1 9 2 6 , 711 c a s e s r e c e i v e d
u n c o n c e n t r a t e d serum (400 u n i t s o f a n t i t o x i n per c . c )
#49 •
The p e r c e n t a g e o f serum r e a c t i o n s was 44#3
During 1926 - 2 7 , 770 c a s e s r e c e i v e d 75$
u n c o n o e n t r a t e d serum and 2 5$ c o n c e n t r a t e d
serum, and t h e p e r c e n t a g e r e a c t i o n was
red uced t o 3 1 . 4 $ #
Prom 1927 onwards
o n l y c o n c e n t r a t e d serum was used (800 - 1000
u n i t s p e r c # c ) , and the i n c i d e n c e o f serum
r ea ctio n s f e l l to 15.7$.
V a r i a t i o n in i n c i d e n c e o f serum r e a c t i o n s w i t h
c o n c e n t r a t e d and u n c o n c e n t r a t e d s e r a .
Author
Type o f Serum
P e r c e n t a g e o f Serum R e a c t i o n
Unc o n o e n t r a t e d Concentra t e d
Park and Throne
(1906)
D i p h t h e r i a A .T .
70.0
Ronaldson (1923)
D i p h t h e r i a A.T*
76.5
Von P i r q u e t and
S chick (1926)
S c a r l e t Fever
85.0
M.A.B. Report
(1928-29)
D i p h t h e r i a A .T .
44.3
46.0
15.7
G o o d a ll (1928)
Do.
40.1
Tooraey and August
(1930)
Do.
10.6
16.6
53-92
20.6
C e c i l and Plummer
(1930)
(Intravenous
Pneumococcal)
Hunt, (1932)
D i p h t h e r i a A.T .
28 . 1
D a v i s (1938)
Do.
17.3
B e l v i d e r e Fever
H o s p i t a l (1930-36)
Do.
9.9
Present In v e stig a tio n
Do. ( r e f i n e d )
2.4
(b)
Sera d e r i v e d from Animals o t h e r than the Horse
D i p h t h e r i a and t e t a n u s a n t i t o x i n s have been
d e r i v e d from Immunizing o a t t l e . Kraus e t a l
1 &2
(1921
) found o n l y 4 . 5 $ o f r e a c t i o n s i n a
s e r i e s o f 198 c a s e s t r e a t e d w i t h d i p h t h e r i a
a n t i t o x i n d e r i v e d from c a t t l e .
Of the 198
o a s e s , 93 had had a p r e v i o u s i n j e c t i o n o f
h o r se serum, and o f t h i s number the
p e r c e n t a g e r e a c t i o n r a t e was 5 . 3 .
(o) Homologous Sera:
These are r a r e but do o c c u r .
D o o le y (1932)
r e p o r t e d a c a s e o f a boy who was g i v e n ,
i n t r a m u s c u l a r l y , 45 o . c * s o f p o o l e d
p o l i o m y e l i t i s c o n v a l e s c e n t serum.
The
p a t i e n t d e v e lo p e d a g e n e r a l i z e d u r t i c a r i a ,
oedema o f the f a c e and a mild a r t h r i t i s t h r e e
days l a t e r .
One month l a t e r he showed s k i n ,
s e n s i t i v i t y t o the same b a t c h o f serum but
t o no o t h e r .
Tedstrom (1934) r e p o r t e d a
c a s e where a blo o d donor, who, a t t h e time o f
t r a n s f u s i o n , was s u f f e r i n g from u r t i c a r i a due
t o s t r a w b e r r i e s , t r a n s m i t t e d the u r t i c a r i a t o
the r e c i p i e n t .
The u r t i c a r i a d e v e lo p e d in
the p a t i e n t in t h i r t y m i n u t e s .
A transfusion
was done some time l a t e r when the d o n o r f s
u r t i c a r i a had p a s s e d o f f , and t h i s tim e the
. 51*
r e c i p i e n t d id no t d e v e l o p u r t i o a r i a .
(d)
Serum from c e r t a i n h o r s e s would appear t o c a u s e
a g r e a t e r i n c i d e n c e o f serum r e a c t i o n s than
o t h e r s ( G o o d a l l , 1928; Coca, 1 9 3 1 ) .
The p r a c t i c e nowadays i s t o p o o l a l l sera and
so e l i m i n a t e t h i s f a c t o r .
(e) Some t y p e s o f s e r a produce a h i g h e r r a t e
of
r e a c t i o n s - pneumococcal and a n t i - s c a r l a t i n a l
sera.
The f i g u r e from the s o a r l e t f e v e r
c a s e r e p o r t s in B e l v i d e r e H o s p i t a l du rin g
t h e y e a r s 1930 - 36 was 1 0 . 7 $ a g a i n s t 9 . 9 $
for d ip hth eria.
The r e a s o n f o r the
d i f f e r e n c e may depend upon the c o n c e n t r a t i o n ,
t h e amount and r o u t e o f a d m i n i s t r a t i o n .
(vi) Presence o f P r e se r v a tiv e :
T h is does not i n f l u e n c e
the number o f r e a c t i o n s o c c u r r i n g .
I t has no
a c t i o n on the s e n s i t i s i n g p r o p e r t y o f h o r s e serum
(Rosenau and Anderson, 1 9 0 7 ) , nor does i t c a u se
r e a c t i o n s (P a rk , 1 9 1 3 ) .
( v i i ) H y p e r s e n s i t i v i t y o f the I n d i v i d u a l :
(a) P r e v i o u s Serum I n j e c t i o n s .
Both Currie (1907)
and S t u r t e v a n t (1916)
found no p r o o f o f an I n c r e a s e d r e a c t i o n
r a t e I f the serum were a d m i n i s t e r e d i n two
or more i n j e c t i o n s , p r o v i d e d t h a t t h e
i n t e r v a l between the f i r s t and l a s t dose
. 52,
did not exceed 8 - 1 0
days.
The l a t e n t
p e r i o d i s not reduced and the d u r a t i o n o f
t h e r e a c t i o n i s not I n c r e a s e d .
Where a second dose o f serum i s g i v e n a f t e r a
p e r i o d o f more than 10 days t h e p e r c e n t a g e
o f serum r e a o t i o n s i s d e f i n i t e l y I n c r e a s e d .
No. o f
Cases
Author
T .A .T .
100
45
D ip h . A . T .
17.8
28
T .A .T .
14.3
D i p h .A .T .
63.5
151
D ip h .A .T .
43.0
556
T .A .T .
74.1
53
D ip h .A .T .
26.4
42
T.A.T.
45.0
6
S t e w a r t , 1926
Spicer,
r e v i o u s Serum P r e v i o u s Serum
No P______
Type
% of Reactions
T s?
R eactions
164
1928
8,523
G o o d a l l , 1928
13.4
39.5
203
1,750
Gordon and C r e s w e l l
1929
Toomey and August
1930
B elvidere H ospital
6,046
Case R epo rts 1930-36
554
16.0
8.6
120
Present In v estig a tio n
Note:
884
96
20
18.4
Sc.Fev.A .T .
36.6
2.4
DIph. A .T . s D i p h t h e r i a A n t i t o x i n ;
A n titoxin ;
D i p h . A .T .
2.1
5.0
T .A .T . s Tetanus
and S c . F e v . A.T . = S c a r l e t F ever A n t i t o x i n .
.5 3 .
(B)
P r e v i o u s i n j e c t i o n o f T . A . T . , T .A .M ., e t c :
Gordon and C r e s w e l l , 1 9 2 9 .
As n o t e d a b o v e ,
t h e y r e p o r t e d a 7 4 . 1 $ o f serum r e a c t i o n s i n
c h i l d r e n who had p r e v i o u s l y been Immunized
w i t h T .A .T .
The h ig h i n c i d e n c e was th o u g h t
t o be due t o the c h i l d r e n f s h av in g r e c e i v e d
s e v e r a l s m a l l d o s e s o f ho rse serum.
Park 1 9 2 8 .
In h i s o p i n i o n , p r e v i o u s
immunization w i t h m a t e r i a l c o n t a i n i n g s m a l l
d o s e s o f ho rse serum had l i t t l e
e f f e c t upon
th e i n c i d e n c e o f serum r e a c t i o n s .
Fleming and P e t r i e , 1 9 3 4 .
N o tin g the f a c t
t h a t most immunizing s o l u t i o n s c o n s i s t e d
mainly o f f o r m a l i z e d t o x o i d s o l u t i o n w i t h
little
a n t i t o x i n p r e s e n t , t h e y were o f the
opinion that t h i s f a c t o r (previou s
immunization) would s h o r t l y be e r a d i c a t e d
a s a p o s s i b i l i t y in i n c r e a s i n g th e
p e r c e n t a g e o f serum r e a c t i o n s .
(C) N a tu ra l A l l e r g y t o Horse P r o t e i n s See s e c t i o n on serum a c c i d e n t s (Page 6 4 )
(v iii)
Methods o f A d m i n i s t r a t i o n :
Opinion v a r i e s
as t o whether serum r e a c t i o n s are more
f r e q u e n t a f t e r i n t r a v e n o u s i n j e c t i o n or
a f t e r intra-m uscular i n j e c t i o n .
Coca, D e l b e r t and Menger ( 1 9 2 2 ) , s t a t e d
*54 *
t h a t r e a c t i o n s are much more f r e q u e n t a f t e r
i n t r a v e n o u s i n j e c t i o n than a f t e r i n t r a m u s c u l a r *
In one s e r i e s o f 367 c a s e s the i n c i d e n c e was
9 2 .4 $ a f t e r intravenous a d m in is tra tio n o f the
serum ( B o sto n C i t y H o s p i t a l ) •
Hecksher ( 1 9 2 6 ) , d e a l i n g w i t h a s e r i e s o f s e v e r e
c a se s o f diphtheria considered th at r e a c tio n s
were l e s s f r e q u e n t w i t h i n t r a v e n o u s than w i t h
i n t r a m u s c u l a r therapy#
Maokenzie and Hangar (1930)
c o u l d f i n d no d e f i n i t e
d i f f e r e n c e between t h e two methods*
Hunt (1932) found t h a t r e a c t i o n s were more f r e q u e n t
a f t e r i n t r a v e n o u s t h e r a p y and t h a t t h e r e a c t i o n
was u s u a l l y o f th e immediate type*
London County C o u n c i l Report (1936)
stated that
r e a c t i o n s may f o l l o w th e a d m i n i s t r a t i o n by any
r o u t e , but were more f r e q u e n t when the serum was
given intravenously*
When c o n s i d e r i n g the " p r o s” and ’’Cons” in c o n n e c t i o n
w i t h I n t r a v e n o u s t h e ra p y we must b e a r in mind two
points (a) I n t r a v e n o u s i n j e c t i o n i s u s u a l l y o n l y r e s o r t e d
t o when the p a t i e n t i s v e r y 111 and r e q u i r e s
a l a r g e dose o f serum*
(b) The immediate r e a c t i o n s may be o f the t h e r m a l ,
n o n - a n t l g e n i c t y p e , and so should not be
*55*
c l a s s e d a s serum r e a c t i o n s *
C# S i g n s and Symptoms o f Serum R e a c t i o n :
S in c e t h e I n t r o d u c t i o n o f c o n c e n t r a t e d sera t h e
i n c i d e n c e o f serum r e a c t i o n s has d e f i n i t e l y
diminished*
The v a r i o u s m a n i f e s t a t i o n s o f serum
r e a c t i o n can be c l a s s i f i e d under the f o l l o w i n g
headings:( i ) Prodoraal P e r i o d .
The prodomal s i g n s may come
on a few days b e f o r e the r a s h a p p e a r s .
These s i g n s a r e , u s u a l l y , s w e a t i n g , d r o w s i n e s s ,
oligu ria
(Ron a ld so n , 1923) and e l e v a t i o n
o f tem perature - up t o 1 0 6 ° p / C o c a , 1931) •
(ii)
L o c a l Rash.
T h is u s u a l l y a pp ears between the
second t o the s i x t h day and b e f o r e th e g e n e r a l
r a s h (C oca, 1931; Bray 1 9 3 7 ) .
( i l l ) G e n e r a l i z e d Rash.
(a) Day or o n s e t .
Hunt (1932) foun d t h a t 85*8^
appeared b e f o r e the e l e v e n t h d a y , the
a vera ge being between th e 5 t h . and the
1 5 t h . day, and the day on which most r a s h e s
appeared was the 9 t h . day a f t e r the
a d m i n i s t r a t i o n o f the serum.
Coca, D e i b e r t and Menger (1922)
in a s e r i e s
o f 223 c a s e s found an 80 $ i n c i d e n c e o f r a s h e s *
70$ o f t h e s e appeared between the 1 s t * and
the
3 0 t h . d a y.
>5 6 *
G o o d a l l (1928) o b s e r v e d r a s h e s from t h e 1 s t *
t o t h e 2 9 t h . day.
Ronaldson (1923)
r e p o r t e d a o i r o i n a t e r a s h which
appeared on the 3 3 r d . day
G o o d a ll (1932)
ob s er v ed an e ryth e m a tou s r a s h on
t h e 4 0 t h . d8y.
B e l v i d e r e H o s p i t a l Case Records ( 1 9 3 0 - 3 6 ) :
The days on which most r a s h e s appeared were the
8 t h . and 9 t h . , r a s h e s s t i l l d e v e lo p e d up t o t h e
1 8 t h . d a y , and 98$ o f r a s h e s o c c u r r e d b e f o r e t h e
1 3 th . day.
(b) Types o f rash*
Prom two s e r i e s r e p o r t e d by
1
Davidson (1919)
and G oodall (1928)
th e
percentages a re:M o r b i l l i f o r m , 16 - 30$ o f a l l r a s h e s .
U rtica ria l,
57 - 7 7 . 6 $
,,
,,
C ircinate,
7 - 12$
,,
,,
U r t i c a r i a l appear f i r s t , a v e r a g e , 9th* day*
M orbilliform
C ircinate
,,
second,
,, la st,
,,
12th. , ,
,,
14th.
,,
S t a n l e y (1932) r e p o r t e d 52$ ery the m ato us r a s h e s
and 26$ u r t i c a r i a l .
F i g u r e s from th e B e l v i d e r e H o s p i t a l :
D i p h t h e r i a Case Reports (1 930 - 36) a r e : -
U rtica ria l,
86.5$ of a l l rashes;
E r y t h e m a t o u s,
4*7$
,,
,,
M orbilliform ,
4.2$
,,
,,
C ircinate,
2.3$
,,
,,
Polymorphus,
2 .3$
,,
,,
and f o r t h e time o f appear a n c e : U r t i c a r i a l appear
Erythematous , ,
M orbilliform
Polymorphus
,,
Ci r e i n a t e
,,
(o) R e cu rr en t R a s h e s .
first,
se c o n d ,
third,
fourth,
last,
a v e ra g e 8th* day
,,
9th* , ,
,,
10th*
,,
,,
11th* , ,
,,
12th* , ,
These were more oommon
a f t e r the a d m i n i s t r a t i o n o f whole serum*
1
Davidson (1919) found i n h i s s e r i e s an
i n c i d e n c e o f 3 . 6 $ but i n the B e l v i d e r e H o s p i t a l
D i p h t h e r i a Case Records (1930 - 36) t h e
i n c i d e n c e i s 1$*
(iv) A r th r itis *
F o l l o w i n g the a d m i n i s t r a t i o n o f
whole serum an i n c i d e n c e o f 1 - 3$ has been
r e p o r t e d and i n 14 - 20 $ o f a l l serum r e a c t i o n s
Coca, D e l b e r t and Menger ( 1 9 2 2 ) , r e p o r t i n g upon
a s e r i e s o f 223 c a s e s , found a r t h r i t i s in
36*7$ o f th e c a s e s *
Bray (1937)
observed t h a t the commonest j o i n t s
t o be a f f e c t e d were the i n t e r p h a l a n g e a l j o i n t s *
The p a t i e n t c o m p la in s o f p a i n and t e n d e r n e s s
i n t h e j o i n t s , but s w e l l i n g i s s l i g h t or a b s e n t
Bo o ts and S w i f t ( 1 9 2 3 ) •
S i x out o f te n c a s e s
.5 8 .
which had r e c e i v e d Type 1 pneumococcal
a n t i - s e r u m i n t r a v e n o u s l y d e v e lo p e d a r t h r i t i s .
Four o f the p a t i e n t s had p a i n and s w e l l i n g
o f the k n e e s .
The knee j o i n t s were
a s p i r a t e d , and i n two o f t h e c a s e s h o r s e
serum was found in the a s p i r a t e d f l u i d .
(v)Oedema.
T h is o c c u r s u s u a l l y i n t h e l o o s e
t i s s u e s o f t h e f a c e and h a n d s .
1
S t u r t e v a n t ( 1 9 1 6 ) , Davidson (1919 ) , and
Mackenzie and Hangar (1930) foun d t h i s
in 4 . 8 $ , 7 - 8 $
reacting c a s e s .
and 33$ r e s p e c t i v e l y o f
Oedema i n o t h e r r e g i o n s
i s r a r e , but i t does occur i n t h e muoous
membrane o f the b r o n c h i , the bowel and the
o o n j u n c t i v a e ( D a v id s o n , 1919 ; Coca, 1 9 3 1 ) .
(vi) A d e n itis.
Von P i r q u e t and S c h ic k (1905)
n o t e d the p r e s e n c e o f an i n g u i n a l a d e n i t i s
on t h e s i d e n e a r e s t t h e s e a t o f i n j e c t i o n o f
the serum.
T h is u s u a l l y oc cu rr ed during the
f i r s t 7 days f o l l o w i n g th e i n j e c t i o n and
p r i o r t o the appearance o f the r a s h ; a s the
symptoms o f the serum r e a c t i o n s u b s i d e d ,
so a l s o d i d t h e g l a n d s .
R o l l e s t o n (1908) , i n v e s t i g a t i n g a l a r g e s e r i e s o f
d i p h t h e r i a c a s e s where the a d e n i t i s due to the
diphtheria had s u b s i d e d , found a d e n i t i s due to
.5 9 .
the serum t o oc cur in 9% o f o a s e s ,
i n 111
out o f 133 c a s e s r e p o r t e d , t h e f a u c e s were
n o r m al.
Most o f the c a s e s occu rr ed w i t h i n
t h e second week .
He r e p o r t e d t h a t serum
.. a d e n i t i s i s more f r e q u e n t a f t e r s e v e r e
a t t a c k s o f d i p h t h e r i a than a f t e r m i l d , and
may oc cu r a t any a g e , whereas th e l a t e
a d e n i t i s o f d i p h t h e r i a b e a r s no r e l a t i o n t o the
s e v e r i t y of the a t t a c k and i s c o n f i n e d t o
young c h i l d r e n .
Coca, D©ibert and Menger (1922)
o b s er v ed a 1 9 . 5 $
i n c i d e n c e o f a d e n i t i s in a s e r i e s o f 223 c a s e s
t r e a t e d at the H o sp ita l of the R o c k e f e lle r
In stitu te•
Davidson ( 1 9 1 9 1) gave a s h i s f i n d i n g s
incidence
o f a d e n i t i s f o l l o w i n g the a d m i n i s t r a t i o n o f
antiserum .
(v ii)
A lbu m inu ria .
S t u r t e v a n t (1916) found a
p e r c e n t a g e o f 7 In c a s e s showing serum
reaction•
Davidson (1919 ) c o nclu ded t h a t album inuria had
no r e l a t i o n s h i p w i t h serum d i s e a s e and
occu rred i n o n l y *4% o f r e a c t i o n s and a f t e r
the f i r s t I n j e c t i o n o f serum.
Mackenzie and Hangar (1930) are o f the o p i n io n
t h a t albuminuria a s s o c i a t e d w i t h serum
*60 *
r e a c t i o n i s due t o temporary impairment
o f r e n a l f u n c t i o n , d u rin g w h ic h c h l o r i d e s
are r e t a i n e d and the volume o f u r i n e
passed i s dim inish ed .
(v iii)
Fever*
T h is o c cu rs In about 3 0 $ o f
r e a c t i o n s in c a s e s t r e a t e d w i t h whole
serum.
The a ve ra ge tem perature i s
100 - 1 0 2 °F . and the f e v e r i s o f the
Interm ittent type.
The h i g h e s t In o id e n o e
o f f e v e r r e a c t i o n i s a s s o c i a t e d w i t h the
m o r b i l l i f o r m and c i r c i n a t e t y p e s o f r a s h e s *
(Davidson 1919^; Mackenzie and Hangar 1930;
Bray 1937)
( I x ) Blood Changes.
These a r e no t c h a r a c t e r i s t i c
and depend a g r e a t d e a l upon the natu re o f
the i l l n e s s .
Von P i r q u e t and S chick (1905) f o u n d , in
c h i l d r e n , a l e u c o c y t o s i s du rin g the
I n c u b a t i o n p e r i o d and a p o ly - m o r p h o n u c le a r
l e u c o p e n i a w i t h the o n s e t o f the symptoms*
Mackenzie and Hangar (1930)
ob s er ved In some
c a s e s a l e u c o c y t o s i s and an e o s i n o p h i l i a
towards th e end o f the symptoms.
(x) O r c h i t i s and Abdominal P a i n .
R o l l e s t o n (1924) q u o t e s t h r e e c a s e s from
French o b s e r v a t i o n s o f o r c h i t i s , but the
<61*
c o n d i t i o n I s not a common o n e .
G o o d a l l (1925)
r e p o r t s a c a s e o f a boy
o f 10 y e a r s , s u f f e r i n g from s e v e r e
d i p h t h e r i a , who d e v e lo p e d u r t i c a r i a
on the 1 3 t h . day a f t e r serum i n j e c t i o n ,
abdominal p a i n and a r t h r i t i s on the
1 8 t h . and 1 9 t h . d a y s , and a c u t e b i l a t e r a l
o r c h i t i s on the 2 0 t h . d ay .
A recurrent
erythe m ato us r a sh appeared on t h e 22nd#
and 32nd. d a y s .
(xi)
N e u r o lo g ic a l C om plications.
These were
f i r s t r e p o r t e d upon by Roux, Martin and
C h a l l l o n s a t the Budapest M ed ic a l
Congress o f 1 8 9 4 .
A llen (1931)•
Reviewing the l i t e r a t u r e
on t h i s s u b j e c t , he s t a t e s t h a t over a
p e r i o d o f 40 y e a r s o n l y about 50 o a s e s
have been r e p o r t e d and t h e s e were m a i n l y
in French l i t e r a t u r e .
One c a s e i s
r e p o r t e d i n England i n 1918 by Dyke.
A llen
d i v i d e d the c a s e s i n t o f o u r groups
(a) R a d i c u l a r Type - Erb-Duchenne p a r a l y s i s
of acute o n s e t.
(b) N e u r o t i c - S i n g l e nerve t ru n k s a f f e c t e d .
(c) P o l y n e u r i t i c - Resembles t o x i c p o l y ­
n eu ritis.
•62.
(d) I n t r a c r a n i a l - P r o b a b ly due t©
C e r e b r a l Oedema.
The n e u r i t i s i s due t o oedema o f t h e p e r i ­
n e u r a l t i s s u e s and t h e r e i s a c o m p r e s s io n
paralysis*
Recovery i s s l o w , but a good
p r o g n o s i s can be g i v e n .
( P o s t e r Kennedy,
1929; Gordon 1932) .
Young ( 1 9 3 2 ) , r e p o r t i n g upon 7 o a s e s , found
an a s e p t i o m e n i n g i t i s i n v o l v i n g t h e c e n t r a l
nervous sy s t e m .
W ils on and Hadden (1932)
describe s ix oases
o f m u l t i p l e n e u r i t i s f o l l o w i n g the
a d m i n i s t r a t i o n o f t e t a n u s and d i p h t h e r i a
serum.
They found t h a t the upper cord o f
the b r a c h i a l p l e x u s was most o f t e n i n v o l v e d *
Doyle ( 1 9 3 3 ) , a n a l y s i n g 49 c a s e s , foun d t h a t
34 f o l l o w e d t e t a n u s a n t i t o x i n , 7 d i p h t h e r i a ,
5 s c a r l e t f e v e r , and 3 pneumonia, a n t i - s e r u m .
44 o f the c a s e s were males and 5 were f e m a l e s *
The a v e ra g e age was 2 7 .
Onset o f symptoms
o c c u r r e d most o f t e n on the 9 t h . day a f t e r
i n j e c t i o n and about 2 days a f t e r t h e
r e a c t i o n had been p r e s e n t .
C a t h a l a , G a r c i a , G a b r i e l and Laplane ( 1 9 3 4 ) ,
d e s c r i b e a c a s e o f a woman o f 25 y e a r s who
had had a p r e v i o u s i n j e c t i o n o f a n t i -
*
63*
d i p h t h e r i t i c serum, and who, on b e i n g
g i v e n 60 c . c ’ s o f a n t i - s c a r l a t i n a l serum
d e v e l o p e d r e c u r r e n t u r t i c a r i a and
m u l t i p l e n e u r i t i s on t h e 1 4 t h . , 5 7 t h .
and 7 3 r d . d a y.
Roger and P a i l l a s (1936)
define 3 cereb ral
forms which may o ccu r (a)
Isolated
p a r a l y s i s o f the c r a n i a l n e r v e s , i n c l u d i n g
optic n e u r it is ,
(b) C e r e b r a l symptoms in
t h e c o u r s e o f g e n e r a l p a r a l y s i s and
(o)
I s o l a t e d e n c e p h a l o p a t h y i n th e form o f
h e m i p h l e g i a , c h o r e if o r m movements and
v a r i o u s p s y c h i c a l symptoms.
(x ii)
Arthus Phenoneraa.
Gatewood and B a l d r id g e (1927) r e p o r t 6
c a s e s who had r e p e a t e d i n j e c t i o n s o f
serum and d e v e lo p e d p a i n , r e d n e s s and
s w e l l i n g , which p r o g r e s s e d t o a c t u a l
necrosis.
T h is I s more l i a b l e t o o ccu r
I f the r e i n j e c t i o n I s g i v e n during a serum
r e a c t i o n from a p r e v i o u s dose o f serum.
Dudgeon (1927) r e p o r t e d a s i m i l a r c a s e i n a
h o r se s e n s i t i v e a d u l t who was g i v e n
subcutan eous d o s e s f o r p o r p o s e s o f
d esen sitisa tio n •
#64 4
(x iii)
Serum A c c i d e n t s .
Severe and f a t a l
r e a c t i o n s f o l l o w i n g the a d m i n i s t r a t i o n
o f serum are r a r e .
within 2 - 3
They come on
m in u te s o f t h e g i v i n g o f
th e serum, and i f d e a th does f o l l o w i t
i s u su a lly w ithin 5 - 1 0
m inutes.
Acco rding t o Lamson (1924)
th ese severe
r e a c t i o n s are most common i n p a t i e n t s
who have not been s e n s i t i s e d by a
p r e v i o u s I n j e c t i o n o f serum, but who,
i f t h e y had been t e s t e d by sk i n t e s t s ,
would have shown r e a c t i o n t o h o r s e serum.
Prom a s e r i e s o f 41 c a s e s he found t h a t
34$ had a h i s t o r y o f asthma or hay f e v e r
and t h a t 1 9 . 5 $ had had a p r e v i o u s
i n j e c t i o n o f serum.
Park (1928) has e s t i m a t e d t h e number o f
f a t a l i t i e s o c c u r r i n g a f t e r the
a d m i n i s t r a t i o n o f serum, and b e i n g
d i r e o t l y due t o th e serum, t o be 1 In
50,000.
Ratner ( 1 9 3 0 ) ,
s e n s i t i s e d guinea p i g s
by i n h a l a t i o n s o f horse dander and
induced serum shock In t h e same
anim a ls by i n j e c t i n g them w i t h horse
r. 6 5r«
serum#
He th o u g h t t h a t a s i m i l a r
sequenoe might ocour in man#
Bray ( 1 9 3 7 ) , t h o u g h t t h a t th e s e v e r e
r e a c t i o n s t o a f i r s t i n j e c t i o n o f serum
might be caused by the p a t i e n t * s h a v in g
been s e n s i t i s e d by l y i n g on h o r s e - h s i r
beds or c h a i r s .
Walker ( 1 9 1 7 ) , proved t h a t a l t h o u g h a p erso n
may s u f f e r from asthma i t did not
n e c e s s a r i l y mean t h a t he would e x h i b i t
s i g n s o f serum r e a c t i o n when he was
i n j e c t e d w i t h serum.
H is f i n d i n g s were:
20% o f a s t h m a t i c s were s e n s i t i v e t o
h o r s e p r o t e i n , but o n l y 4% r e a c t e d t o
ho r se serum.
In man the t r a i n o f symptoms i n a l l c a s e s
o f serum r e a c t i o n which prove f a t a l , i s
remarkably c o n s t a n t .
These are d y spn oea,
c y a n o s i s , r e s t l e s s n e s s , coughing and
extreme a n x i e t y .
These ar e l a t e r
f o l l o w e d , i n c a s e s where d e a th comes
s l o w l y , by headache, u r t i c a r i a and oedema.
The a c t u a l c a u se o f d e a t h i s u s u a l l y
r e s p i r a t o r y f a i l u r e , the h e a r t c o n t i n u i n g
t o b e a t even a f t e r r e s p i r a t i o n has c e a s e d .
The post mortem f i n d i n g s a r e ,
there i s
**66 **
pulmonary emphysema w i t h enormous
d i s t e n s i o n o f the l u n g s , d i l a t a t i o n o f
th e r i g h t h e a r t , g e n e r a l venous s t a s i s
and v l s o e r a l c o n g e s t i o n (Boughton 1919;
B u llo w s and J a c o b i , 1 9 3 0 ) •
The m a j o r i t y o f f a t a l c a s e s have f o l l o w e d
th e i n t r a v e n o u s i n j e c t i o n o f serum, but
t h i s i s not a lw a y s s o .
Boughton (1919) rec ord ed a c a s e where t h e
p a t i e n t die d a f t e r h av in g r e c e i v e d o n l y
one minim o f horse serum i n t r a v e n o u s l y
a s a d e s e n s i t i s i n g dose f o r h or se asthma*
Park and Bolduan (1908) d e s c r i b e a c a s e o f
a young man o f 16 y e a r s who r e o e i v e d h i s
serum s u b c u t a n e o u s l y .
There was no
immediate r e a c t i o n and t h e d o c t o r l e f t t h e
room.
A fe w minutes l a t e r he r e t u r n e d
t o f i n d the p a t i e n t d e a d , a p p a r e n t l y due
t o the serum.
Freedman ( 1 9 3 5 ‘L) d e s c r i b e d a f a t a l c a s e in
an a s t h m a t ic c h i l d f o l l o w i n g the
a d m i n i s t r a t i o n o f 0 . 0 5 c . c f s o f h o r se
serum i n t r a c u t a n e o u s l y f o r d e s e n s i t i s a t i o n
purposes.
(xiv)
Severe Serum Shook w i t h Recovery:
Numerous c a s e s have been r e c o r d e d o f p a t i e n t s
i67<
who w e r e , and o t h e r s who were n o t ,
s e n s i t i s e d by p r e v i o u s i n j e c t i o n o f
serum; s i m i l a r l y , where th e p a t i e n t w a s ,
or was n o t , a l l e r g i c t o h o r s e serum*
Park and Bolduan ( 1 9 0 8 ) •
A young man w i t h
a n e g a t i v e h i s t o r y , s u f f e r i n g from
d i p h t h e r i a , was g i v e n 5 c . c 1s o f serum
subcutaneously*
In about two m in u te s he
f e l t t i n g l i n g s e n s a t i o n s , f a i n t n e s s and
a sinking f e e l i n g .
He q u i c k l y became
o y a n o s e d , had a r a p i d p u l s e and then
p a s s e d i n t o coma.
He was g i v e n s t r y c h n i n e
and a r t i f i c i a l r e s p i r a t i o n and he
reoovered.
Faw cett and Ryle ( 1 9 2 3 ) •
The p a t i e n t had
had a n t i - d i p h t h e r i t i c serum 19 y e a r s
previou sly.
On b e i n g g i v e n 50 o . c f s o f
a n t i s t r e p t o c o o o a l serum, he d e v e l o p e d
symptoms on t h e 8 t h . d a y.
These were
dy s p n o ea , u r t i c a r i a and oedema o f t h e f a c e .
A d r e n a l i n was a d m i n i s t e r e d , and t h e
symptoms p a s s e d o f f in 20 minutes*
Dudgeon ( 1 9 2 7 ) •
A known a s t h m a t i c who was
s e n s i t i v e t o ho rse serum was g i v e n 0 . 2 5
o . c 1s o f normal ho rse serum s u b c u t a n e o u s l y .
F iv e minutes l a t e r he d e v e lo p e d oedema o f
th e f a o e , d y s p n o ea , c y a n o s i s and then
f e l l i n t o coma.
An hour l a t e r a
d i f f u s e m o t t l e d rash appeared which
p e r s i s t e d f o r 12 h o u r s .
The p a t i e n t
made a complete r e c o v e r y .
D* D e s e n s i t i s a t i o n ;
As I t i s known t h a t the a d m i n i s t r a t i o n o f s m a l l
d o s e s o f serum d e s e n s i t i s e s a n im a ls and p r e v e n t s
a n a p h y l a x i s , I t was thought t h a t the same
p r i n c i p l e co uld be a p p l i e d t o man*
Gordon and C r e s w e l l (1929)
c ono lud ed t h a t
d e s e n s i t i s i n g o f horse serum s e n s i t i v e p a t i e n t s
p r e v e n t e d immediate r e a c t i o n s , but had l i t t l e
i n f l u e n c e on t h e development o f l a t e serum d i s e a s e *
B a t t l e y (1931)
r e p o r t e d a c a s e o f s e v e r e serum shock
a f t e r an i n j e c t i o n o f serum in a p a t i e n t who had
been d e s e n s i t i s e d 17 days p r e v i o u s l y *
He
conoluded t h a t a l o n g e r p e r i o d I s n e c e s s a r y f o r
d e s e n s l t i s a t I o n than I s u s u a l l y a llo w e d *
Method o f D e s e n s i t i s i n g :
D e s e n s i t i s a t i o n i s based on the p a r t i t i o n o f
the dose and slow a d m i n i s t r a t i o n o f th e serum.
The r o u t i n e t o be adopted i s :
primary i n j e c t i o n
of |
o . o . o f a d r e n a l i n (1 in 1,000) and
•»
atropine sulphate g r . /1 0 0 subcutaneously.
T h is i s f o l l o w e d by 0 . 2 o . o ' s o f a 1 in 10
d i l u t i o n o f the t h e r a p e u t i o serum g i v e n
subcutaneously.
I f , a f t e r h a l f - a n - h o u r , no
r e a o t i o n i s o b s e r v e d , 0*5 o . e ' s o f u n d i l u t e d
serum may be g i v e n i n t r a m u s c u l a r l y , and i f ,
a f t e r a n o t h e r h a l f - a n - h o u r has e l a p s e d , no
r e a c t i o n has o c c u r r e d , the f u l l dose o f serum
may be g i v e n i n t r a m u s c u l a r l y .
I f reaction
sh o u ld occu r a t any o f the s t a g e s , t h e dose
should be red uced and the p r o c e s s c o n t i n u e d
over a l o n g e r p e r i o d (Bray, 1937; Fleming and
P e t r i e , 1934; L.C.C. R e p o r t , 1 9 3 6 ) .
I f the p r e l i m i n a r y i n j e c t i o n i s g i v e n i n t o t h e
forearm and a g e n e r a l r e a c t i o n o c c u r s , t h i s
can be minimized by t h e a p p l i c a t i o n o f a
t o u r n i q u e t t o th e arm.
This p r e v e n t s the
a n t i g e n s from e n t e r i n g the g e n e r a l c i r c u l a t i o n .
T h i s method has been used f o l l o w i n g an a c u t e
r e a o t i o n in an a l l e r g i o
i n f a n t who was b e i n g
o
S c h ic k T e s t e d (Freedman, 1935 ) .
P r e v e n t i o n and Treatment o f Serum R e a c t i o n s ?
(A). P r e v e n t i o n .
The serum t o be used must be
considered.
E a r l y o b s e r v a t i o n s r e v e a l e d t h a t serum from
c e r t a i n h o r s e s was more apt t o c a u se serum
r e a c t i o n s than o t h e r s , and a l s o t h a t f r e s h l y
drawn serum c a u s e d r e a c t i o n s more f r e q u e n t l y
* 70,
than t h a t which had been l e f t f o r
longer periods*
Serum s t o r e d i n e x c e s s i v e o o l d or h e a t
had a l s o t h e same f a u l t .
Nowadays
serum i s p o o l e d from s e v e r a l h o r s e s , i s
k e p t f o r some time b e f o r e use and the
s t o r a g e tem perature i s c a r e f u l l y r e g u l a t e d *
C o n ce n tr a ted serum i s now g e n e r a l l y u s e d ,
and t h i s , as has been shown, in c onsequence
o f i t s lower c o n t e n t o f n o n - s p e c i f i o
substance,
has l e s s e n e d the i n c i d e n c e and s e v e r i t y o f
serum r e a c t i o n s .
I n q u i r y should always be made from the p a t i e n t
Ipr r e l a t i v e s )
f o r a h i s t o r y o f a l l e r g y or
p r e v i o u s i n j e c t i o n o f serum.
D esen sitisation
should be c a r r i e d out I f a p o s i t i v e answer I s
o b t a i n e d , as t h i s l e s s e n s t h e p o s s i b i l i t y o f
t h e rare a c u t e shock in the h o r se - se r u m
se n sitiv e ind ividu al.
I f a p a t i e n t I s known t o be s e n s i t i v e t o ho rse
serum, serum d e r iv e d from a n o t h e r animal
should be used - b o v in e or g o a t .
Certain
drugs have a p r e v e n t i v e a c t i o n : Anderson and S c h u l t z ( 1 9 1 0 ) •
They found
t h a t by u s in g a t r o p i n e s u l p h a t e , a d r e n a l i n
and c h o r a l h y d r a t e , snd i n h a l a t i o n o f oxygen
.
71 .
in a n a p h y l a c t i c a n im a ls who were g i v e n serum,
t h e y c o u l d reduc e the i n c i d e n c e o f r e a c t i o n s
t o 2 8 $ , 41$ and 43$ r e s p e c t i v e l y .
Park (1913)
and Bray (1937) b o t h a d v i s e d t h e i n j e c t i o n o f
a t r o p i n s u l p h a t e and a d r e n a l i n h y d r o o h l o r i d e
( 1 in 1000)
i n known or s u s p e o t e d s e n s i t i v e
p atien ts•
Arvray ( 1 9 3 3 ) ,
a d v o c a t e d th e o r a l a d m i n i s t r a t i o n
o f ephedr^ne c h l o r i d e
t a b l e t s (1 t o 3 e g .
a c o o r d in g t o age)
hour b e f o r e t h e serum
one
was g i v e n , and e v e r y 16 hours f o r 14 day s
thereafter.
M er cier (1934) •
He
r ea c tio n s in a s e r ie s
reduced t h e i n c i d e n c e
of
o f c a s e s t o 6 $ . To each
p a t i e n t he gave an i n t r a m u s c u l a r i n j e c t i o n o f
camphosulphate and e p h e d r e n e .
When serum i s b e i n g g i v e n i n t r a v e n o u s l y , i t
should be h e a t e d t o b lo o d h e a t and i n j e c t e d
very slo w ly .
I t may be d i l u t e d w i t h s a l i n e
or g l u c o s e , and 2 - 5 minims o f a d r e n a l i n
h y d r o c h l o r id e added t o i t .
No m atter how serum i s g i v e n , a d r e n a l i n
h y d r o o h lo r id e (1 i n 1000)
sh ou ld always be a t
hand on th e serum t r a y .
B. Treatment:
(i)
Serum Shock.
Treatment must be immediate
i72a
to r e l i e v e the r e s p ir a t o r y d i s t r e s s *
A r t i f i c i a l r e s p i r a t i o n , i n h a l a t i o n o f oxygen
and carbon d i o x i d e , and i n j e c t i o n o f a d r e n a l i n
t o reduce th e b r o n c h i a l spasm, have a l l been
t r i e d w i t h s u c c e s s even where the
p a t i e n t was i n
coma (Mavor 1934; Grant and S c o t t , 1 9 3 4 ) •
Hurst (1934) *
He recommended an i n i t i a l dose o f
2 - 3 minims o f a d r e n a l i n (1 i n 1000) f o l l o w e d
by one minim e v e r y 3 0 - 6 0 s e c o n d s , a c c o r d i n g to
t h e r e a c t i o n o f the p a t i e n t , u n t i l r e c o v e r y
ensued.
(ii)
Serum R e a c t i o n .
Acute u r t i c a r i a and oedema o f the t i s s u e s
u s u a l l y respond w e l l to i n j e c t i o n
of a d r e n a lin .
o f §■ t o 1
Cooling a p p l i c a t i o n s ,
o .c .
such a s
c alam ine l o t i o n are welcomed by the p a t i e n t .
(Curphey and Solomon, 1 9 3 6 ) .
They recommended
l a r g e d o s e s o f ealo lum in an a s s i m i l a b l e form
(10 to 20 c . c ’ s o f 20$ c a lc iu m g l u c o n a t e
i n t r a v e n o u s l y and 10 c . c ! s o f 10$ s o l u t i o n
i n t r a m u s c u l a r l y , as
soon as th e r a s h appea red -
the in t r a m u s c u l a r i n j e c t i o n t o be r e p e a t e d
e v e r y 12 hours i f n e c e s s a r y ) •
Most serum r e a c t i o n s do not r e q u i r e more than
l o c a l t r e a t m e n t , but s a l i c y l a t e s do h e l p i n
cases of a r t h r i t i s .
SUMMARY AND
CONCLUSIONS.
The t y p e s o f serum r e a o t i o n s o c c u r r i n g in man
are:
(1) Normal - a f t e r primary i n j e c t i o n and a l a t e n t
p e r i o d o f from 7 - 1 5
days*
(2) Abnormal - in a s e n s i t i s e d i n d i v i d u a l , which may
be im med iate, o c c u r r i n g w i t h i n 24 h o u r s , or
a c c e l e r a t e d , when the l a t e n t p e r i o d I s
2 - 6
days#
(3) Serum a c c i d e n t s or serum shock - the s e v e r e bu t
r a r e l y f a t a l r e a c t i o n s which u s u a l l y oocur
im m e d ia t e ly a f t e r i n j e c t i o n i n a h o r se serum
s e n s i t i v e or a l l e r g i c person*
The main f a c t o r s I n f l u e n c i n g th e i n c i d e n c e o f
serum r e a c t i o n s a r e:
(1)
The q u a n t i t y o f serum g i v e n .
(2)
The type o f serum - u n c o n c e n t r a t e d or
concentrated.
(3)
P r e se n c e or absence o f s e n s i t i v i t y in the
p a t i e n t due e i t h e r t o p r e v i o u s serum
i n j e c t i o n or n a t u r a l ho rse serum s e n s i t i v i t y *
(4)
The method o f a d m i n i s t r a t i o n , i n t r a v e n o u s or
intram uscular•
An ac cou n t has been g i v e n o f the
m a n i f e s t a t i o n s o f serum r e a c t i o n In man and
i74i
th e ir incid en ce.
The q u e s t i o n o f
d e s e n s i t i s a t i o n i n man and the p r e v e n t i o n
and tr e a t m e n t o f serum shook and serum
r e a c t i o n s has been d i s c u s s e d .
The r e s u l t s when " R e f i n e d ” d i p h t h e r i a
a n t i t o x i n was u sed are r e p o r t e d i n t h e n e x t
s e c t i o n o f t h i s work.
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.7 5 .
A n a l y s i s and Comparison o f the I n o i d e n o e and
M a n i f e s t a t i o n s o f Serum R e a c t i o n o o c u r r i n g in
a S e r i e s o f 6 , 7 2 0 C o n s e c u t i v e C a ses o f
D iphtheria tr e a te d with ooncentrated
D i p h t h e r i a A n t i t o x i n , and 1 , 0 0 0 C o n s e c u t i v e
C a s es o f D i p h t h e r i a t r e a t e d w i t h r e f i n e d
Diphtheria A n t it o x i n .
A l l t h e c a s e s were t r e a t e d a t the B e l v i d e r e ( C i t y o f
Glasgow) F ev e r H o s p i t a l .
The 6 , 7 2 0 r e p r e s e n t a l l the
o a s e s o f d i p h t h e r i a i n the H o s p i t a l du rin g the y e a r s 1930
t o 1936 i n c l u s i v e .
The 1 , 0 0 0 c a s e s t r e a t e d w i t h r e f i n e d
a n t i t o x i n were i n th e H o s p i t a l during the p e r i o d August
1937 t o A p r i l 1 93 9 .
D efin itio n of R eactions.
For the purpose o f t h i s a n a l y s i s , serum r e a c t i o n i s
i n t e r p r e t e d as i n c l u d i n g any r e a c t i o n which may be
a t t r i b u t e d t o t h e I n j e c t e d serum, a p a r t from th e immediate
therm al r e a c t i o n a f t e r i n t r a v e n o u s t h e r a p y .
Serum r e a c t i o n s are t h e r e f o r e d i v i d e d i n t o : (1) L o c a l r e a c t i o n where t h e r a sh i s l i m i t e d t o the
s i t e o f serum i n j e c t i o n .
(2) General r e a c t i o n ; r e s u l t s o f r e a c t i o n due t o
c i r c u l a t i n g serum, i n c l u d i n g r a s h e s o c c u r r i n g
8 part from the s i t e o f i n j e c t i o n and symptoms
such as f e v e r , oedema and a r t h r i t i s , which may
occur i n t h e absen ce o f a r a s h .
,
76.
A n a l y s i s o f Serum R e a o t l o n s .
Concentrated
Serum
Refined
Serum
T o t a l Number o f C a s e s .....................
6,720
1,000
T o t a l Number w i t h no Serum
R e a c tio n ......
6,050
976
T o t a l Number w i t h Serum
R e a ctio n ......
670
24
P e r c e n t a g e o f Serum R e a c t i o n s . .
G e n er a l Serum R e a c t i o n ..................
L o c a l R e a c t i o n o n l y .................................
2.4
9 .9
594 = 8 . 8 $
19 = 1 . 9 #
76=1 . 1 #
5 = 0 .5#
The main f a c t d e r i v e d from th e above t a b l e
i s t h e d e f i n i t e r e d u c t i o n in the i n c i d e n c e o f serum
r e a c t i o n from 9 . 9 # t o 2 . 4 # .
.7 7 .
D e t a i l e d A n a l y s i s o f the I n c i d e n c e o f
Serum R e a c t i o n s in 6 , 7 2 0 Cases o f D i p h t h e r i a
T r e a t e d w i t h C o n ce n tr a ted Serum, and o f 1 , 0 0 0
e s s e s o f D i p h t h e r i a t r e a t e d w i t h R e f in e d A n t i t o x i n .
C o n ce n tr a ted
Age
Group
Sex
Total
Cases
0- 6
M
F
M
F
M
F
M
F.
M
F
M
F
M
F
953
982
780
1068
785
1112
149
449
138
281
12
10
1
6-10
11-20
21-30
31-40
41-60
51-60
Serum.
..SSrJML R e a c t i o n ______ .- G e n e r e l ^ Q r u m ^ B e a s i i p n ___
Number
Percentage
Percentage
Number
69
72
189
158
47
83
17
22
6
7
-
-
, ________
R e f in e d
Age
Group
Sex
Total
Ca s e s
0- 5
M
F
M
F
M
F
M
F
M
F
M
F
M
F
93
98
247
197
130
109
42
29
15
12
20
3
5
6-10
11-20
21-30
31-40
4 1 -5 0
51-60
61
62
176
146
40
74
10
16
4
5
-
7.2
7.3
24.2
14.8
6.0
7.5
11.4
4.9
4.3
2.4
..
-
-
-
Serum.
Serum R e a c t i o n
Number P e r c e n t a g e
2
1
7
3
4
3
2
1
1
-
6 .4
6.3
22.5
13.7
5.1
6.7
6.6
3.5
2.9
1.7
-
2.2
1.0
2 .8
1.5
3.1
2 .7
4.7
3.4
6.7
-
-
G en eral Serum R e a c t i o n
Number * P e r c e n t a g e
i
2
!
2.2
1
j
1.0
5
*
2.0
2
1.0
3
‘
2.3
2
»
1.8
2
!
4.7
1
J
3.4
1
•i
6.7
i
i
-
:
_
.7 8 .
With c o n c e n t r a t e d serum th e i n c i d e n c e o f r e a c t i o n
i s h i g h e s t in the 6 - 1 0 age gr ou p, and t h e r e a f t e r d i m i n i s h e s
w i t h a g e , e x c e p t f o r the 2 1 - 3 0 group (male) where t h e r e i s a
sharp r i s e .
In th e r e f i n e d s e r i e s t h e r e i s a g r a d u a l i n c r e a s e
in i n c i d e n c e w i t h a g e , but a f t e r 40 no r e a c t i o n s were o b s e r v e d .
With both sera, males would appear t o have a h i g h e r i n c i d e n c e
o f r e a c t i o n s than f e m a l e s .
A comparison i s drawn between the i n c i d e n c e o f serum
- r e a c t i o n s c o r r e l a t e d w i t h the dosage o f serum a d m i n i s t e r e d .
Up TO 8 ,0 0 0
C o n centra ted
Age
Group
Sex
0- 5
M
P
M
P
M
P
M
P
M
P
M
P
M
F
6-10
11-20
21-30
31-40
4 1-5 0
51-60
i'
Total
Cases
357
376
271
397
246
406
39
107
47
99
6
5
1
—
UNITS
Serum.
Serum-BSSS±J.0D_____
Number P er ce n ta g e
15
17
31
26
7
11
4
3
1
1
-
-
4.2
4.5
11.4
6.5
2.8
2.7
10.2
2.8
2.1
1.0
-
Number
Percentage
12
11
27
23
5
8
3
2
1
1
-
3.3
2.9
9.9
5.8
2.3
1.9
7 .7
1.8
2 .1
1.0
-
-
-
.7 9 .
UP
TO
8 ,0 0 0
Refined
Age
Group
0- 5
Sex
M
F
6-10
M
11-20
M
P
21-30
31-40
41-50
51-60
P
M
P
M
P
M
T
r71
M
F
Total
Gases
21
25
94
61
27
24
11
9
6
3
4
UNITS
Serum.
_ _ S firum _ffiactiD n ________ - G e n e r a l . Serum - B ase t i o n —
Number ! P e r c e n t a g e
Number
Percentage
t
i
i
i
_
i
“
i
-
-
5
’
i
t
J
i
-
-
-
-
-
_
-
-
i
i
The f e e t t h a t no r e a c t i o n s were ob ser v ed in
any p a t i e n t s who r e c e i v e d 8 , 0 0 0 u n i t s or l e s s o f r e f i n e d serum,
w h i l e r e a c t i o n s were f a i r l y common a f t e r i n j e c t i o n o f
c o n c e n t r a t e d serum, i s t h e most n o t a b l e f e a t u r e o f t h e t a b l e s ,
and i s p r o b a b l y due t o the p a t i e n t s who were g i v e n r e f i n e d
a n t i t o x i n r e c e i v i n g o n l y v e r y minute q u a n t i t i e s o f n o n - s p e c i f i c
p rotein .
Prom t h e s e t a b l e s i t i s se en t h a t t h e r e a c t i o n
r a t e i n m ales i s s l i g h t l y h i g h e r than i n f e m a l e s .
.8 0 ,
B.
UP
r "1■
Age
Group
Co n ce ntr a ted
Serum.
___S erum 'Reacti on______ . . G e n e r a l . S e r u m . R e a c t i o n .
Number
Percentage
Percentage
Number
to
i
o
6-10
11-20
21-30
31-40
41- 50
51-60
Sex
Total
Ca s e s
M
P
M
P
M
P
M
P
M
P
M
P
M
P
501
451
349
481
401
472
89
232
52
94
3
3
-
39
38
106
89
30
52
9
12
3
4
UP
Age
Group
Sex
0- 5
M
P
M
F
M
P
M
P
11-20
21-30
31-40
M
P
41-50
M
51-60
P
M
P
Total
Ca se s
42
44
89
72
65
43
17
11
6
5
12
3
-
4 0 ,0 0 0
UNITS
7.8
8.4
30.4
18.3
7.5
11.0
10.1
5.2
5.7
4.2
37
37
102
84
27
49
5
9
2
3
7.4
8.2
29.2
17.4
6.7
10*4
5.6
3.6
3.8
3.2
-
-
-
-
-
-
-
-
-
-
-
-
TO
R e f in e d
■-
6-10
TO
4 0 jOOP
UNITS
Serum.
.Ssrnm. Ess fit io n ______ .G sB sra l.S srn m .B ssfition ..
Number
Percentage
1
2.4
3.4
1.4
3.1
2.4
5.8
3
1
2
1
1
—
—
—
Number
Percentage.
1
2.4
1
1.2
1
1
-
1.5
-
-
-
-
5.8
-
-
-
—
—
L.......- ............. .... •
The p e r c e n t a g e o f serum r e a c t i o n s f o l l o w i n g the
a d m i n i s t r a t i o n o f r e f i n e d serum i s v ery much lower than t h a t
81
f o l l o w i n g the i n j e c t i o n o f c o n c e n t r a t e d serum, and the
p e r c e n t a g e w i t h d o s e s o f 8000 u n i t s or l e s s o f c o n c e n t r a t e d
serum i s h i g h e r than t h a t when th e l a r g e s t dose o f r e f i n e d
a n t i t o x i n g i v e n , was 4 0 , 0 0 0 u n i t s .
With b o th sera m a les have
t h e s l i g h t l y h i g h e r r a t e , and the r a t e i s h i g h e s t in t h e
6 - 1 0 y e a r s group w i t h c o n c e n t r a t e d , and i n the 2 1 - 3 0 y e a r s
(male) group w i t h r e f i n e d serum.
The I n c i d e n c e o f r e a c t i o n s
w i t h c o n c e n t r a t e d serum has i n c r e a s e d w i t h t h e i n c r e a s e in the
dose o f serum g i v e n .
C.
40,000
UNITS
Concentrate d
Age
Group
Sex
0- 6
M
F
M
P
M
P
M
P
M
P
M
P
M
P
6-10
11-20
21-30
31-40
41-50
51-60
Total
Ca se s
95
155
160
190
138
234
21
110
39
88
3
2
-
OR
OVER
Serum.
________
Number
15
17
52
43
10
20
4
7
2
2
-
P e r ce n ta g e
15.8
10.9
32.5
22.6
7.2
8.8
19.0
6.4
5.1
2.3
—
-
l _ £ § r y 2LB §§ £ t Ion.
Number
Percentage
12
14
47
39
8
17
2
5
1
1
—
—
—
12.6
9.0
29.3
20.8
5.7
7.6
9.5
4.5
2.6
1.2
—
—>
.8 2 .
4 0 ,0 0 0
UNITS
OR
-> 4. J . U Q U
Age
Group
Sex
Total
Cases
0- 5
M
F
M
F
M
F
M
F
M
F
M
r
M
F
30
29
64
64
38
42
14
9
3
4
4
6-10
1 1 -2 0
21-30
31-40
41-60
5 1 -60
OVER
UU1 •
___Serum_Reactions__ .Gen era1_Serum_Reactiogs
Number i P e r c e n t a g e Number
Percentage
1
1
4
2
2
2
1
1
1
i
!
J
i
!
j
i
i
J
3.3
3.4
6.3
3.1
5.2
4.7
7.1
11.1
33.3
1
1
4
2
2
2
1
1
1
3.3
3*4
6.3
3.1
5*2
4.7
7.1
11.1
33.3
1
1
__
1
|
1
1
1
1
1
-
— .-n .
,
---------------------f -
-
—
'
---------------------.1
Again the i n c i d e n c e r a t e i s on the upgrade w it h b o t h
se ra*
Males a g a i n have the h i g h e r i n c i d e n c e *
Using c o n c e n t r a t e d
serum t h e age group 6 - 1 0 has the h i g h e s t p e r c e n t a g e o f r e a c t i o n s ,
but w i t h r e f i n e d serum i t i s the 3 1 - 4 0 (male)
group which i s
highest*
(1)
FACTORS INFLUENCING
________________
Sex*
THE INCIDENCE OF SERUM
REACTIONS*_______________
C oncentrated
Sex
M
F
Total
Number
2,818
3,902
Sex
Total
Number
M
F
552
448
Serum.
_.5srUBL BsSfitiPB _____
Number P e r ce n ta g e
11.6
328
8.6
342
Number
291
303
J Percentage
!
10.3
|
7.8
R e f in ed
Serum.
-Sernm- B e a ctio n____ - - Ge ne ra 1- Se rum.Reaction-,
Percentage
Number ! P e r c e n t a g e
Number
16
8
2.9
1.8
13
6
|
*
2.3
1.3
With both sera males have much t h e h i g h e r r a t e , the
83.
d i f f e r e n c e b e i n g more marked w i t h r e f i n e d serum than w i t h
c o n c e n t r a t e d - 66*6$ and 48*9$ r e s p e c t i v e l y *
(2) A£®
Age Group
Co n centrated Serum*
Number o f Cases
__ot io n s _
T o t a l % [G en eral %
0- 5
6-10
11-20
21-30
3 1-4 0
41-6 0
61-60
1,935
1 ,8 4 8
1,8 97
598
419
22
1
R e f in e d
Age Group
0- 5
6-10
11-20
21-30
31- 40
41-50
51-60
7.3
18.7
6.8
6.5
3.1
-
!
!
[
J
!
J
i
6.3
17.3
6.0
4.3
2.1
-
Serum
Number o f Cases
191
444
239
71
27
23
5
. __S©;rum_R©a c t i o n s __
Tota1 % | General $
1.6
2.3
2.9
4.2
3.7
—
------------
;
i
|
J
i
i
1.6
1.6
2 .1
4.2
3.7
— .. *~
Using c o n c e n t r a t e d serum the p e r c e n t a g e i n c i d e n c e
o f r e a c t i o n s f l u c t u a t e s from age group t o age g r o u p , b e i n g
h i g h e s t i n the 6 - 1 0 group and f a l l i n g sudd enly ove r t h e age
o f 30*
With r e f i n e d serum the p e r c e n t a g e i n c i d e n c e i s s t e a d i l y
p r o g r e s s i v e up t o the 3 1 - 4 0 group, when i t f a l l s s l i g h t l y , and
o v e r 40 no r e a c t i o n s were r e c o r d e d .
.8 4 .
(3)
Dosage o f Serum.
Con centrated
Dosage
(Units)
8,000
8-40,000
Over 4 0 , 0 0 0
Serum.
Serum R e a c t i o n s
Ma l e
%
Total
General
Total
General
Total
G en eral
i
R e f in ed
Dosage
( U n it s )
8,000
8-40,000
Over 4 0 , 0 0 0
Serum R e a c t i o n s
Total
General
Total
General
Total
General
5.9
4.9
1 3 .4
12.7
18.2
14.3
Female
*
Total
%
4.1
3.2
11.2
10.4
11.2
9.7
5.0
3.9
12.2
11.4
14.0
11.9
Serum.
Male
$
3.0
1.7
5.9
5.9
Female
$
-
1.1
4.0
4.0
These t a b l e s show t h a t as we i n c r e a s e th e dose
o f serum t h e p e r c e n t a g e i n c i d e n c e o f serum r e a c t i o n
i n c r e a s e s , and th a t t h e r a t e i s h i g h e r f o r males than
fo r fem ales.
This c o n c l u s i o n h o ld s f o r both r e f i n e d
and c o n c e n t r a t e d a n t i s e r a .
Total
-
2.05
0.85
4.95
4.95
•,85
(4)
I n t r a v e n o u s I n j e c t i o n o f the Serum:
_______________________C on ce n tr ated Serum.
Number o f
__ §§r^BLg§8c;t?ion_______ ___ General_§erutp_g§ast i£Q_._
Ca s e s .
Number ! P er c e n t a g e
Number
! Percentage
i
.. ...........
—J "
■■
476
91
!
19.1
72
!
15.1
759
81
! 10.7
74
!
9 .7
i
........... -mi ... . ..
R e f in ed
Number o f
Ca s e s
150 i n t r a v e n o u s
(intravenous
25G(
and
( intram uscular
600 i n t r a m u s c u l a r
-
Serum.
--SemiLjBsactiPz? _____
Number i P er ce n ta g e
5
16
3
!
«|
i
i
i
i»
i
. ---- -------
Number
3.3
5
8.0
14
0.5
i Percentage
!
i
i
i
i
i
i
___
3.3
5.6
With c o n c e n t r a t e d serum none of the c a s e s r e c e i v e d
the serum by i n t r a v e n o u s i n j e c t i o n a l o n e .
476 o a s e s
r e c e i v e d a combined i n t r a v e n o u s and in t r a m u s c u l a r i n j e c t i o n ,
and a l l o f t h e s e c a s e s had over 4 0 ,0 0 0 u n i t s o f serum.
In
t h e t a b l e s a bove, w i t h c o n c e n t r a t e d serum the comparison i s
made w i t h th e c a s e s who r e c e i v e d the serum by combined
i n t r a m u s c u l a r and i n t r a v e n o u s i n j e c t i o n and th e c a s e s who
r e c e i v e d over 4 0 ,0 0 0 u n i t s o f serum i n t r a m u s c u l a r l y .
With
r e f i n e d serum the t a b l e i s s e l f - e x p l a n a t o r y .
I t i s s e e n t h a t with c o n c e n t r a t e d serum the p e r c e n t a g e
o f r e a c t i o n s i s h i g h e r where the p a r t o f the serum was g i v e n
i n t r a v e n o u s l y , but t h i s f i g u r e i s much h i g h e r than f o r the
same group in the r e f i n e d serum t a b l e .
In the l a t t e r t a b l e
i t i s se en t h a t the i n c i d e n c e o f r e a c t i o n s i s l o w e s t where
the serum was g iv e n i n t r a m u s c u l a r l y , h i g h e s t when g i v e n by
• 86 •
t h e combined method, and t h a t i n t r a v e n o u s t h e r a p y
o c c u p i e s the i n t e r m e d i a t e p l a c e .
The p a t i e n t s i n the
i n t r a m u s c u l a r - i n t r a v e n o u s group were the most s e r i o u s l y
ill,
and so r e c e i v e d most serum, and t h i s pro ba b ly a c c o u n t s
f o r t h e h i g h e r serum r e a c t i o n r a t e .
(5)
Yearly V a r ia tio n s :
Year
No. o f
Ca s e s
Serum
R e a ction
No.
i
1930
1931
1932
1933
1934
1935
1936
1,177
929
952
837
1 ,0 5 4
962
809
118
92
97
85
101
99
78
10.0
9.9
10.2
10.1
9.5
1 0 .3
9.7
107
79
88
72
89
90
69
9.1
8.5
9.2
8.6
8.5
9.3
8.5
121 ( 1 0 $
93 ( 1 0 $
98 (1 0 .3 $
85(10.1$
101( 9 . 5 $
9 9(10.3$
77( 9 . 5 $
Total •
6,720
670
9.9
594
8.8
674 ( 1 0 $
2,964(44.3)
24
2.4
19
1.9
116(11.6$
6 5 0 ( 6 5 .0 )
Cases
treated
with
refined
an titoxin .
Aug.1 9 3 7 A p r i l 193S . 1 , 0 0 0
General Serum
R e a ctio n
No.
%
No. w i t h
Previous
Serum
Percentage
Over 20 ,000
U n its.
521(44.1)
417(44.8)
435(45.7)
391(45.5)
416(39.3)
419(44.6)
365(45.1)
From the t a b l e i t i s seen t h a t t h e p e r c e n t a g e
r a t e v a r i e s l i t t l e from year t o y e a r .
The s l i g h t i n c r e a s e s
are e i t h e r a s s o c i a t e d w i t h an i n c r e a s e d p e r c e n t a g e of
p r e v i o u s e s s e s who had been s e n s i t i s e d t o serum or w i t h a
hig h i n c i d e n c e of p a t i e n t s who had r e c e i v e d l a r g e d o s e s
o f serum.
.8,7.
(6)
P r e v i o u s I n j e c t i o n o f Serum:
(a) C o n c e n t r a t e d Serums
Of 6 , 7 2 0 o a s e s t r e a t e d , 674 had r e c e i v e d p r e v i o u s serum = 1 0 . 0 $
Of 6 , 0 6 0 c a s e s w i t h no serum r e a c t i o n , 628 had r e c e i v e d
p r e v i o u s serum.................................................................................. = 8*7$
Of 670 c a s e s w i t h serum r e a c t i o n , 146 had r e c e i v e d
p r e v i o u s serum................................................................................. * 2 1 . 6 $
Of 594 o a s e s w i t h g e n e r a l serum r e a c t i o n , 132 had
r e c e i v e d p r e v i o u s serum
= 22.2$
(b) R e f i n e d Serum:
Of 1 , 0 0 0 c a s e s t r e a t e d , 116 had r e c e i v e d p r e v i o u s serum
Of 976 o a s e s t r e a t e d w i t h no serum r e a c t i o n , 113 had
r e c e i v e d p r e v i o u s serum
Of 24 c a s e s w i t h serum r e a c t i o n , 3 had r e c e i v e d
p r e v i o u s serum
Of 19 c a s e s w i t h g e n e r a l serum r e a c t i o n , 3 had
r e c e i v e d p r e v i o u s serum
= 11.6$
= 11.5$
- 12.5$
= 15.8$
C o n ce n tr a ted Serum
Serum
Re a c t ion
General Serum R e a o tio n
Tlwrifi
o f Case
Total
T rea ted
Number
Percentage
No
previous
serum.
6,046
524
8.6
462
7.6
674
146
21.6
132
19.5
6,720
670
9.9
594
8.8
P revious
serum.
Combined
Group
Refined
Type
o f Case
No
previous
serum.
Total
Treated
884
Number
Percentage
Serum.
Serum R e a c t io n
Number j P er c e n t a g e
i
i
i
21 |
2.4
G en era l Serum R e ao tio n
Number « P e r c e n t a g e
16
1.8
2.6
3
2.6
2.4
19
1.9
|
P revious
serum.
116
3
Combined
Group
1 ,0 0 0
24
1
|
i
1
1
!
i
1
1 H
G
t ©
O
1 G
«H
1 © E 43
1 G P 0
1
1 © G ©
iO ® ©
t
CO 04
1 V?.
1
1^ ^
—
l
H
>
©
t
43
O
1
0
03
1
EH
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• 90.
Conclusions:
The e f f e o t o f p r e v i o u s i n j e c t i o n o f serum
i s i l l u s t r a t e d in the fo reg o in g ta b le s*
P a t i e n t s who
have had a p r e v i o u s i n j e c t i o n of serum, a r e , w i t h
c o n c e n t r a t e d serum t w o - a n d - a - h a I f t i m e s a s l i a b l e to
d e v e l o p serum r e a c t i o n a s t h o s e r e c e i v i n g a f i r s t
in jection .
Using r e f i n e d serum, t h i s l i a b i l i t y i s
red uoed t o 1 . 4 t i m e s .
With both sera the high
do sage o f serum, c o r r e l a t e d w ith p r e v io u s i n j e c t i o n
o f serum, g i v e s the h i g h e s t r e a c t i o n r a t e , but th e
d i f f e r e n c e between the i n c i d e n c e a f t e r the i n j e c t i o n
o f a se co nd dose o f c o n c e n t r a t e d and of r e f i n e d serum i s
marked, b e i n g 2 1 . 6 $ and 5 . 2 $ r e s p e c t i v e l y .
With no
p r e v i o u s i n j e c t i o n o f serum, as the dosage i n c r e a s e s ,
so does the p e r c e n t a g e i n c i d e n c e o f serum r e a c t i o n s ;
w i t h c o n c e n t r a t e d serum i t r i s e s from 2 . 9 $ , t o 1 0 . 6 $ ,
and w i t h r e f i n e d serum from 0 t o 4 . 9 $ .
• 91 ,
SERUM
REACTIONS*
An s o c o u n t i s g i v e n o f t h e i n c u b a t i o n p e r i o d ,
duration
e n d m a n i f e s t a t i o n s o f t h e s erum r e a c t i o n s w h i c h o c c u r a f t e r
c o n c e n t r a t e d and r e f i n e d s e r a have b e e n i n j e c t e d .
(a)
Incubation Period.
Day
of
Occurrence
Con centrated Serum
Length o f I n c u b a t i o n P e r io d
Number o f C a s e s .
R e f in e d Serum
Length o f I n c u b a t i o n P e r io d
Number of C a s e s .
No
Previous
Serum
Previous
Serum
Total
No
P r e v io u s
Serum
P r e v io u s
Serum
Total
1
8
14
22
3
1
4
2
8
10
18
1
-
1
3
9
18
27
3
-
3
4
21
19
40
1
1
2
5
40
29
69
2
1
3
6
51
40
91
5
-
5
7
61
11
72
3
-
3
8
91
4
95
3
-
3
9
94
1
95
-
-
-
10
92
-
92
-■
-
-
11
29
-
29
-
•»
12
11
-
11
-
-
-
13
2
-
2
-
-
-
14
1
-
1
-
-
-
15
16
2
2
-
-
-
-
-
2
2
-
—
17
1
-
1
-
-
—
18
T otal.
1
146
1
670
524
21
j*
■3
24
. 92.
Summary of Occurrence of
G e n e r a l Serum R e a c t i o n .
Co n centrated Serum.
Type o f
Case
No. o f
Ca s e s
No
P revious
Serum
524
P revious
Serum
146
Total
H ig h es t
$ Of
Reactions
3- Day
Group
of
H ig h es t
$ of
Reactions
Length o f I n c u b a t i o n P e r i o d .
Less
'6 -12
than
Days
6-Days incL
9th.
Da^
17.9$
8 - 10th.
Day ,
52.8$
86=
16.4#
429=
81.8#
6th.
Day
27.4$
4-6th.
D85
58.8$
90=
61.7#
56=
38.3#
176=
26 .3 #
485=
72.4#
670
13-18
Days
in cl.
19 Days
and
Over •
9=
1 .8#
-
-
9=
1.3#
-
---------------
R e f in ed
Type o f
Ca se
No
P revious
Serum
Previous
Serum.
Total
No. o f
Ca s e s
21
3
24
H ig h e s t
# of
Reactions
Serum.
3-Day
Group
of
H igh est
# of
R e a c t io n s
Length o f I n c u b a t i o n P e r i o d .
Less
6 -1 2
than
Days
6-Days i n c l .
6th.
£>ay .
26.3;#
6-8th.
Day
57.8$
10=
47.6#
1 ,4 &
5th.
Day
33.3#
4th. &
5th.
Day
66.6$
3=
100#
13=
54.2#
11=
52.4#
-
45^8®
1 3 -1 8
Days
in cl •
19 Days
and
Over.
-
..
-
-
-
.9 3 .
Prom th e f o r e g o i n g t a b l e s i t
i s se en t h a t w i t h
c o n c e n t r a t e d serum the 8 t h . and 9 t h . day are t h e days on
which most serum r e a c t i o n s appear, but f o r r e f i n e d serum
i t i s t h e 6 t h . day.
Using c o n c e n t r a t e d snd r e f i n e d
sera t h e m a j o r i t y o f r e a c t i o n s appear i n n o n - s e n s i t i s e d
p e o p l e between the 5 t h . - 1 1 t h . day and the 3 r d . - 8 t h .
day r e s p e c t i v e l y , and w i t h both sera between the day o f
i n j e c t i o n and the 6 t h . day in s e n s i t i s e d p e o p l e .
A
p r e v i o u s i n j e o t i o n o f serum appears to h a s t en the o n s e t
o f t h e serum r e a c t i o n .
Immediate and A c c e l e r a t e d R e a c t i o n s .
An immediate r e a c t i o n i s one o c c u r r in g w i t h i n 24
hours o f i n j e c t i o n w i t h the serum, and an a c c e l e r a t e d
r e a c t i o n i s one o c cu rr in g between the 2nd. and 7 t h . days
(Von P i r q u e t and S c h i c k , 1905) •
The f o l l o w i n g t a b l e s show the number o f t h e s e t y p e s o f
r e a c t i o n o c c u r r i n g a f t e r the a d m i n i s t r a t i o n o f c o n c e n t r a t e d
serum, compared with t h o s e where r e f i n e d serum was u s e d .
Concentrated
Serum.
*.....
Immediate ••
w i t h i n 24 hours
A ccelerated:
2 n d . - 7 t h . Day.
8
190
........
Total •
a
No.
%
1.5
14
9.5
22
3.3
; 36.2
127
86.9
317
47.3
«
1
!1
•
No.
P r e v io u s Serum
o
Type o f
R eaction.
No .P r e v io u s Serum
%
.9 4 .
Refin ed
Type o f
R eaction•
Serum.
T otal.
j
•
o
S3
%
i
i •
1 o
I £5
i
P r e v io u s Serum
r
i
i
i
l
I
i
1
Immediate
w i t h i n 24
hours•
A ccelerated:
2nd.- 7 t h .
Day
L
No P r e v i o u s Serum
4
No.
/°
3
1 5 .8
1
20
4
13
68.4
4
80
17
i
16.6
,
A f t e r the p a t i e n t has been s e n s i t i s e d by a p r e v i o u s
i n j e c t i o n o f serum the p e r ce n ta g e of both immediate and
accelerated reactions increases.
sera.
This i s t r u e f o r both
I t i s a l s o seen t h a t w it h r e f i n e d serum i n both
n o n - s e n s i t i s e d and s e n s i t i s e d p a t i e n t s the m a j o r i t y o f
r e a c t i o n s are o f the a c c e l e r a t e d t y p e .
With c o n c e n t r a t e d
serum, i n n o n - s e n s i t i s e d p a t i e n t s the p e r c e n t a g e o f
a c c e l e r a t e d r e a c t i o n s i s 3 6 . 2 , whereas in s e n s i t i s e d
p a t i e n t s i t r i s e s to 8 6 .9 .
D u ra tio n o f Serum R e a c t i o n s .
In the t a b l e s below a comparison i s drawn between
t h e d u r a t i o n o f the r e a c t i o n s which f o l l o w e d the
a d m i n i s t r a t i o n o f the two t y p e s o f serum.
.9 5 .
D u ra tio n
in
Days.
1
2
3
4
5
6
7
8
9
No P r e v i o u s S e r u m . .
No.
156
107
121
41
43
29
17
8
2
|
fo
•
i
1 29.7
'
20.4
i
23.1
!
7.8
!
8.2
i
5.5
|
3.3
;
1.6
.
.4
t
»
1 100.0
i
i
SERUM
P r e v i o u s Serum
No.
%
17
29
18
19
17
16
15
10
5
11.8
19.8
1 2 .3
13.0
11.8
10.9
10.2
6.8
3.4
146
100.0
Combined T o t a l .
No. !
%
\
.......
i
173 ! 2 5 . 8
136 » 2 0 . 3
139 « 2 0 . 8
60
8.9
60 |
8.9
45 »
6.8
32 |
4.7
18 J
2.7
7 i
1.1
»i ...........
670 ! 1 0 0 . 0
i
......
. . . . . . . . . .
524
REFINED
No P r e v i o u s Serum.
D u ra tio n
in
No.
;
%
D a y s,. .... —i—
_____v.
1
2
!
9.5
4
! 19.1
2
9
’ 42.9
4
2
! 9.5
2
!
9.5
5
2
!
9.5
6
7
8
9
1
1
Total
21
! 1 0 0 .0
1
SERUM.
P r e v i o u s Serum
No.
1
1
1
—
3
i
33.3
33.3
33.3
-
100.0
Combined T o t a l .
S25
o•
Total
L—
CONCENTRATED
3
4
10
3
2
2
!
|
!
1
J
i
12.5
16.7
41.7
12.5
8.3
8.3
i
i---- ..... . T
1
24
! 100.0
.. ------------------- j
. .
.
.
.
i
• 96 •
P a rt o f the serum in some o f the c a s e s , was
a d m i n i s t e r e d by i n t r a v e n o u s i n j e c t i o n *
D u rati on
in
Day s.
Concentrat ed
No.
!
»
1
2
3
4
5
6
7
8
7
15
18
22
26
2
1
!
!
J
'
!
;
<
Total
91
i
i
J
i
$
R efined.
No.
!
i
%
2
4
9
2
2
2
!
!
[
i
!
|
9.5
19.1
42.9
9.5
9.5
9.5
21
i
»
!
1
i
100
7.7
16.5
19.7
24.2
28.6
2.2
1.1
100
-
-
..........................................
-
-
.
Conclusions*
Prom the data g i v e n i t i s seen t h a t the e f f e c t s o f
serum r e a c t i o n i n n o n - s e n s i t i v e p a t i e n t s has i n 73$ o f o a s e s
( c o n c e n t r a t e d serum) pa ssed o f f in 3 d a y s , and t h a t the
e f f e c t o f a l l serum r e a c t i o n s has pas se d o f f w i t h i n 9 d a y s .
In s e n s i t i s e d p a t i e n t s the e f f e c t l a s t e d l o n g e r in frhe
m a j o r i t y o f c a s e s , but th e y t oo had a l l r e c o v e r e d w i t h i n 9
days.
Using r e f i n e d serum, i t i s seen t h a t in n o n - s e n s i t i s e d
p a t i e n t s the e f f e c t s o f serum r e a c t i o n have p a sse d o f f in
3 days in 71$ o f e s s e s , and a l l were b e t t e r by t h e end o f the
6 th . day.
In the s e n s i t i s e d p a t i e n t s i n t h i s group a l l had
f u l l y r e c o v e r e d by the 4 t h . day .
Where the serum was g i v e n i n t r a v e n o u s l y , the
d u r a t i o n o f the r e a c t i o n tended to be p r o l o n g e d , but t h i s was
.9 7 .
p r o b a b l y due ( e s p e c i a l l y w i t h the c o n c e n t r a t e d serum
cases)
t o l a r g e d o s e s of serum having been g i v e n .
TYPES
OF
HASHES.
The t h r e e main ty p e s which occur in serum r e a o t i o n s
a r e u r t i c a r i a l , erythematous and m o r b i l l i f o r m , but o t h e r s
have been d e s c r i b e d , such a s macular, c i r c i n a t e , pa p u la r
and polymorph us.
In the 670 r e a c t i o n s f o l l o w i n g t h e
a d m i n i s t r a t i o n o f c o n c e n t r a t e d serum, 668 e x h i b i t e d r a s h e s ,
and i n t h e r e f i n e d s e r i e s , 2 4 .
The f o l l o w i n g t a b l e shows the p e r c e n t a g e o f e a ch type
and th e de j on which the d i f f e r e n t t y p e s o f rash a pp eared.
Concentr ated Serum
Ha sh es Day o f Appearance
Type
0-5
6-1 2 ! 13-
U rtica ria l
578
Erythematous 32
M o r b i l l i f o r m 28
15
C ircinate
15
Polymorphus
i
86.5
4.7
4.2
2.3
2.3
148
10
9
5
4
426
20
18
10
9
668
100-0
176
483
No. 1
Total •
j 4
' 2
! 1
J «i 2
—4—-----1 9
i
R e fin ed Serum.
Ra sh es
D8y o f Appearance
No.
10
8
4
1
1
D-5
*
41.6 6
33.3 5
16.7 2
4.2 4.2
J 6-12
!
4
| J 3
; « 2
! !
i
: ;
1
; ---------- 1------------ 1------ :_T
24 loao 1 3 ! i i
! —
i
i
,
The u r t i c a r i a l r a sh predominates and the i n c i d e n c e
i s h i g h e r w i t h c o n c e n t r a t e d than w i t h r e f i n e d serum where
the p e r c e n t a g e d i f f e r e n c e between the u r t i c a r i a l and the
eryth e m a tou s i s not so marked ( 4 1 . 6 - 3 3 . 3 , a s a g a i n s t
8 6 .6 - 4.7) •
J 13-
There was a h i g h e r p e r c e n t a g e i n c id e n o e o f
e r y t h e m a t o u s , m o r b i l l i f o r m , c i r c i n a t e and polymorphus r a s h e s
when r e f i n e d serum was used than when c o n c e n t r a t e d serum was
.9 8 .
adm inistered.
C i r o i n a t e and polymorphus r a s h e s
o c c u r r e d i n t h e same number w i t h e a ch serum.
Recurrent Rashes.
These are o f rare oc cu rren ce w i t h c o n c e n t r a t e d
s e r a , and did n o t occur w i t h r e f i n e d serum.
With
i
c o n c e n t r a t e d serum o n l y 7 were o b s e r v e d .
They were n o t
*
c o n f i n e d t o any d e f i n i t e batch o f serum, and t h e serum was
g i v e n by the in t r a m u s c u l a r r o u t e .
Three o f t h e c a s e s
were m al es and f o u r were f e m a l e s .
Age Groups:
0 -5 years
2 cases.
6-10
,,
3
11-20
,,
2
Dosage o f Serum Given:
,,
8 , 0 0 0 u n i t s or l e s s . . . . .
1
8 , 0 0 0 - 4 0 , 0 0 0 u n i t s ..................4
40,000
I n a l l o f them two r a s h e s appeared.
In two the time
between the r a s h e s was t h r e e da y s , in f o u r i t was f i v e d a y s ,
and i n one i t was s i x d a y s .
g en era lized u r tic a r ia l type.
The r a s h e s were a l l of the
Four o f the c a s e s had had a
p r e v i o u s i n j e c t i o n o f serum, and t h r e e had n o t .
.9 9 .
S ig n s o f General Serum R e a c t i o n o t h e r
________ than Cutaneous ._________________
B elo w , in t a b u l a r form, i s an a n a l y s i s o f the msin s i g n s
o f g e n e r a l serum r e a c t i o n ot h e r than serum r a s h e s .
Concentrated
No. o f C a s e s . . . .
Percentage of
Cases t r e a t e d . ..
P e r c e n ta g e of
Serum r e a c t i o n s .
Sex:
M a l e .............
Pemale . . . .
A v e r a g e Age .
Years. . . . .
D o s a g e : Up t o
8,000 u n i t s . .
8,000-40,000.
40,000 u n its
& over. . . . .
No P r e v i o u s Ser um;
Number. . . . .
No P r e v i o u s Ser um:
Day o f O c c u r r e n c e
P r e v i o u s Serum:
Number.. . . . . .
P r e v i o u s Serum:
Day o f O c c u r r e n c e .
Number who h a d
I n t r s v e n o u s Ser um.
Concom ittent Signs:
G e n e r a l R a s h ...............
L o c a l R a s h ....................
Ra s h A b s e n t . . . . . . . .
A l b u m i n u r i a ..................
Oedema
......................
A r t h r i t i s .................... ..
A denitis
..........
F e v e r .................................
Fever
99°F •
Upward
Oedema
17
418
-
.
to
CO
>edema A r t h r i t i s
R efined.
.25%
6.2%
-
2.8^
10
9
2.5%
12
5
62.4%
256
162
8.7
17.2
11.1
2
6
3
5
11
19
—
A rth ritis
Fev e r
99 ®F
Upwarc
1
4
• 4%
4 . lie
i
-
16.6%
2
2
-
14
16
56
256
_
-
-
-
9
106
-
1
4
9
6
187
-
-
3
2-12
4 -1 1
8-9 ,
-
-
1
10
11
231
-
1
1
2-7
5-6
-
5
1
87
-
1
4
418
-
_
1
4
-
-
-
1-4
1
4
16
2
1
8
12
4
1
7
-
8
12
-
106
12
12
-
-
-
-
-
-
-
2
-
-
-
-
-
1
-
-
-
*
1
C onclusions.
The a l l - r o u n d r e d u c t i o n in the c o m p l i c a t i o n s due to
serum by the use o f r e f i n e d serum i s s t r i k i n g .
The h i g h e r
i n c i d e n c e o f c o m p l i c a t i o n in males i s shown, e x c e p t in f e v e r
c a u se d by r e f i n e d serum, where the i n c i d e n c e was e q u a l .
As
the dose o f serum i n c r e a s e s so does the l i a b i l i t y t o serum
com p lication s.
A p r e v io u s i n j e c t i o n o f serum i n c r e a s e s t h i s
l i a b i l i t y , and a l s o ,
in the use of c o n c e n t r a t e d serum, r e d u c e s
the i n c u b a t i o n p e r io d o f the r e a c t i o n .
Fever i s common, more
so w i t h c o n c e n t r a t e d serum, where i t occurred in 6 . 2 $ o f a l l
c a s e s , a s compared w i t h •4% w ith r e f i n e d a n t i t o x i n .
Albuminuria was a f r e q u e n t c o m p l i c a t i o n w ith c o n c e n t r a t e d serum,
but o n l y occu rred i n two c a s e s t r e a t e d w ith r e f i n e d a n t i t o x i n .
General Serum R e actio n w i t h No Rash.
T h i s occurred in two c a s e s t r e a t e d with c o n c e n t r a t e d
serum.
Both c a s e s were m ales .
Summary o f each c a s e s -
(1) A boy o f 9 y e a r s r e c e i v e d 2 0 , 0 0 0 u n i t s i n t r a m u s c u l a r l y .
He d e v e lo p ed a r t h r i t i s , albuminuria and a temperature
o f 1 0 0 . 6 ° on the 7 t h . day.
He was g iv e n a d r e n a l i n
m . 5 . t . i . d . f o r two d a y s , t o g e t h e r w i t h a s p i r i n g r . 5 .
q .i.d .
In fo u r days the albuminuria and the
a r t h r i t i s had passe d o f f .
t h e t h i r d day.
H is temperature s e t t l e d on
.
(2)
101.
A young man o f 19 was g i v e n 1 6 ,0 0 0 u n i t s
intram uscularly.
6 days l a t e r he d e v e lo p e d a
tem perature ( 1 0 1 . 4 ° )
and a r t h r i t i s o f h i s
i n t e r p h a l a n g e a l j o i n t s o f both hands.
He was
g i v e n a s p i r i n g r . 1 0 . q . i . d . , and a f t e r two days
h i s tem per at ure s e t t l e d , and i n t h r ee days more
t h e l a s t t r a c e o f h i s a r t h r i t i s had p a s s e d o f f .
C onclusion.
A r t h r i t i s , albuminuria and p y r e x ia can d e v e lo p in
the a b s e n c e o f cuta neous s i g n s .
LOCAL
D efin itio n -
SERUM RASH.
Where the rash i s c o n f i n e d t o s i t e o f i n j e c t i o n .
T h is occu rred in 76 o f the c o n c e n t r a t e d serum s e r i e s ,
and in 5 o f t h e r e f i n e d s e r i e s .
In t h e c o n c e n t r a t e d group
6 c a s e s were a s s o c i a t e d with s i g n s o f g e n e r a l r e a c t i o n , 2 havin g
oedema and fo u r having a r t h r i t i s , p l u s the r a sh a t the s i t e o f
in jection .
These 6 c a s e s had a l l been s e n s i t i s e d t o horse
serum by 8 p r e v i o u s i n j e c t i o n o f a n t i s e r u m .
70 c a s e s , a n a l y s i s o f the r a s h e s was:
4 e r y t h e m a t o u s , and 2 m o r b i l l i f o r m .
In the rem aining
64 u r t i c a r i a l ,
Of t h e s e c a s e s 62 had
had no p r e v i o u s serum, w h ile 8 had had serum p r e v i o u s l y .
The
day o f occu rr en ce o f the rash In the 76 c a s e s was: 0 - 6 d a y s , 2 2 .
6 - 1 2 , 4 8 , and 12 days upwards 6 .
r a s h e s were o b s e r v e d .
With r e f i n e d serum, 5 l o c a l
These 5 c a s e s had had no p r e v i o u s
i n j e c t i o n o f serum and were not accompanied by any o t h e r
m a n i f e s t a t i o n o f serum d i s e a s e .
The 5 r a s h e s were o f the
u r t i c a r i a l t y p e , and occu rred 3 on the 5 t h . day and 2
on t h e 6 t h . day a f t e r i n j e c t i o n .
C onclusion.
L o c a l r a s h e s can occur even a l t h o u g h the p a t i e n t
h a s been s e n s i t i s e d by a p r e v i o u s i n j e c t i o n , but a p r e v i o u s
i n j e c t i o n o f serum makes th e p a t i e n t l i a b l e t o a g e n e r a l
r e a c t i o n t o the serum.
u r t i c a r i a l tyne .
The r a s h e s are mainly of the
The day o f oc currence o f t h e s e l o c a l
r a s h e s ap p ro xim ate s t o the day o f o n s e t o f g e n e r a l serum
reaction •
RECURRENT
LOCAL
RASHES.
None were observed in t h i s s e r i e s .
ALBUMINURIA.
The d i f f i c u l t y o f de ter m ining whether album in uria i s
c a u s e d by t h e t o x i n s c i r c u l a t i n g in the blood stream or whether
i t i s due t o the serum per se i s o b v i o u s .
In t h i s a n a l y s i s i t
was r e g a r d e d a s a c o m p l i c a t i o n due t o serum when i t occu rred
during t h e p e r io d when serum r e a c t i o n s do o c c u r , and in the
a b s en ce o f any o t h e r oause f o r a lb u m in u r ia .
I n c i d e n c e o f Serum Albuminuria.
Number o f C a s e s .....................................
C oncentrated
Serum.
122
A lbum inuria
a nd
General R e a c t i o n .
121
A lbum inuria
and
Local R e a c t i o n . . .
1
R e f in e d
Serum.
2
2
.i o a .
■Day
■1.
o f ■Appearanoe
o f Albuminuria.
i,
.. ,
—i,
„,,,
Under
6 - 1 2
12
6
g
C on c e n t r a t e d
Serum.
d a y s . . ..............................................
40
d a y s . . .................................................
R e fin ed
Serum.
^
73
d a y s ........................................................
1
1
122
2
R e l a t i o n t o Appearance of Rash.
C o n ce n tr a ted
Serum.
R e f in e d
Serum.
Time o f Appearance.
B e fore the rash app ear e d. . . . . . . .
A fter
11
11
22
100
2
122
2
Con ce ntr a ted
Serum.
R e f in e d
5erum.’
11
T o t a l .................................. ...... ...................
D u r a t io n o f A lb u m in u ria .
Time •
1 - 5
d a y s ........................................
5-10
10
days
d a y s ...............................................
76
2
44
••
2
C onclusions.
Albuminuria o ccu rs as a serum phenomenon in 1 . 8 $ o f a l l
c a s e s t r e a t e d w i t h c o n c e n t r a t e d serum, and i n 1 8 . 4 # o f c a s e s o f
serum r e a c t i o n s caused by the same serum.
With r e f i n e d serum
t h e f i g u r e s are .2 # o f a l l c a s e s and 8 . 3 # o f serum r e a c t i o n s .
With c o n c e n t r a t e d serum i t makes i t s appearance most o f t e n between
the
6
th.
and the
and p e r s i s t s
1 2 th.
for 1 - 5
day, m ostly a f t e r the r a s h has appeared,
d a y s . With r e f i n e d
serum the i n c i d e n c e
.1 0 4 .
i s e q u a l l y d i v i d e d between the 1 - 6 ,
and 6 - 1 2
day p e r i o d s ,
alw ays a f t e r the r a s h has appeared, and l a s t s f o r 1 - 5
THERMAL
days.
REACTIONS.
These occur most f r e q u e n t l y a f t e r the i n t r a v e n o u s
a d m i n i s t r a t i o n o f serum*
With c o n c e n t r a t e d serum 476 c a s e s
r e c e i v e d serum i n t r a v e n o u s l y , and 87 ( 1 8 . 2 $
reaction .
4 (1%)
had a f e b r i l e
With r e f i n e d serum 400 had serum i n t r a v e n o u s l y , and
had a thermal r e a c t i o n .
as a r i s e
A thermal r e a c t i o n was d e f i n e d
o f temperature above 9 9 . 4 ° and p e r s i s t i n g f o r more
than two h o u r s .
The t o t a l number of p a t i e n t s who r e c e i v e d
c o n c e n t r a t e d serum and who showed a thermal r e a c t i o n was 126,
which i s 1 . 8 $ o f a l l c a s e s r e c e i v i n g serum, and 1 8 . 8 # o f a l l
reaction s.
Using r e f i n e d serum, 4 o a s e s , r e p r e s e n t i n g
. 4 # o f a l l c a s e s and 1 6 . 6 # o f a l l r e a c t i o n s , had -a thermal
reaction .
C onclusion.
R e f in e d serum d e f i n i t e l y r ed u c es the i n c i d e n c e o f
t herm al r e a c t i o n s .
.1 0 5 .
PREVIOUS HISTORY OP ALLERGY.
In t h e c o n c e n t r a t e d serum s e r i e s , 18 gave a h i s t o r y o f
asthma o r p r e v i o u s a t t a c k s o f u r t i c a r i a .
In t h i s group 14
d e v e lo p e d g e n e r a l serum r e a c t i o n s and 4 d id n o t .
were accompanied by u r t i c a r i a l r a s h e s .
The r e a c t i o n s
Of the 1 , 0 0 0 c a s e s t r e a t e d
w i t h r e f i n e d serum 12 gave an a l l e r g i c h i s t o r y (asthma or u r t i c a r i a )
but none d e v e l o p e s serum r e a c t i o n .
Conclusion.
Where a h i s t o r y o f a l l e r g y i s g i v e n i t i s u n s a f e t o u s e
c o n c e n t r a t e d serum u n l e s s th e p a t i e n t has been d e s e n s i t i s e d .
R e f in ed serum s h o u ld be u s e d .
SERUM
ACCIDENTS.
T h i s term i s used t o denote t h e o c c a s i o n a l s e v e r e and
sometimes f a t a l r e a c t i o n o c c u r i n g a f t e r serum has been g i v e n .
In n e i t h e r o f t h e s e r i e s under c o n s i d e r a t i o n was t h e r e a f a t a l
a c c i d e n t , b u t s e v e r e r e a c t i o n s were o b s e r v e d .
(1 )
C o n ce n tr a ted Serum.
A f t e r the u s e o f i n t r a v e n o u s serum
22 such r e a c t i o n s were o b s e r v e d .
This r e p r e s e n t s 0 . 3 ^
o f a l l c a s e s r e c e i v i n g serum, 4 . 6 ^ o f a l l c a s e s r e c e i v i n g
t h e serum i n t r a v e n o u s l y , and 3 . 3 $ o f a l l r e a c t i o n s . 14 had
r e c e i v e d a p r e v io u s i n j e c t i o n o f serum.
There w e r e .n o
serum a c c i d e n t s where t h e serum was g i v e n , i n t r a m u s c u l a r l y .
The t r a i n o f s i g n s and symptoms i n a l l t h e c a s e s were the
same.
They were - t i g h t n e s s a c r o s s th e c h e s t , p a l p i t a t i o n ,
c y a n o s i s , b r e a t h l e s s n e s s , c o ld p e r s p i r a t i o n , extreme
.1 0 6 .
a n x i e t y and v o m i t i n g .
The p a t i e n t s were g i v e n . 5 c . c * s
o f 1 / 1 0 0 0 a d r e n a l i n h y d r o c h l o r i d e , oxygen and k e p t i n
F o w l e r ' s p o s i t i o n - a d r e n a l i n was r e a d m i n i s t e r e d where
necessary.
(2)
A ll cases recovered.
R e f i n e d Serum.
in jection .
Two s i m i l a r c a s e s occu rred w i t h i n t r a v e n o u s
This r e p r e s e n t s . 2 cjo o f a l l c a s e s ,
*5$ o f
c a s e s who were g i v e n serum i n t r a v e n o u s l y , and 8 . 3 $ o f
a l l reaction s.
Conclusions.
Serum a c c i d e n t s a r e r a r e and t h e i r i n c i d e n c e i s i n c r e a s e d
by i n t r a v e n o u s t h e r a p y .
of choice.
Re fined serum s h o u l d be t h e serum
A d renalin sh ould always be kept a t hand on
t h e serum tray*
■■ i ::r?
.1 0 7 .
GENERAL
SUMMARY.
An a n a l y s i s has been mad© and a comparison drawn o f the
m a n i f e s t a t i o n s o f serum r e a c t i o n s f o l l o w i n g upon the i n j e c t i o n
o f c o n c e n t r a t e d and r e f i n e d a n t i - d i p h t h e r i t i s s e r a .
The t o t a l
i n c i d e n c e was -
Concentrated.
T o t a l Serum R e a c t i o n
670(9.9$)
24(2.4$)
G e n e r a l Serum R e a c t i o n ................................
594(8.9$)
19(1.9$)
L o c a l R e a c t i o n ....................................................
76(1.1$)
5(0.5$)
The f a c t o r s w h i c h i n f l u e n c e
( a)
Sex and A ge.
serum r e a c t i o n s a r e -
M a le s have a h i g h e r r a t e t h a n f e m a l e s , a n d
t h i s r a t e v a r i e s i n t h e d i f f e r e n t ag e g r o u p s .
incidence
(k)
R efined.
Dosage.
The
i s l o w e r w h er e r e f i n e d serum i s u s e d .
As t h e d o s e o f serum i n c r e a s e s ,
in cid e n c e of r e a c t i o n s .
in m ales than in f e m s le s .
so a l s o d o e s t h e
The i n c i d e n c e i s more m a r k e d
The serum r e a c t i o n r a t e
is
l o w e r w h e r e r e f i n e d serum was g i v e n .
( c) I n t r a v e n o u s I n j e c t i o n .
Where t h i s method o f t h e r a p y i s
em p l o y e d t h e i n c i d e n c e o f serum r e a c t i o n s r i s e s .
I n t r a v e n o u s t h e r a p y i s u s u a l l y co mbined w i t h i n t r a m u s c u l a r
in jectio n ,
and t h e t o t a l dose g i v e n i s u s u a l l y l a r g e .
T h i s i s a f a c t o r i n c a u s i n g an i n c r e a s e d i n c i d e n c e .
c o n c e n t r a t e d s eru m , t h e i n c i d e n c e was 1 9 . 1 $ .
U s in g
In th e
r e f i n e d s e r i e s , wher e i n t r a v e n o u s serum was g i v e n a l o n e ,
t h e r e a c t i o n r a t e was 3 . 3 $ , w h i l e w i t h c o m bined
intravenous- i n t r a m u s c u l a r i n j e c t i o n ,
i t was 8 . 0 $ .
.1 0 8 .
Here a g a i n r e f i n e d serum had t h e lower r e a c t i o n r a t e .
D i f f e r e n t Batches o f Serum.
little
This would appear t o have
i n f l u e n c e on t h e i n c i d e n c e o f serum r e a c t i o n s .
Over a p e r i o d o f s i x y e a r s , u s i n g c o n c e n t r a t e d s e r a ,
t h e r a t e v a r i e d from 9 . 5 $ - 1 0 . 3 $ .
(e)
R e i n j e c t i o n o f Serum.
This has a d e f i n i t e b e a r i n g
t h e i n c i d e n c e o f serum r e a c t i o n s .
on
With c o n c e n t r a t e d
serum t h e i n c i d e n c e r o s e from 7 . 6 $ t o 1 9 . 5 $ , and w i t h
r e f i n e d serum from 1 . 8 $ t o 2 . 6 $ .
These are s i g n i f i c a n t
i n c r e a s e s . The much lower p e r c e n t a g e o f r e a c t i o n s a f t e r
r e f i n e d serum i s n o te w o r th y .
O b s e r v a t i o n s on Serum R e a c t i o n s .
(a)
Incubation Period.
The 9th day a f t e r i n j e c t i o n o f
c o n c e n t r a t e d serum i s t h e day on which most r e a c t i o n s
occur.
This i s reduced t o 6 days i n the c a s e o f r e f i n e d
serum, and, i n b b th , a p r e v io u s i n j e c t i o n o f serum b r i n g s
a b o u t a r e d u c t i o n in the i n c u b a t i o n p e r i o d .
(b)
Duration.
The e f f e c t s i n most c a s e s have passed o f f w i t h i n
3 d a y s , but a p r e v io u s i n j e c t i o n o f serum would appear t o
p r o l o n g t h e symptoms.
(o)
Types o f Rash e n c o u n t e r e d .
F iv e d i f f e r e n t r a s h e s have been
d e s c r i b e d . For both s e r a , th e u r t i c a r i a l type o f r a s h i s
most f r e q u e n t , but the p e r ce n ta g e i n c i d e n c e o f t h i s t y p e
i s much h i g h e r f o r concen trated than f o r r e f i n e d .
U r t i c a r i a l r a s h e s a r e the r u l e i n s e n s i t i s e d p a t i e n t s .
(4)
Recurrent Rashes.
These are r a re and a r e n o t c o n f i n e d
.1 0 9 .
t o any age grou p, but no c a s e s were r e c o r d e d i n t h i s
s e r i e s i n p a t i e n t s over 20.
(e)
Oedema.
T h is u s u a l l y d e v e lo p e s i n l o c a l i z e d s i t e s su ch a s
t h e f a c e or t h e h a n d s•
I t i s commoner i n males than i n
f e m a l e s , where l a r g e d os es o f serum were g i v e n , and
p r e v i o u s i n j e c t i o n o f serum had l i t t l e
incid en ce.
i n f l u e n c e on i t s
I t te n d s t o occur i n young p e o p l e .
No c a s e s
o f oedema were recorded where r e f i n e d serum was u s e d .
A r t h r i t i s . This occurred i n 2 . 5 °/o and 4.1^> o f serum r e a c t i o n s
f o l l o w i n g th e a d m i n i s t r a t i o n o f c o n c e n t r a t e d and r e f i n e d
sera r e sp ectiv ely .
I t was more f r e q u e n t i n males than i n
f e m a l e s , and was more common in s e n s i t i s e d p a t i e n t s .
(g)
ffever•
Some f e v e r i s p r e s e n t in most g e n e r a l r e a c t i o n s
a f t e r c o n c e n t r a t e d serum - 62.4^> o f r e a c t i o n s .
This
f i g u r e f e l l t o 1 6 . 6 ^ when r e f i n e d serum was u s e d .
In
t h e c o n c e n t r a t e d s e r i e s p r e v i o u s i n j e c t i o n o f serum and
h i g h dosage o f serum were c o n t r i b u t o r y f a c t o r s t o t h i s h ig h
in cid en ce.
In t h e other s e r i e s , high dosage was a f a c t o r ,
but p r e v i o u s i n j e c t i o n o f serum was n o t .
Looal Serum R a s h e s .
These u s u a l l y have no accompanying g e n e r a l r e a c t i o n where
r a s h i s l i m i t e d t o a sm all area around the s i t e o f
i n j e c t i o n , b u t i n 6 o f the recorded c a s e s where c o n c e n t r a t e d
serum was
u s e d ,
g e n e r a l i z e d symptoms were a l s o p r e s e n t .
Album inuria.
m s
occurs i n a lm o st l / 5 t h o f a l l c a s e s a s a s i g n o f
g e n e r a l serum r e a c t i o n .
I t makes i t s appearance m o s t l y
.1 1 0 .
a f t e r t h e r a s h has appeared, and between t h e 6 t h and
t h e 1 2 t h day a f t e r i n j e c t i o n .
I t i s l e s s common a f t e r
t h e a d m i n i s t r a t i o n o f r e f i n e d serum than a f t e r c o n c e n t r a t e d
serum.
Serum A c c i d e n t s .
These a r e r a r e and o c c u r a f t e r i n t r a v e n o u s i n j e c t i o n .
They a r e more l i k e l y t o happen i n s e n s i t i s e d p a t i e n t s .
With r e f i n e d serum t h e i r i n c i d e n c e i s much r e d u c e d .
f a t a l c a s e was r e c o r d e d .
k; i
r-*o
S i ig 1;;? £ 1 $ c:f r h e
I t s o f"
i , 0 -jo
of c lin ic a l
0 * 0 wi tth
fin e d f iphtfeoa,,l«s
*
No
SECTION
111.
An a n a l y s i s o f the r e s u l t s o f t re a t m en t
o f 1,000 eases of c l l n i e a l diphtheria
t r e a t e d w it h r e f i n e d d i p h t h e r i a a n t i t o x i n .
.111 .
TREATMENT OF DIPHTHERIA BY REFINED ANTITOXIN.
A s e r i e s o f 1,000 consecutive oases of c l i n i c a l dip hth eria
was i n v e s t i g a t e d in B e l v i d e r e Fever H o s p i t a l , Glasgow, from
August 1 9 3 7 , t o A p r i l 1939*
A l l were g i v e n r e f i n e d a n t i t o x i n .
T h i s was s u p p l i e d in ampoules c o n t a i n i n g ( w ith s l i g h t
v ariation s)
4.000
6.000
8.000
20,000
units
units
units
un its
in 0 . 8
in 1 . 3
in 1 . 7 5
in 3 . 0
c .o 's
c .c's
c.c's
c.c's
of
of
of
of
serum.
serum.
serum.
serum.
I n each c a s e the f o l l o w i n g p a r t i c u l a r s were n o t e d : (a) Age o f p a t i e n t •
(b) Sex o f p a t i e n t .
(c) C l i n i c a l type o f d i p h t h e r i a .
(d) S t r a i n o f c . dip h th er ia s r ec o v e r e d from t h e o a s e .
(e)
Time o f occurren ce of serum r e a c t i o n s or r a s h e s .
(f)
Time and type o f c o m p l i c a t i o n .
(g) H i s t o r y o f p r e v io u s i n j e c t i o n o f serum, asthma or
u rticaria•
F o u r - h o u r l y o b s e r v a t i o n s were made upon:(a)
Temperature and p u lse r a t e .
(b) Rate o f disapp earance of membrane / or d i s c h a r g e s /
or a d e n i t i s .
(c) Degree o f to xa em ia .
The 1 , 0 0 0 c a s e s were d i v i d e d i n t o three g r o u p s : (a)
600 who were g i v e n the serum by in t r a m u sc u la r
in jectio n alone.
fb} 250 who r e c e i v e d a combined in t r a v e n o u s and
intram uscular i n j e c t i o n ; and
t G) T5 0 who r e c e i v e d the a n t i t o x i n by i n t r a v e n o u s
injection alone.
O u t l i n e o f G en eral Treatment and Nursing o f the P a t i e n t s .
Each c a s e was rev iew ed s e p a r a t e l y and t r e a t e d a c c o r d i n g
to i t s
s p e c i a l requirem ents.
G e n e r a l l y s p e a k i n g , however,
t h e r o u t i n e proc ed ur e in the wards w a s : Im m e d ia tely a f t e r the p a t i e n t had been a d m itted t o t h e
ward and had been b ath ed , the tem p erature, p u l s e and
r e s p i r a t i o n r a t e s were t a k e n , and a specimen o f u r i n e o b t a i n e d
( if p ossib le).
The p a t i e n t was then examined and the e x t e n t
o f t h e membrane / or d i s c h a r g e s / or a d e n i t i s was n o t e d .
d e g r e e o f t o x i c i t y was observed and r e c o r d e d .
P r i o r t o the
serum b e i n g g i v e n , a swab was taken o f the membrane /
discharges.
The
or
T his was i n o c u l a t e d on to a L e o f f l e r s l o p e and
on t o a p l a t e o f the media o f Kerrln and Gaze (1936) •
These
were t h e n p l a c e d in the incub ato r a t 37° C.
Prom the p s t i e n t , or from the n u r s e ' s c a se r e c o r d ,
o b t a i n e d a t the p a t i e n t ' s home ( i f the p a t i e n t were t o o i l l br
t o o young t o a s s i s t )
i t was a s c e r t a i n e d whether the p a t i e n t
had s u f f e r e d from asthma or u r t i c a r i a or whether he had had a
p r e v i o u s i n j e c t i o n o f serum.
recorded.
P r e v io u s i l l n e s s e s were a l s o
The p a t i e n t was now examined as t o h i s soundness
o f h e a r t and l u n g , and f o r any e v id en ce o f o th e r d i s e a s e .
The serum was then g i v e n .
Although a p r e v i o u s h i s t o r y
o f asthm a, u r t i c a r i a or p r e v io u s I n j e c t i o n o f serum was g i v e n ,
the p a t i e n t r e c e i v e d the r e f i n e d a n t i t o x i n w i t h o u t d e s e n s i t i s a t i o n .
On t h e serum t r e y , a syring e charged with . 5 c . o ' s o f a d r e n a l i n
h y d r o c h l o r i d e s o l u t i o n 1 / 1 0 0 0 , was kept a t hand In c a se I t was
.113,
required#
The serum having been g i v e n , the p a t i e n t was c l o s e l y
o b s e r v e d f o r s i g n s o f serum r e a c t i o n #
The t e m p e r a t u r e , p u l s e
and r e s p i r a t i o n r a t e s were taken 5 , 10 and 30 minutes
a f t e r w a r d s , t h e r e a f t e r , 4 ho u rly o b s e r v a t i o n s were made#
The
u r i n e was examined d a i l y f o r abnormal c o n s t i t u e n t s , such a s
a lb u m in , b l o o d , sugar and a c e t o n e .
A l l p a t i e n t s were kept l y i n g down f o r t h r e e weeks, and
c a s e s which r e c e i v e d more than 4 0,0 0 0 u n i t s o f a n t i t o x i n were
k e p t f l a t f o r 8 minimum p e r io d o f f o u r w e ek s.
Those r e c e i v i n g
v e r y l a r g e d o s e s - 2 0 0 ,0 0 0 u n i t s - were not a llo w e d t o
s i t up
in bed f o r p r o l o n g e d p e r i o d s , e x te n d in g in one c a se to
14 w e e k s .
I f a c o m p l i c a t i o n was o bser v ed , th e p a t i e n t was
ke pt l y i n g down u n t i l the c o m p l ic a t io n was c u r e d .
F o l l o w i n g the lying-down p e r i o d , p a t i e n t s were a l l o w e d
t o s i t up in b e d , f o r a minimum p e r io d of one week.
P atients
who had had l a r g e d o s es o f serum or t h o s e who had d e v e lo p e d
c o m p l i c a t i o n s were brought g r a d u a l l y to the s i t t i n g p o s i t i o n by
means o f p i l l o w s .
A f t e r the s i t t i n g - u p p e r i o d , the p a t i e n t s
were a l l o w e d up to walk about the ward and the grounds o f t h e
h o s p i t a l f o r another minimal p e r io d of one week.
A d d i t i o n a l N o n - S p e c i f i c Treatment of the Cases*
Schwentker and N o e l , 1930 .
They fo und, i n c a s e s
which had a f a t a l t e r m i n a t i o n , a h yp o g ly ca e m ia .
I f death did
no t t a k e p l a c e , the blood sugar c o n t e n t r o s e u n t i l f i n a l l y t h e r e
was a d e f i n i t e hy p er g ly ca e m ia .
They found, a l s o , a r e d u c t i o n
.114.
o f t h e h e p a t i c and muscular g ly co g e n during the t o x a e m i a ,
and a d e f i n i t e r e d u c t i o n in the a b i l i t y t o a s s i m i l a t e d e x t r o s e .
They a d v o c a t e d t h e use o f i n s u l i n and In t r a v e n o u s d e x t r o s e .
Begg and H a r r ie s (1935) a l s o recommended the use o f I n t r a v e n o u s
d e x t r o s e but found no b e n e f i t s from the use of i n s u l i n .
As
t h e c o n t e n t o f d e x t r o s e in the blood r o s e , so did t h e l i a b i l i t y
t o cardiac p a r e s i s .
McLean, 193 7, thought t h a t the hypoglycaemia found in
t h e a c u t e s t a g e s o f d i p h t h e r i a was due t o the p a t i e n t ' s
fastin g.
He found t h a t the g l u c o s e t o l e r a n c e c u r v e s i n the
a c u t e s t a g e s o f d i p h t h e r ia took the form commonly c a l l e d the
’’l a g ” c u r v e .
In c o n v a l e s c e n t p a t i e n t s the c u r v e s were o f
th e normal t y p e .
He thought t h a t the f,l a g lf curve was due not
t o d i m i n i s h e d a b s o r p t i o n o f g l u c o s e from the a l i m e n t a r y t r a c t
bu t t o a d im in u t io n o f the a b i l i t y of the p e r i p h e r a l t i s s u e s
t o a s s i m i l a t e i t from the b l o o d .
Muir 192 4, noted th a t the su pra rena l g l a n d s showed
d e g e n e r a t i o n and haemorrhages i n t o t h e i r su bsta nce f o l l o w i n g
d e a t h from d i p h t h e r i a .
R o l l e s t o n , 1 925, agreed with the f i n d i n g s o f Muir but
o n l y in the c a s e o f guinea p i g s which had die d from d i p h t h e r i a .
In humans t h e r e were few ffnaked e y e ” c h a n g e s, and th e
m i c r o s c o p i c a l changes
were not c o n s t a n t .
Ker, 1929, s u b s t a n t i a t e d the o b s e r v a t i o n s o f Muir.
Harrop e t a l , 1933, found t h a t , in dogs where the
s u p r a r e n a l g l a n d s had been removed, the dogs l i v e d l o n g e r i f
.1 1 5 .
t h e y were g i v e n i n j e c t i o n s o f sodium c h l o r i d e .
They
c o n c l u d e d t h a t the su p r a re n a l c o r t e x had a r e g u l a t i n g
i n f l u e n c e over the e x c r e t i o n o f w a t e r and sodium c h l o r i d e .
Thaddea, 1935, showed t h a t , f o l l o w i n g upon the
i n j e c t i o n o f guinea p i g s with d i p h t h e r i a t o x i n , t h e r e Is
n e c r o s i s and haemorrhage o f the su prarenal c o r t e x and a
d i s a p p e a r a n c e o f l i p o i d m a t e r i a l a l s o from t h e c o r t e x .
These
c h an g e s c o u l d he avoided or dim inish ed i f the g uinea p i g s
were g i v e n e x t r a c t s o f su pra rena l c o r t e x combined w ith
a s c o r b i c a c i d (Vitamin C) which i s normally found i n the
cortex.
McLean, 1936, In a c o n t r o l l e d s e r i e s o b t a i n e d good
r e s u l t s by a d m i n i s t e r i n g one t e a s p o o n f u l o f s a l t p er mouth,
t h r e e t i m e s a day f o r the f i r s t fo ur weeks t h a t the p a t i e n t
was In h o s p i t a l .
In p a t i e n t s who were too i l l t o ta ke s a l t
by mouth he employed c o ntinu o us r e c t a l s a l i n e s .
In t h e
p a t i e n t s who d i d not r e c e i v e the a d d i t i o n a l sodium c h l o r i d e
t h e r e was a h i g h e r c o m p l ic a t io n r a t e , and t h e i r s t a y In
h o s p i t a l was l o n g e r than tho se who did r e c e i v e the e x t r a
sodium c h l o r i d e .
McLean 1 93 7 .
In o a s e s where death took p l a c e , he
found t h a t t h e r e was a f a l l in the serum sodium and i n the
serum c h l o r i n e .
By t r e a t i n g the p a t i e n t s w i t h sodium
c h l o r i d e t h i s f a l l was m i t i g a t e d .
From the data g i v e n above i t i s s e e n t h a t in
d ip h th eria there i s : -
.116.
(a) A hypoglyoaemia in p r e l e t h a l c a s e s and i n c a s e s
which r e c o v e r , a h y p e r g l y e a e m ia •
(b)
There i s some up set in metabolism whereby the
p e r i p h e r a l t i s s u e s l o s e t h e i r power t o a s s i m i l a t e
t h e d e x t r o s e in the b l o o d .
( c ) D u r i n g d i p h t h e r i a t h e r e i s damage t o the s u p r a r e n a l
glands.
( d ) I n d i p h t h e r i a t h e re i s a d e f i c i e n c y in the blo o d o f
sodium and c h l o r i n e .
(e)T he e f f e c t s o f the damage to th e su p r a r e n a l g l a n d s
oan be l e s s e n e d by the a d m i n i s t r a t i o n o f sodium
c h l o r i d e and a s c o r b i c a c i d .
( f ) D e x t r o s e i s a u s e f u l a dju nct in the treatm ent o f
d ip hth eria•
A l l p a t i e n t s on adm ission to h o s p i t a l were t r e a t e d w i t h
f l u i d s , g l u c o s e ( t o which one t e a s p o o n f u l o f s a l t per p i n t of
g l u c o s e s o l u t i o n had been added) and l i b e r a l s u p p l i e s o f f r u i t
j u i c e s , the f r u i t j u i c e s supplyin g the a s c o r b i c a c i d
(Vitam in C) .
membrane /
Three days f o l l o w i n g the disa pp ea ra nce o f the
or d i s c h a r g e s , some s o l i d food was g r a d u a l l y
i n t r o d u c e d i n t o the d i e t , and sl o w l y the p a t i e n t was brought
back t o normal d i e t , the time taken f o r t h i s b e i n g 10-16 d a y s .
As many o f the p a t i e n t s l i k e d ice -cr eam and a s i t o o n t a i n s
s u g a r , m ilk and c o r n f l o u r , t h i s was g i v e n each day,
commencing on the 3rd. day f o l l o w i n g the disapp ea ra nce of
t h e membrane or d i s c h a r g e s .
Where, in c o n j u n c t io n w ith the d i p h t h e r i a , t h e r e
.1 1 7 .
a ppeared a s t r e p t o c o c c a l or s t a p h y l o c o c c a l
in fe ctio n of
t h e t h r o a t , the p a t i e n t s were g i v e n a sulphanilaraide
p r e p a r a t i o n - the p r e p a r a t i o n used be in g S t r e p t o o i d e ( E v a n s ) ,
th e dose v a r y in g from J t o 1 gramme 4 h o u r l y .
The p a t i e n t s were g iv en mouth washes o f gly oo th ym o len e
e v e r y f o u r h o u r s , and where th e p a t i e n t was t o o i l l or t o o
young t h e mouth was c l e a n e d by n u r s e .
Where c e r v i c a l a d e n i t i s was p r e s e n t , when t h e p a t i e n t
had s u f f i c i e n t l y r e c o v e r e d from the i n i t i a l to x a e m i a , he was
g i v e n chewing gum.
This appeared to reduce the a d e n i t i s
by c a u s i n g massage o f the c e r v i c a l gland s by the a c t i o n o f the
jaw i n c h e w in g .
When t h e p a t i e n t had r eturned to normal d i e t , an ir o n
t o n i c was g i v e n .
The p r e s c r i p t i o n was:S y r . F e r r i P ho s. Co.
Syr. F e r r i . I o d .
a a 3 lv .
3 ,1*
Syr. Simplex
Aq. ad.
S ig.3jy.
m
t . i . d . ex aq. p #c .
— *
Treatment o f C o m p l i c a t i o n s due to the Toxin o f D i p h t h e r i a .
(a)
Cardiac P a r e s i s .
When during t h e p a t i e n t * s s t a y
i n h o s p i t a l , an e l e v a t i o n o f th e p u l s e r a t e o f more than 10
b e a t s p e r minute was o b s er v ed , the p a t i e n t was kept l y i n g
f l a t in bed.
I f he had been on normal d i e t , he was put on
f l u i d s u n t i l the p u l s e r a t e had f a l l e n .
The p a t i e n t s were
examined f r e q u e n t l y i n order t o determine th e to n e o f th e
a1X8 •
h e a r t m u s c l e , and to d e t e c t any arrhythmia whioh might
he p r e s e n t .
I f no marked e v id e n c e o f c a r d ia c d i s e a s e
was f o u n d , t h e p a t i e n t was kept l y i n g down f o r one week
a f t e r h i s p u l s e r a t e had retu r n e d t o normal.
Thereafter
he was brought t o a s i t t i n g p o s t u r e in bed by p i l l o w s and so
on u n t i l he c o u l d g e t up from bed.
When a d e f i n i t e arrhythmia d e v e lo p e d , the p a t i e n t , in
a d d i t i o n to the tre a tm en t d e t a i l e d above, was g i v e n i o . c .
a d r e n a l i n h y d r o c h l o r id e s o l u t i o n 1 /1000 4 - h o u r l y u n t i l the
normal rhythm was r e s t o r e d .
The f o o t o f the bed was
e l e v a t e d on b l o c k s .
In a c u t e c a r d ia c f a i l u r e s , the p a t i e n t was im m ed ia te ly
g i v e n . 5 c . c ! s o f 1 /1 0 0 0 s o l u t i o n a d r e n a l in h y d r o c h l o r i d e , the
f o o t o f t h e bed was e l e v a t e d , and oxygen was g i v e n c o n t i n u o u s l y .
No fo o d was g i v e n by mouth, but the p a t i e n t was g i v e n s p i c u l e s
o f i c e t o c o o l h i s mouth.
a t l e a s t 24 h o u r s .
This treatm en t was p e r s i s t e d i n f o r
I f the p a t i e n t had improved, some f l u i d s
were a l l o w e d by mouth, but I f n o t , r e c t a l g l u c o s e was g i v e n .
T h is t r e a t m e n t was then p e r s i s t e d in u n t i l the p a t i e n t had
improved s u f f i c i e n t l y t o be allowed some f l u i d s by mouth.
The
r e a s o n f o r the stop p in g o f o r a l f e e d i n g i s t h a t one o f the
c a r d i n a l symptoms of c a rd ia c f a i l u r e in d i p h t h e r i a i s v o m i t i n g .
I f no f o o d i s put i n t o th e stomach, the r i s k o f v o m itin g i s
lessen ed .
(b)
P alatal P aresis.
As soon as t h i s c o m p l i c a t i o n was
r e c o r d e d , t h e p a t i e n t was kept in the recumbent p o s i t i o n u n t i l
.1 1 9 .
one week a f t e r h i s speech had r e tu r n e d to normal*
While
s u f f e r i n g from t h i s p a r e s i s , he was g i v e n a f l u i d d i e t
which was a d m i n i s t e r e d t o him by n u r s e , who took e a r e t h a t
none o f t h e f o o d p a s se d i n t o the r e s p i r a t o r y t r a c t *
The
p a t i e n t was g r a d u a l l y brought to the s i t t i n g p o s i t i o n , and
f i n a l l y a l l o w e d t o g e t up from bed.
(c) A lbu m inu ria .
T his was t r e a t e d by the p a t i e n t 1s
b e i n g g i v e n a d i e t c o n s i s t i n g mainly o f f l u i d s , c arb o -h y d r a t e
and m i l k .
Return t o normal d i e t was gra dual and was on the
l i n e s f o l l o w e d in the nu rsing o f acute n e p h r i t i s .
(d) O cu la r P a r e s i s .
This occurred in s i x p a t i e n t s ,
a l l o f whom were in the same ward a t the same t i m e .
The
p a r e s i s to o k the form o f a t h i r d nerve p a l s y , w i t h e x t e r n a l
s t r a b i s m u s , d i p l o p i a , d i l a t e d p u p i l s , l o s s o f power o f
accommodation and no r e a c t i o n to l i g h t .
The s i x p a t i e n t s
were k e p t t o g e t h e r In the c o n v a l e s c e n t p a r t of the ward, which
was d a r k e n e d .
They were kept l y i n g f l a t , f e d on f l u i d s ,
and were n o t allow ed t o r e a d .
p ath ological
They a l l r e c o v e r e d .
No
c o n d i t i o n o f the r e t i n a or o p t i c ne rve was seen
on o ph tha lm o sco pic e x a m i n a t io n .
Treatment o f the c o m p l i c a t i o n s due t o serum.
(a)
Serum Rash.
The p a t i e n t was g i v e n J to 1 e . c . o f
1 / 1 0 0 0 a d r e n a l i n h y d rochlo rid e s o l u t i o n , and c o o l i n g
a p p l i c a t i o n s o f oalaraine l o t i o n or m eth ylate d s p i r i t were
ap p lied .
At the same t im e , calc iu m g l u c o n a t e (10 g r a . t . i . d . )
was a l s o g i v e n .
•120*
(b)
A rth ritis.
and sodium b i c a r b o n a t e a
This was t r e a t e d by sodium s a l i o y l a t e
5 gr.
5 - 10 q . i . d .
In t h i s c a s e
t h e p a i n in the ankle j o i n t s was very s e v e r e , a cage b e i n g
used t o t s k e the w e ig h t o f the b l a n k e t s from the f e e t .
The
a n k l e s were rubbed w it h methyl s a l i c y l a t e end wrapped In
cotton w ool.
Recovery was com p lete .
(o) A lbu m inu ria.
The two c a s e s which de v e lo p ed t h i s
c o m p l i c a t i o n a l s o had an accompanying serum r a s h .
.5 c . o f s
o f a 1 / 1 0 0 0 s o l u t i o n o f a d r e n a l in h y d ro c h lo r id e was g i v e n
s u b c u t a n e o u s l y e v e r y f o u r hours u n t i l the albuminuria had
e l e a r e d up.
(d) A d e n i t i s .
This i n v o lv e d the c e r v i c a l g l a n d s .
p a t i e n t was g i v e n a d r e n a l i n .5 c . c ’ s 4 - h o u r l y .
The
The c o n d i t i o n
was cured in t h r e e d a y s .
(e)
Serum Ac oide nt or Shock.
This occurred i n two
c a s e s and was t r e a t e d by e l e v a t i o n o f the f o o t o f the bed,
i n t r a m u s c u l a r i n j e c t i o n o f . 5 c . c . 1/1000 a d r e n a l in
h y d r o c h l o r i d e s o l u t i o n , r e p e a t e d in 30 minutes and In one
h o u r ’ s t i m e , and a d m i n i s t r a t i o n o f oxygen.
S t r a i n s o f C. Diph therias
rec ov er ed from the 1 , 0 0 0 C a s e s .
The l i t e r a t u r e on the v a r i o u s s t r a i n s found i s
a bundant.
Anderson e t a l ,
G r a v i s s t r a i n predominated.
(1931) found in Leeds t h a t the
Carter (1933 and 1936) found
t h e I n t e r m e d i a t e type t o be the most common in the Glasgow
area.
In 1936, Carter r ep o r t e d f o r the f i r s t time In the
Glasgow area the p r e s e n c e o f the two t y p e s , named i v and v i
.1 2 1 .
by Wright and C h r i s t i s o n ( 1 9 3 5 ) •
These o b s e r v e r s used
McLeod’ s T e l l u r i t e Medium (1931) .
In B e l v i d e r e H o s p i t a l
t h e medium used was t h a t o f Kerrln and Gaze (1936) •
A ll
c u l t u r e s were t e s t e d f o r t h e i r b i o c h e m ic a l and h a e m o l y t lc
r e a c t i o n s and f o r t h e i r growth in b r o t h .
To d i f f e r e n t i a t e
betw e en t y p e s i v and v i , animal v i r u l e n c e t e s t s were
necessary.
Taking o f the Swab.
Many p a t i e n t s are swabbed and a n e g a t i v e r e s u l t i s
r e t u r n e d when the c l i n i c i a n i s sure t h a t the c a se i s
dip h th eria.
The r ea so n s f o r t h i s may b e : -
(a) The c a s e i s not d i p h t h e r i a .
(b) There i s f r e q u e n t l y p r e s e n t a good d e a l of
exudate which i s s t a p h y l o c o c c a l or s t r e p t o c o o c a l
in o r i g i n .
(c) The nurse f a l l s to swab the membrane because o f t h e
r e s i s t a n c e of the p a t i e n t .
Swabbing a p a t i e n t i s an o p e r a tio n in which the d o c t o r
t a k i n g th e swab r e q u i r e s the he lp o f a n u r s e .
The d o c t o r sta n d s
a t th e s i d e o f the bed on the p a t i e n t ’ s l e f t with a tongue
d e p r e s s o r i n h i s l e f t hsnd, the swab in the r i g h t .
The nurse i s
a t t h e o p p o s i t e s i d e o f the b e d , a p e n c i l to rc h i n her l e f t hand,
her r i g h t hand s t e a d y i n g the p a t i e n t ' s head.
The p a t i e n t ' s
mouth i s ope ne d, the l i g h t shone i n t o the back o f the mouth, the
amount o f membrane noted and then swabbed.
Immediately t h i s had been done i t was i n o c u l a t e d on t o
•1 2 2 .
a L o e f f l e r ’ s egg medium s l o p e (1884) and, a t t h e same t i m e ,
on t o a p l a t e o f Kerrin and Gaze medium.
These were then
l n o u h a t e d a t 37°C. f o r 24 hours b e f o r e being exam ined.
If,
a f t e r t h i s p e r i o d , the c u l t u r e s on t h e s e media were n e g a t i v e ,
t h e y were r e i n c u b a t e d f o r a f u r t h e r 24 h ou rs, when t h e y were
re-exam ined.
In th e meanwhile, a second swab had been ta k e n
a f t e r t h e f i r s t n e g a t i v e had been r e t u r n e d .
The second
c u l t u r e s were s u b j e c t e d to the same t r e a t m e n t .
I f the r e s u l t
were n e g a t i v e from a l l the c u l t u r e s , a t h i r d swab was taken
and a l l s i x C u lt u r e s were Incubated.
Each c u l t u r e was
examined a t t h e end of 24 hours u n t i l I t had been in the
i n c u b a t o r f o r 72 h o u r s .
I f a t the end o f t h i s p e r io d a l l had
been r e p o r t e d n e g a t i v e , t h e swab was r ep o r t e d as n e g a t i v e .
If
a p o s i t i v e c u l t u r e was o b t a i n e d , i t was t e s t e d f o r i t s growth
in b r o t h , i t s b i o c h e m i c a l and haemolytic r e a c t i o n s .
I f the
r e s u l t were s t i l l d o u b t f u l when t h e s e r e s u l t s were c o r r e l a t e d
w i t h t h e c o l o n y appearance on the t e l l u r i t e medium, the
c u l t u r e was s e n t f o r a v i r u l e n c e t e s t .
P r e p a r a t i o n o f the Medium o f Kerrln and Gaze.
A.
O n e - a n d - a - h a l f pounds o f minced ox h e a r t muscle i s
added t o 1 , 0 0 0 c . c ’ s o f tap water and the mixture h e a t e d
t o 4 8 ° C . and kept a t t h a t temperature f o r one hou r.
The
j u i c e i s then squeezed out through muslin and f i l t e r e d
t hr o ugh ohardin f i l t e r paper in the i c e c h e s t .
i s n o t made up w i t h w a te r.
The volume
To every 1 ,0 0 0 c . c ’ s o f t h i s
f i l t r a t e , 20 grammes o f W i t t e ’ s peptone and 5 grammes of
.1 2 3 ,
Sodium C h l o r i d e A.R. are added*
t o 45
The mixture i s now h e a t e d
C. and kept a t t h a t temperature u n t i l a l l th e peptone
and s a l t are d i s s o l v e d .
The pH o f the mixture i s a d j u s t e d
as f o l l o w s : 50 o . c ’ s o f th e mixture are heated to 8 0-9 0°C . f o r
5-10 m inutes.
allow ed to c o o l.
The mixture i s f i l t e r e d through paper and
The amount of N / l NaOH r e q u ir e d t o b r i n g a
q u a n t i t y o f the mixture t o a pH of 7 . 6 i s c a l c u l a t e d and added.
The m ixture i s now f i l t e r e d through chardin paper and then
through a s e l t z 5 . K . f i l t e r d i s c i n t o a s t e r i l e f l a s k .
filtra te
The
i s s t o r e d in 100 c . c f l s s k s and t e s t e d f o r s t e r i l i t y
by i n c u b a t i n g f o r 24 hours at 37° C.
B.
A 5 per c e n t , s o l u t i o n of agsr i s made in w a t e r .
The r e a c t i o n o f t h i s does not req uire to be a d j u s t e d .
Q u a n t i t i e s o f 100 c . c ' s are p la c e d in 250 c . c ’ s f l a s k s and
a u t o c l a v e d a t 115° C. f o r 20 m in u te s.
C.
A 1 per c e n t , s o l u t i o n o f potassium t e l l u r i t e
i s made i n d i s t i l l e d w a t e r .
D.
a
(B.D.H .):
This must be f r e s h l y p r e p a r e d .
q u a n t i t y o f ox serum i s s t e r i l i z e d by f i l t r a t i o n .
To 100 c . c ’ s o f mixture (A ),
8 c . c ’ s o f the
p o t a s s i u m t e l l u r i t e s o l u t i o n , 15 c . c ’ s o f s t e r i l e ox serum,
2 grammes o f sacch aro se (B.D.H. and A.R.) and 2 c . c ’ s o f
Andrade’ s i n d i c a t o r are added ,
The mixture i s h ea ted t o
7 5 - 8 0 ° C . and kept at th a t temperature f o r 10 m i n u t e s .
During
t h i s h e a t i n g the mixture should be w e l l shaken to a v oid
c lu m p in g .
T h is mixture i s now added t o a f l a s k c o n t a i n i n g
.1 2 4 .
5 per c e n t , agar (B) a t 75° C. and t h i s mixture i s kept
a t t h a t tem perature f o r 10 m i n u t e s .
The medium can now be
p l a c e d in s t e r i l e t u b e s f o r s l o p e s or c o o l e d to 45° C. f o r
p lates.
The f i n i s h e d product i s a semi-opaque b u f f -
coloured su bstance.
The appearance of the d i p h t h e r i a c o l o n i e s when grown
on t h i s medium a r e : (a)
G ravis.
A f t e r 24 h o u r s , a w e l l - s e p a r a t e d c o lo n y which
i s a p p r o x i m a t e ly two mms. in d i a m e t e r , hss a r a i s e d c e n t r e and
a s l i g h t l y irreg u la r edge.
and f i n e l y g r a n u l a r .
The s u r f a c e i s u s u a l l y d u l l i s h
The c e n t r a l p a r t o f the c o lo n y i s p a l e
g r e y w i t h a l i g h t e r p e r i p h e r y which i s t r a n s l u c e n t a t the e d g e .
T h is p e r i p h e r y
shows some t en dency to r a d i a l s t r i a t i o n .
After
48 ho u rs ' i n c u b a t i o n the d iam eter o f the c o lo n y i s i n c r e a s e d
t o 3 - 5 rams.
The c e n t r e i s dark, the p e r i p h e r y g r e y , and the
s t r i a t i o n s are w e l l marked, g i v i n g a " d a is y head" app earance.
(b)
Interm edius.
A f t e r 24 ho urs ' i n c u b a t i o n th e y are
s m a ll umbonate c o l o n i e s about .5 mm. in d i a m e t e r .
The o u t l i n e
i s r e g u l a r , the s u r f a c e smooth, the c e n t r e dark brown and the
periphery t r a n slu c e n t.
In 48 hours the s i z e of the c o lo n y has
i n c r e a s e d t o 1 . 5 mms. in d i a m e t e r , t h e brown c o l o u r I s more
i n t e n s e and the p e r i p h e r y i s reduced in s i z e .
The edge may be
s l i g h t l y i r r e g u l a r , and some f i n e c o n c e n t r i c r i n g s s r e o f t e n
s een on t h e su r f a c e o f the c o l o n y , which may a l s o be f i n e l y
granular.
(c)
M itis.
A f t e r 24 hours the c o l o n y I s about 1 mm. in
.1 2 5 .
d i a m e t e r , low and c o n v e x , has a r e g u l a r edge and a smooth
surface.
The c e n t r a l p a r t i s b l a c k , the p e r i p h e r y p a l e g r e y .
In 48 hours t h e d ia m e t e r ha s i n c r e a s e d t o 2 - 3 mms. and the
c o l o n y i s much b l a c k e r .
The s u r f a c e i s s h i n y and o n l y the
extreme p e r i p h e r y remains a p a l e c o l o u r .
B i o c h e m i c a l R e a c t i o n s of the Various S t r a i n s .
Starch.
G r a v i s ............................
Glycogen
*
I n t e r m e d i u s .....................
M i t i s ...................................
Type _iv...............................
Type vj. .............................
Growth in B r o t h .
G r 8 v i s .............. In te r m e d iu s
P e l l i c l e and Granular
D eposit.
- Granular •
M i t i s .................-
Uniform T u r b i d i t y .
Type JLv............ -
P e l l i c l e and Granular
D eposit.
Type vj. ..........-
P e l l i c l e and Granular
D eposit.
T e s t f o r H aem ol ysis (Hammerschmldt, 1924 and 1925)
G r a v i s . ............ -
Non-Haemolyt 1c •
I n t e r m e d i u s . . - Non-Hae molytic.
M itis...
- H a e m o l y t ic .
Type i v ............ -
N o n -H aem olytic.
Type . vj............. -
Non-Haemolytic.
.1 2 6 .
Animal P a t h o g e n i c i t y .
G r a v i s ...............
■»
In term ed iu s..
«•
M i t i s .................
♦
Type _iy
f
Type v l ............
No mention has been made o f the m i e r o s o o p i c a l
a p p ea ra nces o f the d i f f e r e n t s t r a i n s o f o . d ip h th er ia s
a s , in
ray o p i n i o n , i t i s not a r e l i a b l e t e s t .
A n a l y s i s o f the 1 , 0 0 0 o a s e s t r e a t e d w i t h r e f i n e d
serum i s shown ( e x c l u s i v e o f n e g a t i v e o a s e s ) •
G rav is
In ter m ed iu s
Appearance on
T e l l u r i t e Medium 295 + 17
Granular f
P e l l i c l e in
B r o t h .....................
295
Granular in
B r o t h . ............ *.
-
263
374
+ 17
Type l v .
Type v l
8
9
8
9
263
Uniform T u r b i d i t y
in B r o t h .............. ..
Ferm en tation o f
S ta r c h and
G ly c o g e n .................
M itis
374
295
374
H a e m o l y t i c ..............
Pathogenicity for
Anim als
295 not
tested
Not
tested
Not
tested
8
C onclusions.
The combination o f the c o l o n y ap pea rances on t h e
.1 2 7 .
medium o f Kerrin and Gaze, t o g e t h e r w i t h the appearance
in b r o t h , the b i o c h e m i c a l and h a e m o l y t ic r e a c t i o n s , a f f o r d s
a c o n c l u s i v e method, in most c a s e s , o f d i f f e r e n t i a t i n g
between the d i f f e r e n t s t r a i n s o f o • d i p h t h e r ia s •
In a few
o a s e s an animal p a t h o g e n i o i t y t e s t i s n e c e s s a r y to
d i f f e r e n t i a t e between c e r t a i n r a r e r t y p e s ( i v and v l) •
The i n c i d e n c e o f the G ra vis s t r a i n i s d e f i n i t e l y
h i g h e r in t h e Glasgow area when compared w i t h th e r e p o r t s
by C a r t e r (1933 and 1936)
and t h e Glasgow Medical O f f i c e r
o f H e a l t h * s R e por t, 1935 (Knightswood H o s p i t a l ) .
D e t a i l e d A n a l y s i s o f the 1 ,0 0 0 Cases t r e a t e d w i t h R e f in ed
Serum.
1*
Age and S e x .
6 -10
11-2 0
Ms l e s ............
93
247
130
42
15
20
5
Fem ales. . . .
98
197
109
29
12
3
0
T o t a l ............ 191
444
239
71
27
23
5
2 1 -3 0
31-40
41- 50
51-'
0-5
Age Groups
Of the t o t a l , 552 ( 5 5 .2 $ ) were males and 448 ( 4 4 . 8 $
were f e m a l e s .
un der.
635 ( 6 3 .5 $ )
o f the p a t i e n t s were aged 10 or
.1 2 8 .
2.
Age o f P a t i e n t s and Type o f C. D i p h t h e r i a s
recovered
from Each Case ( e x p r e s s e d f i r s t a s a P e r c e n t a g e o f Age Groups
and then as a P e r c e n t a g e o f Type o f C. Di phtherias •
Age Group s
G ra v is
I n ter m ed iu s
M itis
Aberrant
3(1.55)
7(1.6)
5(2.1)
2(2.9)
0-5
6-10
11-20
21-30
31-40
41-50
51-60
61(31.9)
1 3 3 ( 2 9 .9 )
84(35.1)
14(19.7)
3(11.1)
56(29.3)
1 2 2 ( 2 7 .5 )
4 9 ( 2 0 .5 )
1 7 ( 2 3 .9 )
14(51.9)
5(21.7)
68(35.6)
1 6 1 ( 3 6 .3 )
85(35.6)
38(53.5)
6(22.2)
1 1 ( 4 7 .8 )
5(100)
Total
296
263
374
Age Group s
0-5
6-10
11-2 0
21-30
31-40
41-5 0
51-6 0
T otal.
Gra vis
In ter m ed iu s
61(20.7)
133(45.1)
84(28.5)
14( 4 . 7 )
3( 1 .0 )
56(21.5)
1 2 2 ( 4 6 .3 )
49(18.6)
17( 6 .5 )
14( 5.3)
5( 1.8)
295
263
3(1.55)
21(4.7)
16(6.7)
4(14.8)
7(30.5)
17
M itis
N egative.
Aberrant
68(18.2)
3(17.6)
1 6 1 ( 4 3 .1 )
7(41.3)
85(22.7)
5(29.4)
2(11.7)
38(10.2)
6( 1.6 )
11( 2 .9 )
5( 1.3 )
17
374
51
N e g a tiv e
3(5.9)
21(41.2)
16(31.4)
4( 7.8)
7(13.7)
51
Of the 0 - 1 0 age gr oup, the a g e s in which the death
r a t e i n d i p h t h e r i a i s h i g h e s t (Graham F o r b e s , 1 9 3 2 ) , 3 0 . 9 $ o f
th e c a s e s had G rav is i n f e c t i o n s and 2 8 . 3 $ had I n t e r m e d i u s .
These
two t y p e s are u s u a l l y a s s o c i a t e d with the s e v e r e s t c l i n l o a l t y p e s
of diphtheria.
(Anderson e t a l 1 9 3 1 ) •
From th e age o f 40
upwards, most i n f e c t i o n s were caused by the M i t i s s t r a i n .
The G r a v i s , In ter m ed iu s and M i t i s s t r a i n s had t h e i r
h i g h e s t i n c i d e n c e in the 6 - 1 0 age grou p, the I n ter m ed iu s having
the h i g h e s t p e r c e n t a g e - 4 6 . 3 .
M i t i s l a s t w ith 4 3 . 1 .
G ravis came n e x t w i t h 4 5 .1 , and
Of the G rav is i n f e c t i o n s , 6 5 . 8 $
occu rred in c h i l d r e n o f 10 and under, and 6 7 . 8 $ o f t h e
129.
I n t e r m e d iu s occu rred in t h i s same age g r o u p .
With M i t i s ,
Aberrant and N e g a t i v e e s s e s , th e h i g h e s t p r o p o r t 3on o f
t h e s e was found in t h e 6 - 2 0 age g r o u p s .
3.
Dosage o f Serum g i v e n in the Various Age Groups ( e x p r e s s e d
f i r s t a s a P e r c e n t a g e o f the Age Groups and then as a
P e r c e n t a g e o f the Number r e c e i v i n g the v a r i o u s doses) .
Age Group.
0-5
6-10
11-20
21-30
31-40
41-50
51-60
Under 6 , 0 0 0
U n its.
19
41
29
9
5
6
2
T otal.
111
0-5
6-10
11-20
21-30
31-40
41-50
51-60
19
41
29
9
5
6
2
Total
(9 .9 )
(9 .2 )
( 1 2 .1 )
( 1 2 .7 )
( I B . 5)
(26.1)
(40)
(1 7 .1 )
(36.9 )
(26.1)
( 8.1 )
( 4 .5 )
( 5.4)
( 1.9)
111
8 ,000-40,000
U n its.
4 0 ,0 0 0 U n it s
and Over •
121 (63 .3 )
263 ( 5 9 . 2 )
lie ( 4 9.4)
32 ( 4 5 .1 )
14 (5 1.8 )
10 (4 3 .5 )
3 (60)
51
140
92
30
8
7
-
561
328
121 (21.5)
263 (4 6 .9 )
lie ( 2 1 .0 )
32 ( 5 .7 )
14 ( 2 .5 )
10 ( 1.8)
3 ( 0*6)
51
140
92
30
8
7
-
561
328
The oa j o r i t y o f p a t i e n t s ( 5 6 . 1 $
rum between 8 , 0 0 0 and 4 0 ,0 0 0 u n i t s .
(26.8 )
(3 1.6 )
(36.5 )
( 4 2 .2 )
( 29.7 )
( 3 0 .4 )
(1 5 .6 )
(4 2 .7 )
(26.0 )
( 9.1 )
( 2.4 )
( 2.2)
r e c e i v e d a dose o f
Doses o f 4 0 , 0 0 0 u n i t s
o ver came n e x t in f r e q u e n c y and sm all d o s e s o f l e s s than 6 ,0 0 0
u n i t s were u s e d l e a s t o f a l l *
The p e r c e n t a g e o f p a t i e n t s
who r e c e i v e d d o s e s o f l e s s than 8 , 0 0 0 u n i t s i n c r e a s e d w i t h a g e .
The p e r c e n t a g e o f p a t i e n t s r e c e i v i n g 8 , 0 0 0 t o
•1*>C.
4 0 , 0 0 0 u B i t s v a r i e d from age group t o age g r ou p , b e i n g
63*3$ in t h e 0 - 5 age group end 4 5 . 1 $ in th e 2 1 - 3 0 gr o u p .
Of* t h e p a t i e n t s who r e c e i v e d 8 , 0 0 0 u n i t s or o v e r , 575 (57 • 5 $
were between the e g e s o f 0 - 1 0 .
4.
Day o f D i s e a s e c o r r e l a t e d w i t h Type o f C• Diph therias
r e c o v e r e d from the c a se ( e x p r e s s e d f i r s t 8s a p e r c e n t a g e
o f Cases p e r Day of D i s e a s e and then as a P er c e n t a g e o f
t h e V a r i o u s Types f o u n d ) •
Day of
D isease
1
2
3
4
5
6
7
8
T otal.
Grav i s
4(11.8)
66(23.9)
117(32.7)
59(32.9)
20 ( 2 8 .9 )
17(24.6)
-
I n t e rmed iu s
8(23.4)
1 9 ( 5 5 •9)
92(33.3)
92(33 . 3)
7 3 ( 2 0 . 4 ) 148(41 *5)
62(34 • 6)
42(23.4)
3 3 ( 4 7 .8 )
13 (18 .9)
13(18.9)
3 8(5 5 .1)
2 ( 5 0 .0)
2(50.0)
Aberrant
Negat i v e .
-
3(6.9)
23(6.4)
12(3.5)
13(7.3)
3(1.1)
7(1.9)
3(1.6)
3(4.4)
1(1.4)
-
-
12(100)
295
263
1
2
3
4
5
6
7
4(1.3)
66(22.4)
117(39.6)
59(20.0)
20( 6 . 8 )
17 ( 5 .8 )
8(3.0)
92(34.9)
73(27.4)
42(15.9)
33(12.5)
13 ( 4 . 9 )
2 ( 0.6)
8
12( 4 .1 )
T otal.
M itis
-
295
-
263
17
374
1 9 (5
.;1)
92(24 .6)
1 48(39 •6)
62(16 • £)
13 ( 3 . 5)
3 8 ( 1 0 • 1)
2( 0 .6)
374
3(17.6)
7(41.2)
3(17.6)
3(17.6)
1( 6 .0 )
17
51
3(5.9)
23(45.1)
12(23.5)
1 3 ( 2 5 .5 )
-
51
Of t h e 1 , 0 0 0 e a s e s , 846 (8 4.6^) had r e c e i v e d serum t r e a t m e n t
w i t h i n f o u r days from t h e o n s e t o f t h e i r i l l n e s s .
Of the
e a s e s which had a Gravis i n f e c t i o n , o n ly 1 . 3 % r e c e i v e d serum
©n t h e f i r s t day o f t h e i r i l l n e s s .
By the end o f t h e f o u r t h
day however, 8 3 . 3 ^ had r e c e i v e d serum t r e a t m e n t .
Of the
I n t e r m e d i u s , M i t i s , Aberrant and N e g a t iv e c a s e s , 8 1 . 2%,
• 131
8 5 . 8 $ , 7 6 . 4 $ and 100$ r e s p e c t i v e l y had been g i v e n a n t i t o x i n
by the end o f the f o u r t h day o f i l l n e s s *
6.
Day o f D i s e a s e c o r r e l a t e d w i t h the Age o f the P a t i e n t
( e x p r e s s e d f i r s t a s a P e r c e n t a g e o f the Number o f Cases
o c c u r r i n g Each Day and s e c o n d l y as a P e r c e n t a g e o f the
Number o f Cases in Each Age Group.
Day o f
Disease
1
2
3
4
5
6
7
8
6 -10
0-5
4(11.7)
54(19.5)
58(16.2)
46(25.6)
14(20.3)
9(13.1)
•___6(50)
T o t a l . 191
7(20.6)
128(46.4)
1 6 1 ( 4 5 .1 )
79(44.1)
35(50.7)
24(34.8)
4(100)
6(50)
444
MMMB
11-20
11(32.4)
7 8 ( 2 8 .3 )
74(20.8)
29(16.1)
18(26.2)
29(42.0)
-
21-30
6(17.7)
10( 3.6 )
37(10.3)
15( 8 .4)
1( 1.4)
2( 2.9 )
-
4(11.7)
4 ( 1.5)
13 ( 3.6 )
3 ( 1.7)
1( 1 .4 )
2( 2 . 9 )
-
-
-
239
1' 1
31-40
71
41- 50
51 -60
2(5.9)
2(0.7)
10(2.8)
6(3.4)
••
-
-
3(4.3)
-
-
27
4(1.2)
1(0.7)
-
-
23
'
11 ( 4.6)
7 8 ( 3 2 .6 )
7 4 ( 3 0 .9 )
29(12.2)
18( 7.5)
29(12.2)
-
-
5
—
_
6( 8.4)
4(14.8)
2(8.7)
10(14.1)
4(14.8)
2(8.7)
37(52.1)
1 3 ( 4 8 . 2 ) 1 0 ( 4 3 . 5 ) 4(80)
1 5 ( 2 1 .1 )
3(11.1)
6 ( 2 6 . 1 ) 1(20)
1( 3 .7 )
l ( 1 .4 )
2( 2 .9 )
2( 7 .4 )
3(13.0)
---- - MMM.
71
239
27
444
T o t a l . 191
23
5
MM~
MM
MM
MM
' "1
■■MB
In t h i s s e r i e s , in t h e age groups where the m o r t a l i t y i s highe s t
1
2
3
4
5
6
- 7
8
4 ( 2 .1 )
54(28.3)
58(30.3)
46(24.2)
14( 7.3)
9( 4.7)
6( 3 .1 )
7 ( 1.5)
1 28 (2 8 .9 )
161(36.3)
79(17.9)
35( 7 .9 )
24( 5 .4 )
4(0.9)
6(1.2)
(0—10 ye a rs) , 537 out o f 635 c a s e s had r e c e i v e d serum b e f o r e
th e end o f the f o u r t h day.
The e a r l i e r the serum i s g i v e n , the
b e t t e r the p r o g n o s i s and t h i s h o l d s e s p e c i a l l y in t h o s e age
p e r i o d s mentioned ab o v e .
Most o f the o a s e s t h a t r e c e i v e d serum
v e r y I s t e were in t h e 0 - 1 0 age group.
For a l l age gr oups, w it h the e x c e p t i o n o f the 11-2 0
group, the p e r ce n ta g e o f c a s e s which came under treat men t r o s e
.1 3 2
t o a maximum on t h e t h i r d day o f i l l n e s s , and t h e r e a f t e r
became l e s s .
The r a t e o f d i m i n u t i o n v a r i e d i n t h e d i f f e r e n t
groups•
6.
Day o f D i s e a s e c o r r e l a t e d w i t h Dose o f Serum g i v e n
( e x p r e s s e d f i r s t a s a P e r c e n t a g e o f Cases p e r Day and
s e c o n d l y a s a P e r c e n t a g e o f Cases r e c e i v i n g t h e d e f i n e d
Doses) .
Day o f
D isease.
Under 8 , 0 0 0
U n its.
1
2
3
4
5
6
7
8
26
46
36
2
1
__ ^
T otal.
Ill
1
2
3
4
5
6
7
8
T otal.
26
46
36
2
1
^
Ill
(7 6 .5 )
(16.7)
(10.1)
( 1.2 )
( 1 .5 )
( 2 3 .4 )
(41.4)
( 3 2 .4 )
( 1 .9 )
( 0 .9 )
8,000-40,000
U n its.
4 ( 1 1 .7 5 )
168 ( 6 0 . 9 )
226 ( 6 3 .3 )
127 ( 7 0 . 9 )
21 ( 3 0 . 4 )
11 ( 1 5 .9 )
3 (75.0)
__ 1 J 8 . 3 )
4 0 ,0 0 0 U n i t s
and Over.
4 (11.75)
62 ( 2 2 . 4 )
95 ( 2 6 .6 )
50 ( 2 7 . 9 )
47 ( 6 8 . 1 )
58 ( 8 4 .1 )
1 (25.0)
11 ( 9 1 . 7 )
561
328
4 ( 0 .7 )
168 ( 2 9 .9 )
226 ( 4 0 .3 )
127 ( 2 2 . 6 )
21 ( 3 .8 )
11 ( 1.9)
3 ( 0 .6 )
1_( 0 . 2 )
561
4 ( 1.2
62 ( 1 8 . 9
95 ( 2 8 . 9
50 ( 1 5 . 2
47 ( 1 4 . 3
58 ( 1 7 . 8
1 (0.3
11 ( 3 . 4
328
As the d u r a t i o n o f i l l n e s s len g t h e n e d b e f o r e t h e a d m i n i s t r a t i o n
o f a n t i t o x i n , the dose r e q u i r e d , i n c r e a s e d .
In the under 8 ,0 0 0 u n i t s s e r i e s , the h i g h e s t number of
p a t i e n t s r e c e i v i n g t h i s dose did so on the second day o f
illn ess.
With the 8 ,00 0 t o 4 0 , 0 0 0 , and 4 0 ,0 0 0 u n i t s and o v e r ,
the h i g h e s t number r e c e i v i n g t h i s , dose did so on the t h i r d day.
.
.1*5 <3
T h e r e a f t e r th e p e r c e n t a g e number f e l l w it h the i n c r e a s e o f
time but the f a l l was s l o w e r w i t h the over 4 0 , 0 0 0 u n i t s
serie s •
7.
The Type o f C. D iphtherias
r e c o v e r e d from the I n d i v i d u a l
Cases i s c o r r e l a t e d w i t h the dose o f Serum g i v e n
( e x p r e s s e d as a P e r c e n t a g e o f Type of C. D i p h t h e r i a s ) •
Type o f C•
Diphtheria.
G ravis.
Interm edius.
M itis.
Aberrant.
N egative.
T otal.
Under 8 ,0 0 0
U n its•
17
14
55
3
22
111
( 5.8)
( 5.3)
( 1 4 .7 )
( 1 7 .6 )
(4 3.1)
8,000-40,000
U n its.
121
121
281
10
28
561
(41.0)
(46.0)
(7 5.1)
( 5 8 .9 )
(55.0)
40,000 Units
and Over.
157
128
38
4
1
328
(5 3 .2 )
(4 8 .7 )
(1 0 .2 )
(23 .5 )
( 1.9)
In t h e G ravis i n f e c t i o n s , the m a j o r i t y of the p a t i e n t s (5 3 .2 # )
r e q u i r e d a dose o f serum o f over 4 0 ,0 0 0 u n i t s , 4 1 . 0 # r e q u i r e d
d o s e s v ar y in g between 8 , 0 0 0 and 4 0 ,0 0 0 u n i t s and on ly a sm all
p e r c e n t a g e ( 5 .8 )
were g i v e n l e s s than 8 , 0 0 0 u n i t s .
With the
I n t e r m e d iu s i n f e c t i o n s s i m i l a r f i g u r e s were o b t a i n e d , t h e s e
b e i n g 4 8 . 7 # , 46# and 5 . 3 # .
In the M i t i s i n f e c t i o n s most o f
the o a s e s ( 7 5 . 1 # ) were g i v e n d o s es v ar yin g between 8 , 0 0 0 and
4 0 , 0 0 0 u n i t s , w h il e 1 4 . 7 # and 1 0 . 2 # r e c e i v e d l e s s than 8 , 0 0 0
u n i t s and over 4 0 , 0 0 0 u n i t s r e s p e c t i v e l y .
In the a b e r ran t
c a s e s much th e same r e s u l t s were o b t a i n e d , the f i g u r e s b e in g
5 8 . 9 # , 1 7 . 6 # and 2 3 . 5 # .
In the n e g a t i v e o a s e s 4 3 . 1 # were
g i v e n l e s s than 8 ,0 0 0 u n i t s , 5 4 . 9 # between 8 , 0 0 0 and 4 0 , 0 0 0
u n i t s and 2# over 4 0 , 0 0 0 u n i t s .
The G ra vis i n f e c t i o n s r e q u ire d the h i g h e s t
134
d o s e s o f serum.
(2) m i t i s ,
Next in order came (1)
interm edius,
(3) a b e r r a n t , and (4) n e g a t i v e c a s e s , which
required l e a s t of a l l .
F a u c ia l diphtheria i s divided in to four d i f f e r e n t
c l i n i c a l t y p e s a c c o r d i n g t o the amount o f membrane p r e s e n t .
(a) Mild:
Where t h e r e was membrane amounting t o t h e s i z e
o f a t hreepenn y p i e c e on one or d i v i d e d between both
t o n s i l s , t h e s e c a s e s r e q u i r e d a dose o f serum up t o
8.000 u n its for t h e ir cure.
(b) Moderate:
Where the t o t a l membrane on one or d i v i d e d
between b o th t o n s i l s amounted to the s i z e o f a f l o r i n ,
t h e y r e q u i r e d a dose o f serum va r yin g between 8 , 0 0 0 and
32.000 u n i t s .
(c)
S e v e re :
Where the membrane was p r e s e n t on both t o n s i l s
and had spread on to the u v u l s , t h e s e c a s e s r e q u i r e d a
dose o f serum v a r y in g from 3 2 , 0 0 0 u n i t s to 8 0 , 0 0 0 u n i t s .
(d) Haemorrhagic:
Where both t o n s i l s , uvula and the hard
p a l a t e were c o v er ed w i t h membrane and t h e r e was b l e e d i n g
from the e d g e s o f the membrane, t h e s e c a s e s r e q u i r e d
from 8 0 , 0 0 0 u n i t s upwards f o r t h e i r c u r e .
8*
Type o f C. D ip h th e rias r e c o v e r e d from the D i f f e r e n t
C l i n i c a l V a r i e t i e s o f D i p h t h e r i a , e x p r e s s e d as a P er ce n ta g e
•135 •
of C lin ic a l Cases.
Percentage of Cases.
C linical
Typ e.
G ra v is
F aucial;
(a) Mild
24(14.1)
(b) Moderate 1 1 2 (2 8 .9 )
(c) Severe
68(41.7)
(d) Haemorrhagic
23(47.0)
Na s a l
4(21.0)
L ar yn g e al
F a u c i a l and
Na s a l
64(33.3)
Cervical
A denitis
220(74.6)
T otal.
295
C ervioal A d e n itis i s expressed as a
In te r m e d iu s
M itis
Aberrant
N egative.
20(11.7)
1 0 3 ( 2 6 .4 )
5 1 ( 3 1 .3 )
94(54.9)
1 5 2 ( 3 9 .4 )
38(23.3)
5(2.9)
8(2.1)
2(1.2)
28(16.4)
12(3.2)
4(2.5)
14(28.5)
2(10.5)
12(24.5)
1 3 ( 6 8 .5 )
13(65.0)
—
7(35.0)
73(38.3)
5 2 ( 2 7 .4 )
1 6 0 (6 0 .8 )
263
1 4 0 ( 3 1 .6 )
374
2(1.0)
6(35.3)
17
—
1 0 ( 1 9 .6 )
61
As t h e c l i n i c a l s e v e r i t y o f th e c a s e i n c r e a s e d , the p e r c e n t a g e
o f G r a v i s and In term ed iu s i n f e c t i o n s i n c r e a s e d .
As t h e s e t y p e s
i n c r e a s e d , th e p e r c e n t a g e o f m i t i s , abe r ra n t and n e g a t i v e c a s e s
de cree s e d .
C e r v i c a l a d e n i t i s was common i n d i p h t h e r i a , o c c u r r i n g most
f r e q u e n t l y i n Gravis i n f e c t i o n s and d e c r e a s i n g in f r e q u e n c y in the
I n t e r m e d iu s , a b e r r a n t , m i t i s and n e g a t i v e c a s e s , in t h a t o r d e r .
Death and C o m p lic a tio n R a t e s .
These f a c t o r s v a r y g r e a t l y i n d i f f e r e n t s e r i e s .
Anderson
e t a l (1931) found th e G rav is s t r a i n t o be a s s o c i a t e d w i t h a
h i g h d e a t h and c o m p l i c a t i o n r a t e , w h i l e C a rter (1936) found the
i n t e r m e d i u s s t r a i n to be the type having the h i g h e s t de at h and
com plication r a t e .
Serum r e a c t i o n s have been d e a l t w i t h i n p r e v i o u s c h a p t e r ,
(a)
The f o l l o w i n g t a b l e shows the Type o f C. D iph the rias
• 136 •
r e c o v e r e d c o r r e l a t e d w i t h the v a r i o u s c o m p l i c a t i o n s observed
and w i t h t h e de at h r a t e ( e x p r e s s e d a s P e r c e n t a g e s o f t h e number
o f t h e Types found) .
C om p lication.
G ravis.
Interm edius. M itis
Albuminuria
Cardiac
P aresis.
P a la ta l ,,
Ocular , ,
Death Rate
16(5.4)
9(3.4)
B (2 .1 )
22(7.4)
1B(6.1)
16(5.4)
12(4.5)
16(6.1)
6(2.3)
8(3.0)
2(0.5)
6(1.5)
3(0.8)
Aberrant N e g a t i v e .
1(5.9)
2(3.9)
1(5.9)
1(2.0)
1(5.9)
1(2.0)
The G r a v i s i n f e c t i o n s , with the e x c e p t i o n of the aberrant s t r a i n
( s e e below) had the h i g h e s t c o m p l i c a t i o n r a t e s , w i t h the
i n t e r m e d i u s c a s e s coming n e x t in f r e q u e n c y .
had the f e w e s t c o m p l i c a t i o n s .
The m i t i s o a s e s
The c o m p l i c a t i o n s shown under
t h e a b e r r a n t column e l l occurred in the same case - a case o f
Type I v .
The n e g a t i v e c a s e s w i t h c o m p l i c a t i o n s were two v e ry
i l l p a t i e n t s from whom s p e r s i s t e n t n e g a t i v e
swab was
o b t a i n e d , a l t h o u g h t h e c a s e s were t y p i c a l l y d i p h t h e r i a .
o f t h e d e a t h s were not due d i r e c t l y t o d i p h t h e r i a .
Three
One was
due t o a n u r s i n g a c c i d e n t and two were due t o s e p t i c
m e n i n g i t i s f o l l o w i n g upon m a s t o i d i t i s .
The two c a s e s de velo ped
m a s t o i d i t i s some weeks a f t e r a d m iss io n t o h o s p i t a l .
They f i r s t
had a s e p t i c t o n s i l i t i s then develo ped o t i t i s med ia, which
progressed in to m a s t o id it is .
Both c a s e s were o p e r a te d on f o r
m a s t o i d i t i s , but d evelo p ed s e p t i c m e n i n g i t i s and d i e d .
.1 3 7 .
(b) Death and C o m p lic a t io n H at es c o r r e l a t e d w i t h the Age o f the
P a t i e n t ( e x p r e s s e d a s P e r c e n t a g e o f the Age G rou p )•
Age Group. Albuminuria P a l a t a l Cardiac
_ _ _ _ _
______________ P a r e s i s P a r e s i s
0-5
6-10
11-20
21-30
31-40
41-50
51-60
T otal.
8(4.2)
17(3.8)
4(1.6)
6(8.5)
1(3.7)
7(3.7)
16(3.6)
12(5.0)
4(5.6)
3(11.1)
10(5.2)
12(2.7)
10(4.2)
3(4.2)
1(3.7)
36
42
36
Ocular
Paresis
Death
Hate •
3(1.6)
3(0.7)
11(5.8)
8 ( 1 . 8)
9(3.8)
1(1.4)
29
G e n e r a l l y , the p e r c e n t a g e o f c o m p l i c a t i o n s was h i g h e s t in
th e 0 - 5 age gro up.
Albuminuria oc cu rred in 4 . 2 $ o f o h i l d r e n under f i v e .
T h e r e a f t e r th e p e r c e n t a g e f e l l u n t i l the 2 1 -30 group was
r e a c h e d , where t h e r e was a sharp r i s e , even above th e 0 - 5 f i g u r e ,
and then i t f e l l a g a i n .
P a l a t a l p a r e s i s was, apart from a s l i g h t f a l l in th e
6-10
age group, a p r o g r e s s i v e l y more f r e q u e n t c o m p l i c a t i o n w i t h
ag©> up to the age o f 4 0.
Cardiac p a r e s i s , t y p i f i e d by r i s e
in pulse r a t e , w ith
or w i t h o u t i r r e g u l a r i t y o f the rhythm, l o s s o f tone o f the
h e a r t , m u s cle s and s o f t n e s s of the p u l s e , was most f r e q u e n t l y
found in t h e 0 - 5 age group.
The i n c i d e n c e rose in the 11-20
and the 3 1 -4 0 age g r o u p s , but was never so high as in the f i r s t
age gro up.
Ocular p a r e s i s occu rred most f r e q u e n t l y in the 0 - 5
age group.
Death r s t e was h i g h e s t in the very young.
It fe ll
.1 3 8 .
i n t h e 6 - 1 0 group but r o se a g a i n in the 1 1 - 2 0 group, but n o t
so h i g h a s in the 0 - 5 group.
(c) Death and C o m p li c a t io n Rates c o r r e l a t e d w ith Day o f D is e a s e
( e x p r e s s e d a s P e r c e n t a g e s o f Day of* D i s e a s e ) •
Day, of Albuminuria
Dise a se •
1
2
3
4
5
6
7
8
Total •
3(1.2)
7(1.7)
14(7.8)
10(14.6)
2(2.9)
P alatal
Paresia
7(2.7)
10(2.8)
12(6.7)
8(11.6)
5(7.3)
-
-
-
-
36
42
Cardiac
Paresis
1(2.9)
4(1.6)
8(2.2)
10(5.6)
4(5.8)
6(8.7)
1(25.0)
2(16.7)
36
Ooular
P aresis
-
4(1.1)
2(1.1)
-
6
Death
Rate •
1(0.4)
7 ( 1 .7 )
6(3.4)
6(8.7)
6(8.7)
1(25.0)
2(16.7)
29
As the time b e f o r e tre a tm en t was commenced i n c r e a s e d , so did
the i n c i d e n c e o f c o m p l i c a t i o n s i n c r e a s e .
In a l l c o m p l i c a t i o n s
( w i t h th e e x c e p t i o n of t h e c a r d ia c p a r e s i s )
the i n c i d e n c e
i n c r e a s e d up t o the f i f t h day.
T h e r e a f t e r the i n c i d e n c e of
c o m p l i c a t i o n s became i r r e g u l a r .
T h is was pr obably due t o some
o f the c a s e s b e i n g ve ry mild and havin g been swabbed by the
p r a c t i t i o n e r because o f some sm all patch becoming a p p a r e n t .
(d) Death and C o m p lic a tio n Rates c o r r e l a t e d w i t h the C l i n i c a l
Types o f D i p h t h e r i a ( e x p r e s s e d a s P e r c e n t a g e s o f C l i n i c a l Types)
C linical
Type
Albuminuria
Pa uo i a l :
(a) Mild
2(1.2)
(b) Moderate 3 ( 0 . 8 )
(c) Severe
5(3.1)
(d) Haemorrhagic 13(26.5)
Nssal
Larynge al
F a u c i a l and
Nasal
13 ( 6.8)
T otal.
68
Death
Rate •
P alatal
P aresis
Cardiac
Paresis
Ocular
P aresis
3 ( 1 . 8)
4( 1 . 0)
7(4.3)
1(0.6)
6(3.6)
1 4 ( 2 8 .7 )
14(28.7)
1 6 ( 3 2 .7 )
4(20.0)
2 ( 1 0 . 0)
14(7.3)
42
1 7 ( 8 .9 )
36
1 ( 0 . 6)
10(5.2)
29
.1 3 9 .
With th e e x c e p t i o n o f th e moderate f a u c i a l c a s e s , a s the
c l i n i c a l s e v e r i t y o f t h e c a s e i n c r e a s e d , so did the
Incidence of c om p lica tion s.
The f a u c i a l - n a s a l c a s e s
o c c u p i e d an I n t e r m e d ia t e p o s i t i o n between s e v e r e and
haemorrhagic f a u c i a l c a s e s when c o n s i d e r e d i n terms o f
com p lication s.
Cardiac c o m p l i c a t i o n s oc curred in 20 % o f the c a s e s
of laryn geal d ip hth eria.
Dose o f Serum.
The tendency I s t o i n c r e a s e d d o s a g e .
This has been
made more e a s y t h r o u g h t h e seru m be in g a v a i l a b l e in
c o n c e n t r a t e d form .
Park (1921)
ad vocated 5 0 , 0 0 0 u n i t s as
t h e l a r g e s t dose o f serum t h a t should be g i v e n .
gave up t o 3 4 0 , 0 0 0 u n i t s w i t h good r e s u l t s .
BIe(1922)
In London
( p r i v a t e l y communicated) l a r g e d o s e s up to 4 0 0 , 0 0 0 u n i t s
h8ve been g i v e n .
I n the s e r i e s under c o n s i d e r a t i o n th e
l a r g e s t dose g i v e n was 3 1 2 , 0 0 0 u n i t s (with r e c o v e r y ) .
Park (1921) was o f the o p in io n t h a t one l a r g e dose
sh o u ld be s u f f i c i e n t f o r a c a s e , but Bie (1922)
8nd Friedmann
(1922) thought t h a t a d d i t i o n a l d o s e s should be g i v e n I f
necessary.
I n the 1 , 0 0 0 c a s e s d e a l t w i t h , se c o n d , t h i r d
end f o u r t h d o s e s were g i v e n .
T h is should be done, because
f r e q u e n t l y w i t h Gra vis and In t e r m e d iu s c a s e s which have
r e c e i v e d a l a r g e i n i t i a l dose the membrane sp rea ds r a p i d l y
i n s t e a d of dim inishing.
I f a f t e r 24 h o u r s f r o m the time of
th e adm inistration o f th e
serum t h e membrane I s s t i l l
•140.
s p r e a d i n g , more serum should be g i v e n .
0f t h e 1 , 0 0 0 c a s e s
t r e a t e d , 205 had two i n j e c t i o n s o f serum, 44 tied t h r e e and
5 had f o u r s e p a r a t e i n j e c t i o n s .
An A n a l y s i s o f t h e Groups o f CBBes
t r e a t e d a c c o r d i n g to the D i f f e r e n t
B o u te s o f A d m in i s t r a t i o n o f t h e Derum.
1* Intravenous*.
Method o f A d m i n i s t e r i n g the Serum i n t r a v e n o u s l y .
A 10 c . c . s i d e n o z z le d (record)
ampoule c o n t a i n i n g the serum
w
b e
s y r i n g e was u s e d .
The
heate d in water to b l o o d - h e a t .
The p a t i e n t ’s arm was c l e a n s e d w i t h m eth ylate d s p i r i t , dr ied
and h e l d f l a t on the bed.
P r e s s u r e on the upper arm was
e x e r t e d by the hand o f the s i B t e r i n charge o f the ward*.
This
was a p p l i e d f o r 30 -60 s e c o n d s and t h e p a t i e n t t o l d t o open and
shut h i s hand.
The serum was t h e n s l o w l y i n j e c t e d i n t o t h e
c e p h a l i c or b a s i l i c v e i n , about 2 c . c ’ s o f serum p er m inu te .
The p a t i e n t was kept under c l o s e o b s e r v a t i o n f o r any Bign o f
serum r e a c t i o n .
A n a ly s is o f th e 150 c a s e s t r e a t e d .
(1) Age and Sex
Age Groups
0- 5
Male s
15
Fem ales
16
Total*
29
6-10
41
27
68
11—20
17
15
52
21—50
7
6
13
51—40
2
2
4
41—50
3
1
4
51—50
—
.
141
.
Of th e t o t a l , 83 (55.3 ^) were males and 67 ( 4 4 . 7 $
f e m a l e s , 97 ( 6 4 . 7 $ )
were
o f the p a t i e n t s were i n th e 0 - 1 0 age
group.
(2) Age o f P a t i e n t snd Tupe o f C. Di phtherias
r e c o v e r e d from
each Case ( e x p r e s s e d f i r s t a s a p e r c e n t a g e o f age groups
and then a s a p e r c e n t a g e of Type o f C- D i p h t h e r i a s ) *
Age Groups
Gra vis
0-5
6-10
11-20
21-30
31-40
41-50
51-60
T otal.
8(27.6)
19(27.9)
9(28.1)
7(53.8)
2 (50.0)
0-5
6 -1 0
1 1 -2 0
2 1 -3 0
3 1 -4 0
4 1 -5 0
51-60
T otal.
-
In term ed iu s
6(20.7)
18(26.5)
7(21.9)
4(30.8)
1(25.0)
2(50.0)
M itis
14(48.3)
2 8(41.2)
15(46.9)
2(15.4)
1(25.0)
2(50.0)
-
-
-
45
36
62
8(17.8)
19(42.2)
9 (20.0)
7(15.6)
2 (4.4)
6(15.8)
18(47.4)
7(18.4)
4(10.5)
1(2.6)
2(5.3)
38
1 4(22.6)
28(45.2)
15(24.2)
2(3.2)
1(1.6)
2(3.2)
62
-
45
Aberrant
m
-
N egative•
1(3.4)
3 (4.4)
1(3.1)
-
-
-
-
-
-
—
-
-
5
1(20.0)
3 (60.0)
1(20.0)
C
*
-
-
-
5
Of t h e 0 - 1 0 age g r o u p s , 2 7 . 8 ^ had g r a v i s i n f e c t i o n s and 2 3 . 6 $
interm edius.
There was a h ig h i n c i d e n c e o f the g r a v i s s t r a i n
i n th e 2 1 - 3 0 age group, where i t was 5 3 . 8 $ .
Of f o u r c a s e s
i n t h e 4 1 - 5 0 age group, two were o f the in t e r m e d i u s and two
were o f m i t i s s t r a i n .
The g r a v i s , in t e r m e d iu s and m i t i s s t r a i n s had t h e i r
h i g h e s t i n c i d e n c e i n the 6 - 1 0 sge group and t h e r e a f t e r f e l l
p r o g r e s s i v e l y in t h e s u c c e e d i n g age g r o u p s .
There was a
s l i g h t r i s e in t h e in t e r m e d i u s and m i t i s p e r c e n t a g e s in the
4 1 -50 sg e group.
No a berrant t y p e s were found and f i v e
.1 4 2 .
c l i n i c a l e a s e s o f d i p h t h e r i a had n e g a t i v e swabs.
(3)
Dosage o f Serum g i v e n in the V a r i o u s Age Groups
( e x p r e s s e d f i r s t as a P e r c e n t a g e o f the Age Groups and
then as a P e r c e n t a g e o f th e Number r e o e i v l n g the v a r i o u s
Doses) •
Age Group.
0-5
6-10
11-20
21-30
3 1 -4 0
41- 50
51-60
T otal•
8(27.6)
12(17.7)
9(28.1)
2(15.4)
2(50.0)
2(50.0)
35
Age Group.
0-5
6 -10
11 -20
21-30
3 1 -4 0
41-50
51-60
T otal.
Under 8 , 0 0 0
U n its•
12(41.4)
31(45.6)
16(50.0)
4(30.8)
-
40,000 Units
and Over.
9(31.0)
25(36.7)
7(21.9)
7 ( 5 3 .8 )
2(50.0)
2(50.0)
-
-
63
Under 8 , 0 0 0
U n its.
8(22.9)
12(34.3)
9(25.7)
2(5.7)
2(5.7)
2(5.7)
35
8,000-40,000
U n its•
52
8,000-40,000
U n its.
40,000 U nits
and Over.
1 2 (1 9 .1 )
3 1 ( 4 9 .2 )
1 6 ( 2 5 .4 )
4(6.3)
9(17.3)
25(48.1)
7 ( 1 3 .5 )
7(13.6)
2(3.8)
2(3.8)
52
-
65
Of t h e 150 c a s e s t r e a t e d , 63 (4 2.0$)
r e o e i v e d a dose of serum
v a r y in g from 8 ,0 0 0 t o 4 0 ,0 0 0 u n i t s .
Doses o f over 4 0 ,0 0 0
u n i t s came next in f r e q u e n c y , and the s m a l l e s t dose was
employed l e a s t of a l l .
In t h e 2 1 -30 age group 5 3 . 8 $ o f
the c a s e s r e o e i v e d over 4 0 , 0 0 0 u n i t s .
A l l t h r e e d o s e s had t h e i r h i g h e s t i n c i d e n c e of
a d m i n i s t r a t i o n in the 6 - 1 0 age group and t h e r e a f t e r the
i n c i d e n c e f e l l in the o l d e r age g r o u p s .
143.
(4)
Day o f D i s e a s e c o r r e l a t e d w i t h t h e type o f C•
Dip h th e rias
r e c o v e r e d from the o a s e s ( e x p r e s s e d
f i r s t l y a s a p e r c e n t a g e o f c a s e s per day, and
s e c o n d l y a s a p e r c e n t a g e o f the v a r i o u s t y p e s f o u n d ) .
Day o f
D isease
1
2
3
4
5
6
7
8
Total
1
2
3
4
5
6
7
8
T otal.
G ravis
I
I
Intsrnadius
M itls
Aberrant
2(22.2)
1(11.1)
17(34.6)
12(24.5)
12(22.6)
15(28.3)
3(16.7)
9(50.0)
3(37.5)
1 ( 1 2 .5 )
2(28.6)
1 ( 1 4 .3 )
2(66.7)
3(100.0)
45
_JJL
5(55.6)
19(38.8)
24(45.3)
5(27.8)
4 (50 .0)
4(57.1)
1(33.3)
62
..
-
1(2.2)
12(26.7)
15(33.3)
9(20.0)
3(6.7)
2(4.4)
5(8.1)
19(30.7)
24(38.7)
5(8.1)
4(6.4)
4(6.4)
1(1.6)
62~
-
-
3(6.7)
45
2(5.3)
17(44.7)
12(31.6)
3(7.9)
1(2.6)
1(2.6)
2(5.3)
56
Of the 150 c a s e s t r e a t e d , 129 ( 8 6 .0 $ )
-
N egative.
1(11.1)
1 ( 2 .1 )
2(3.8)
1(5.5)
___ 5
1 ( 2 0 . oy
1(20.0)
2(40.0)
1 ( 2 0 .0 )
5
had been g i v e n serum
b e f o r e the end of th e f o u r t h day o f t h e i r i l l n e s s .
Of the
G r a v i s i n f e c t i o n s o n l y 2 . 2 $ had r e c e i v e d a n t i t o x i n by the end
o f t h e f i r s t day.
By the end o f the f o u r t h day 8 2 . 2 $ had
been g i v e n serum t r e a t m e n t .
For i n t e r m e d i u s , m i t i s and
n e g a t i v e c a s e s the f i g u r e s were 5 . 3 $ , 8 . 1 $ , 20$ and 8 9 . 5 $ ,
8 5 . 6 $ , 100 $ r e s p e c t i v e l y .
t h i s group o f c a s e s .
No aberrant t y p e s were found in
(5)
Day o f D i s e a s e c o r r e l a t e d w i t h t h e Age o f the P a t i e n t
( e x p r e s s e d f i r s t a s a p e r c e n t a g e o f c a s e s per day and
secondly as a percentage
o f the number o f o a s e s i n each
fige group) .
Day o f
Disease*
1
2
3
4
5
6
7
8
Total
1
2
3
4
5
6
7
8
Total
0-5
6-10
11-20
. 21-30
31-40
41-5 0 5 1 -60
2(22.2) 2(22.2) 3(33.4)
9(18.6)2 2 (4 4 .9 )1 0 (2 0 .1 )
10(18.8)25(47.2)10(18.8)
5(27.8) 6(33.3) 4(22.2)
2 (2 5 .0 ) 3(37.5) 3(37.5)
1 (14.3) 4(57.1) 2(28.6)
3(100)
J 3 U ° 0 ) ___ 29
68
32
1(11.1)
1 ( 1 1 .1 )
6(1 2 .2 ) 1(2 .1 ) 1(2.1)
4(7.6)
3(5.7) 1(1.9)
2(11.1)
1(5.6)
-
2(6.9) 2(2.9)
3(9.4)
9 (3 1 .1 )2 2 (3 2 .4 ) 10(31.2)
10(34.5)25(36.8)10(31.2)
5(17.2) 6(8.8)
4(12.5)
2(6.9 ) 3(4.4)
3(9.4)
1(3.4) 4(5.9)
2(6.3)
3(4.4)
3(4.4)
29
68
32
1(7.7)
1(25.0)
6(46.1) 1(25.0) 1(25.0)
4(30.8) 3 (7 5 .0 )1 (2 5 .0 )
2(15.4)
1 ( 2 5 .0 )
13
1
13
“
_4__
-
4
Of th e 150 c a s e s , 97 were under the age o f e l e v e n , and or t h i s
9 7 , 81 had r e c e i v e d serum tre atm en t by t h e end o f the f o u r t h
day o f t h e i r i l l n e s s .
Three c a s e s in the 6-1 0 group did not
r e c e i v e serum t r e a t m e n t u n t i l the 8 t h . day of t h e i r i l l n e s s .
In a l l a g e s , w ith the e x c e p t i o n o f the 21-30 and 41-50
age g r o u p s , the p e r c e n t a g e number o f o a s e s s e n t to h o s p i t a l
r o s e t o a maximum on t h e t h i r d day o f i l l n e s s and t h e r e a f t e r
fell.
In the 2 1 - 3 0 group th e maximum was r eached by the
second day, and in the 41-5 0 group the p e r c e n t a g e was the
same on the f i r s t ,
se co n d, t h i r d and f o u r t h da y s .
• 145 4
Day o f
Dl se a so
1
2
3
4
5
Under 8 , 0 0 0
U n its *
9(100.0)
15(30.6)
11(20.7)
8,000-40,000
U n its.
40,000 Units
and Over.
24(49.0)
24(45.3)
9(50.0)
3(37.5)
10(20.4)
18(34.0)
9(50.0)
5(62.5)
7(100.0)
6
7
3(100.0)
8
Total
1
2
3
4
5
6
7
35
9(25.7)
15(42.9)
11(31.4)
63
24(38.1)
24(38.1)
9(14.3)
3(4.75)
10(19.3)
1 8 ( 3 4 .6 )
9(17.2)
5(9.7)
7(13.4)
3(4.75)
8
Total
3(100.0)
52
35
63
5(5.8)
52
D e lay in d i a g n o s i n g the d i s e a s e l e d to l a r g e r d o s es o f serum
hav in g t o be g i v e n .
The m a j o r i t y o f p a t i e n t s who r e c e i v e d l e s s than 8 , 0 0 0
u n i t s o f serum d i d so on the second day of d i s e a s e .
Of the
p a t i e n t s who r e c e i v e d 8 ,0 0 0 t o 4 0 , 0 0 0 u n i t s or more than 4 0 , 0 0 0
u n i t s , t h e m a j o r i t y in the f i r s t s e r i e s , were g i v e n serum on
the second day, and in th e l a t t e r group, on the t h i r d day.
T h e r e a f t e r the numbers d e c r e a s e d .
• 146#
(7)
Type of C. Diphtherias
r e c o v e r e d from t h e i n d i v i d u a l
c a s e s c o r r e l a t e d w i t h the dose o f serum g i v e n
( e x p r e s s e d as a p e r ce n ta g e o f Type o f C. D i p h t h e r i a © ) .
T y p e . o f C.
Diphtheriae.
G ra v is
In te r m e d iu s
M itis
Aberrant
N e g a t iv e
T otal.
Under 8 , 0 0 0
U n its.
8,000-40,000
U n its.
4 0 ,0 0 0 U n i t s
and Over.
4(8.9)
5(13.2)
25(40.3)
1(20.0)
35
17(37.8)
15(39.6)
28(45.2)
24(63.3)
18(47.2)
9(14.5)
3j_60.0)
65
1 ( 2 0 .0 )
52
In the g r a v i s i n f e c t i o n s most o f the p a t i e n t s ( 5 3 . 3 $ r e q u i r e d
over 4 0 , 0 0 0 u n i t s o f serum.
37.8/o and 8 . 9 $ r e q u i r e d 8 , 0 0 0 -
4 0 , 0 0 0 and l e s s than 8 , 0 0 0 u n i t s r e s p e c t i v e l y .
With the
i n t e r m e d i u s i n f e c t i o n s s i m i l a r f i g u r e s were o b t a i n e d .
In the
m i t i s and n e g a t i v e c a s e s the h i g h e s t p e r ce n tag e o f t h e s e
r e q u i r e d between 8 , 0 0 0 and 4 0 , 0 0 0 u n i t s of serum.
(8)
Type o f C• Diphtheriae
r ec o v e r e d from the d i f f e r e n t
C l i n i c a l v a r i e t i e s of diphtheria (expressed as a
percentage of c l i n i c a l ty p e s.
C ervical a d e n itis i s
e x p r e s s e d a s a p e r c e n t a g e of c a s e s w ith each s t r a i n
o f C. D i p h th e ria ) •
a-47.
C lin ical
"Type.
Gratis
In t e r m e d iu s
M itis
A b er ra n t
N e g a tiv e
)Fauc i a l ;
(-a) M ild
(■b) Moderate
(c) S ev ere
(d) Haemorr-hagic
Nasal
.Laryngeal
P’au c.ial and
.Ba.aal
C ervical
A d en itis
TToiial.
8(30.8)
14(53.8)
4(15.4)
5 2 ( 71.1)
45
2 0 ( 5 2 .6 )
58
2 5 ( 40.3)
62
C* d i p h th er ia e
g r a v i s and i n t e r m e d i u s were a s s o c i a t e d w i t h
8(23.5)
9(20.5)
10(40.0)
6(17.6)
7(15.9)
4(16.0)
8(42.1) 7(36.8)
2(100.0)
17(50*0)
.27(61*4)
10(40.0)
-
3(8.9)
.1(2.2)
l(-4.0)
4(21.1)
-
j5
the more se v er e c l i n i c a l t y p e s o f d i p h t h e r i a .
The
i n t e r m e d i u s s t r a i n was found most f r e q u e n t l y .in f a u c i a l - n a s a l
on;ses«
I h e p e r c e n t a g e i n c i d e n c e of o e r v i c a l a d e n i t i s was
h i g h e s t w i t h g r a v i s i n f e c t i o n s , .lowest w it h m i t i s and
the i n t e r m e d i u s o ccupied the i n t e r m e d i a t e p o s i t i o n .
.Baath -and G omp.11ca ti on Kates.
(a)
Dype o f C* Diphtheriae r ec o v er ed c o r r e l a t e d w i t h the v a r i o u s
c o m p l i c a t i o n s observed end the death r a t e ( e x p r e s s e d a s a
■percentage o f the number o f the v a r i o u s t y p e s found) .
C o m p l i c a t i o n . Gra vis Interm ed iu s
Albuminuria
6(13.3)
4(10.5)
Cardiac P a r e , s i s l 0 ( 2 2 . 2 )
6(15.8)
P alatal
,,
9(20.0)
7(16.4)
Ocular
,,
,
Beath Rate
6(13.3)
4 ( 1 0 .5 )
"Tw.o n e g a t i v e c a s e s had albuminuria*
-and one d i e d .
before.
M itis
3(4.8)
1(1.6)
2(3.2)
1(1.6)
A berrant
—
~
-
N egative.
2(40*0)
1(20.0)
"■
1(20.0)
One had p a l a t a l p a r e s i s
These two n e g a t i v e c a s e s have been mentioned
The case which died., died through an a c c i d e n t in
nursing - a probationer giving the child a sweet which passed
i n t o t h e r e s p i r a t o r y p a s s a g e s , and d e a th was due to
asphyxia.
G rav is had the next h i g h e s t i n c i d e n c e o f
c o m p l i c a t i o n s , in t e r m e d i u s f o l l o w i n g g r a v i s , and m i t i s
coming l a s t .
(b)
Death and Com p lica tio n Rates c o r r e l a t e d w ith the age o f the
p a t i e n t ( e x p r e s s e d as p e r c e n t a g e s o f the age g r o u p ) •
Age Group.
Albuminurici
0-5
6-10
11-20
21-30
31-40
41-50
51-60
P alatal
P aresis
Cardiac
Paresis
Ocular
Paresis
-
2( 6 . 9 ) 4 ( 1 4 .5 )
9 ( 1 3 . 2 ) 5( 7.3)
4(12.6) 5(15.6)
2 (1 5 .4 ) 2(15.4)
2 ( 5 0 . 0 ) 1 ( 2 5 .0 )
-
-
-
-
-
-
3
6
2
4
(1 0 .4 )
( 8 .8 )
( 6.3 )
(30 .8 )
-
-
19
15
Albu minuria,
4(14.5)
3( 4.4)
4(12.6)
K 7.7)
-
-
T otal•
Death R a te .
17
12
p a l a t a l p a r e s i s and ca rd ia c p a r e s i s a l l tended
t o become more f r e q u e n t w ith a g e .
Albuminuria and c a r d ia c
p a r e s i s had a hig h i n c i d e n c e in the 0 - 5 age group, f e l l in
the 6 - 1 0 group and then r o se B g a i n .
The death r a t e was
h i g h e s t in the 0 - 5 and 11-20 age gr o u p s .
Death and Com p lica tio n Rates c o r r e l a t e d with Day o f D i s e a s e
(c)
( e x p r e s s e d as p e r c e n t a g e s o f Dey o f D is e a s e ) •
Day o f
D isease •
1
2
3
4
5
6
7
8
Total.
Albuminuria
P alatal
P aresis
Cardiac
P aresis
Ocular
P aresis
Death R a t e .
2
4
5
4
( 4.1)
( 7.4)
(2 7 .8 )
(5 0 .0 )
4( 8.2)
5( 9.4)
6(33.3)
3(37.5)
1 ( 1 4 .3 )
_
-
15
19
3( 6.1 )
3( 5.7)
4 ( 2 2 .2 )
3(37.5)
2(28.6)
1(33.3)
1(33.3)
17
-
-
1( 2.0)
3( 5.7)
3(16.9)
2(25.0)
1(14.3)
1 ( 3 3 .3 )
1 ( 3 5 .3 )
12
No c o m p l i c a t i o n s occu rred when the serum was g iven on the f i r s t
.1 4 9 .
day o f i l l n e s s .
The i n c i d e n c e o f a l l c o m p l i c a t i o n s
i n c r e a s e d up t o t h e end of the f i f t h da y .
P alatal paresis
then f e l l in the s i x t h dsy and no f u r t h e r c a s e s were
rec o rd ed i n the 7 t h . and 8 t h . d a y s .
Cardiso p a r e s i s and
th e death r a t e f e l l in the s i x t h day 8nd r o se a g a in in the
7 t h . and 8 t h . day.
Death and C o m p lic a tio n Rat es c o r r e l a t e d w i t h the c l i n i o a l
Type o f D i p h t h e r i a ( e x p r e s s e d as p e r c e n t a g e s o f c l i n i c a l types) •
C lin ical
Type.
P alatal
Cardiao
Albuminuria P a r e s i s
P aresis
Faucial:
(a) M i l d .
(b) Moderate
(o) Seve re
(d) Haemorrhagio.
N as al
Larynge al
F a u c i a l and
Nasal.
T otal.
Ocular
Paresis
Death R ate .
_____________
1( 2 .9 )
2( 4.5)
2( 8.0)
2( 5.9)
2( 4.5 )
2 ( 8 . 0)
1( 4.0 )
1( 4.0)
5(26.3)
8(42.1)
9(47.4)
7(36.8)
5 ( 19.2)
15_
5(19.2)
19^
7(26.9)
17^
4(15.4)
12
As t h e c l i n i c a l s e v e r i t y o f the c a s e i n c r e a s e d so d id the
incidence of com p lica tio n s.
F a u c i a l - n a s a l c a s e s occupied
the i n t e r m e d i a t e p l a c e between se vere and haemorrhagio f a u c i a l
d i p h t h e r i a when c o n s i d e r e d i n terms o f c o m p l i c a t i o n and
d ea th r a t e s .
Dosage o f Serum g i v e n .
The number o f c a s e s which r e c e i v e d a
dose o f serum over 3 2 ,0 0 0 u n i t s was 74, al m ost 50$ o f the
oases.
24 p a t i e n t s had two d o s e s o f serum, f o u r had t h r e e
d o s e s , but none had a f o u r t h i n j e c t i o n o f serum.
The
maximum dose g i v e n was 1 6 8 ,0 0 0 u n i t s , the minimum 4 , 0 0 0 ,
.1 5 0 ..
and t h e a v e r a g e , 4 2 , 5 0 0 u n i t s .
Rate o f Disappe arance o f Membrane/ or D i s c h a r g e / or
C ervical a d e n it is .
The maximum time taken f o r the merabrane/or d i s c h a r g e s /
o f g l a n d s t o c l e a r up was 156 h o u r s .
This c a s e was a boy o f
14 y e a r s who was g i v e n serum on the second day o f i l l n e s s .
membrane was on both t o n s i l s , s o f t and hard p a l a t e .
organism r e c o v e r e d was o f t h e g r a v i s s t r a i n .
The
The
The minimum time
was e i g h t hours; the a v e r a g e , f o r t y - s e v e n ho u rs .
Rate o f Disappearance o f Toxaemia.
Toxaemia was d i v i d e d i n t o f i v e s t a g e s :
(1) No toxaemia
(2) M il d , (3) Moderate, (4) S e v e r e , and (5) Comatose.
Mild Toxaemia - p u l s e normal in rhythm but s l i g h t l y q u i c k e r
than normal - up to 90 b e a t s per m in u te .
nor mal.
R espiration rate
Temperature s l i g h t l y e l e v a t e d (99° F.) , but
p a t i e n t a b l e to answer v e r b a l q u e s t i o n s .
Moderate Toxaemia -
p u l s e - s o f t and r e g u l a r i n rhythm, but
f a s t (120 b e a t s per minute) .
t o 26 per m inu te .
R e s p i r a t i o n r a t e quickened up
P a tie n t s l i g h t l y m entally confused.
Temperature e l e v a t e d ( 1 0 0 - 1 0 1 ° F . )
P a t i e n t may or may not have
been s i c k .
Severe Toxaemia rhythm.
p u l s e f a s t or sl o w , s o f t , i r r e g u l a r in
R e s p i r a t i o n r a t e over 26 per minute and p a t i e n t
s l i g h t l y cyanosed.
Skin c o l d , temperature normal or
s l i g h t l y subnormal.
Frequent s i c k n e s s , tongue dry and f u r r e d .
P a tie n t m entally confused.
•151.
Comatose Toxaemia -
p a t i e n t v e ry drowsy or u n c o n s c i o u s .
P u l s e f e e b l e , i r r e g u l a r , f a s t or s l o w .
and g a s p i n g .
R esp irations f a s t
Skin c o l d and bathed in p e r s p i r a t i o n .
Temperature subnormal, e y e s sunken and d r y .
sick n ess.
Frequent
Tongue f u r r e d on d o r s a l and v e n t r a l s u r f a c e s .
Twenty -sev en p a t i e n t s had s e v e r e to x a em ia , s i x t y moderate,
f i f t y - o n e mild and tw elv e showed no t o x i c e f f e c t s .
maximum time was taken f o r the toxaemia t o pa ss
160 h o u r s .
T h is oase was a
boy aged
The
o f f was
8 y e a r s , who,
a lth ough
t h e membrane and d i s c h a r g e s had o l e a r e d up in 48 ho u rs ,
s t i l l remained t o x i c .
gravis s t r a in .
The
organism
r e c o v e r e d was
of the
The minimum
time was
12 hours , the
average -
40 h o u r s .
2
In t r a m u s c u l a r and I n t r a v e n o u s I n j e c t i o n .
250 o a s e s were t r e a t e d .
The i n t r a v e n o u s serum was g i v e n
a s b e f o r e , the in t r a m u sc u la r serum was i n j e o t e d i n t o the
v a s t u s e x t e r n u s muscle o f the t h i g h .
The same o b s e r v a t i o n s
were made upon each c a s e .
(1)
Age and S e x .
Age Groups.
0-5
6-10
11-20
2 1 -3 0
31-40
4 1 -5 0
51-60
6
1
7
BBSS
**
The m a j o r i t y o f the 250 c a s e s (224) were under the age
Ma l e s
Ferns l e s
T otal.
of 20.
fem ales.
23
24
47
72
56
128
26
23
49
BS-
8
5_
13
4
2
6
Of the 250 c a s e s , 139 were males and 111 were
•152.
(2)
Age o f P a t i e n t s c o r r e l a t e d w i t h t h e typ e o f C•
D i p h t h e r i a s r e c o v e r e d from each c a s e ( e x p r e s s e d f i r s t a s
a p e r c e n t a g e of age groups and t h e n as a p e r c e n t a g e o f the
t y p e o f C. D i p h t h e r i a s )
Age Group Gr a v i s
0- 5
6-10
1 1 -2 0
21-30
3 1 -4 0
41- 50
51-60
T otal.
17(36.2)
36(28.1)
12(24.5)
4(30.8)
1(16.6)
I n ter m ed iu s
M itis
15(31.9)
30(23.4)
10(20.4)
4(30.8)
4(66.6)
14(29.8)
68(46.8)
16(32.6)
5(38.4)
1 ( 1 6 .6 6 )
7(100.0)
103
-
-
-
-
70
63
0-5
6-10
11-20
21-30
31-40
41-50
51-60
17(24.3)
36(51.4)
12(17.2)
4(5.7)
1(1.4)
15(23.8)
30(47.6)
10(15.8)
4(6.4)
4(6.4)
Total
70
-
-
-
63
14(13.6)
60(58.3)
16(15.5)
5(4.8)
1(0.9)
7(6.9)
-
Aberrant
-
N egative•
1(2.1)
2(1.7)
11(22.5)
-
-
-
-
-
-
-
-
-
14
-
1(7.1)
2(14.3)
1 1 ( 7 8 .6 )
-
-
-
-
-
-
-
-
103
14
Of the 0 - 1 0 age grou p, 3 2 . 2 $ s u f f e r e d from g r a v i s and 2 7 . 6 $
from in t e r m e d i u s i n f e c t i o n s .
In the 3 1-4 0 age group t h e r e
was a h i g h i n c i d e n c e - 6 6 . 7 $ o f in t e r m e d i u s c a s e s .
G ra v is i n f e c t i o n s had the h i g h e s t i n c i d e n c e in th e 0 - 5
grou p,
i n t e r m e d i u s cams n e x t , f o l l o w e d by m i t i s and n e g a t i v e
c u l t u r e s , which occu rred in the l o w e s t p e r c e n t a g e .
Prom the
age o f 10 onwards t h e r e was a sharp f s l l in t h e i n o i d e n o e of
g r a v i s s t r a i n s u n t i l a f t e r the age o f 40 none were r e c o r d e d .
With in t e r m e d i u s and m i t i s the numbers a l s o f e l l a f t e r the age
o f 1 0 , but did not f a l l so r a p i d l y a s the g r a v i s s t r a i n s .
In
the n e g a t i v e s e r i e s , no f u r t h e r c a s e s were reoorded a f t e r the
♦1 5 3 .
age o f t w e n t y .
The h i g h e s t i n c i d e n c e o f g r a v i s ,
i n t e r m e d i u s and m i t i s c a s e s oc curred in the 6 - 1 0 age gro up,
bu t o f the n e g a t i v e c a s e s the h i g h e s t i n c i d e n c e occu rred in
t h e 11-2 0 age group.
(3)
Dosage o f Serum g i v e n c o r r e l a t e d w ith age groups
( e x p r e s s e d f i r s t a s a p e r c e n t a g e o f the age groups then a s
p e r c e n t a g e s o f th e number r e c e i v i n g the d e f i n e d d o s e s ) •
Age Group.
Under 8 ,0 0 0
U n its.
8,000-40,000
U n its.
40,000 Units
and Over.
0-5
6 -1 0
11-20
21-30
31-40
4 1 -5 0
51 -60
Total.
6(12.7)
20(15.6)
10(20.4)
4(30.8)
1(16.66)
1(14.3)
19(40.4)
57(44.6)
26(53.1)
6(46.1)
4(66.66)
6(85.7)
118
22(46.9)
51(39.8)
13(26.5)
3(23.1)
1(16.66)
0-5
6 -1 0
11-20
21-30
31-40
41-5 0
51-60
T otal.
-
42
6(14.3)
20(47.6)
10(23.8)
4(9.5)
1(2.4)
1(2.4)
-
42
19(16.1)
57(48.3)
26(22.0)
6(5.1)
4(3.4)
6(5.1)
______ 118
Of the 250 c a s e s t r e a t e d , 118 (4 7 .2 $ )
—
90
22(24.4)
5 1 ( 5 6 .7 )
1 3 ( 1 4 .4 )
3(3.3)
1(1.2)
-
—
90
r e c e i v e d an I n j e c t i o n
o f between 8 , 0 0 0 end 4 0 ,0 0 0 u n i t s of serum.
Doses o f 4 0 ,0 0 0
u n i t s and ove r were used more than t w i c e a s o f t e n as d o s e s
o f under 8 ,0 0 0 u n i t s ( 3 6 $ t o 1 6 . 8 $ ) .
With th e 8 , 0 0 0 -
4 0 , 0 0 0 u n i t d o s e , the p e r c e n t a g e f r e q u en cy t h a t t h i s amount
was g i v e n , r o s e p r o g r e s s i v e l y w i t h the age g r o u p s , w it h t h e
e x c e p t i o n o f the 2 1 - 3 0 age group.
The p e r c e n t a g e of c a s e s i n the 0 - 5 sge group which
<154.
r e c e i v e d d o s e s o f 4 0 , 0 0 0 u n i t s and ove r was h i g h (46*9) •
T h is number r e p r e s e n t e d 2 4 . 4 $ o f a l l d o s e s o f serum o f
4 0 , 0 0 0 u n i t s and over g i v e n in t h i s group o f o a s e s *
Of
the groups o f d o s e s , a l l had t h e i r h i g h e s t i n c i d e n c e in
th e 6 - 1 0 age group and f e l l t h e r e a f t e r *
(4)
Day o f D i s e a s e c o r r e l a t e d w ith the Type o f C. Diphtherias
recovered
from the c a s e ( e x p r e s s e d f i r s t a s a p e r ce n ta ge o f
the c a s e s o c c u r r in g per day and s e c o n d l y as a p e r ce n ta g e o f the
v a r i o u s t y p e s o f C* D i p h t h e r i a s ) •
Day o f
D isease.
Gravis
1
2
3
4
5
6
7
8
T otal.
1(8.3)
19(24.1)
21(29.2)
16(34.8)
6(31.6)
4(22.2)
1
2
3
4
5
6
7
8
T ot8l.
1(1.4)
19(27.1)
2 1 ( 3 0 .0 )
16(22.9)
6(8.6)
4(5.7)
3(4.3)
70
Interm ediu s
-
3(100.0)
70
M itis
Aberrant
3(25.0)
7(58.4)
28(35.4)
24(30.4)
12(16.7)
39(54.1)
14(30.5)
11(23.9)
4(21.0)
9(47.4)
10(55.6)
4(22.2)
1(100.0)
63
103
3(4.8)
24(38.0)
1 2 ( 1 9 .0 )
11(17.5)
9(14.3)
4(6.4)
-
7(6.8)
28(27.2)
3 9 ( 3 7 .8 )
14(13.6)
4(3.9)
10(9.7)
1(1.0)
63
103
Of the 250 i c a s e s , 209 ( 8 3 .6 $ )
-
-
Negative.
1(8.3)
8(10.1)
5(10.8)
-
-
-
-
14
-
—
1(7.1)
8(57.1)
5(35.8)
14
had r e o e i v e d serum trea tm en t
w i t h i n f o u r days from the o n s et o f t h e i r i l l n e s s .
The
i n c i d e n c e o f the g r a v i s s t r a i n was low on the f i r s t day and
r o s e from then onwards u n t i l the f i f t h day , when i t began
to f a l l .
The t h r e e c a s e s which occurred on the 8 t h . day
. 135.
were a l l g r a v i s , g i v i n g a 10 0 $ i n c i d e n c e .
The i n t e r m e d i u s
c a s e s had a h ig h i n c i d e n c e on the 1 s t . and 2nd. days; , i t
th e n f e l l on the t h i r d day, r o s e on the 4 t h . and 5 t h . and
f e l l a g a i n on the 6 t h . day.
No f u r t h e r i n t e r m e d i u s c a s e s
were obser ved a f t e r the 6 t h . day.
M i t i s c a s e s had a high
i n c i d e n c e on the 1 s t . day which f e l l on the 2nd. r o se on
the 3 r d . , f e l l on the 4 t h . and 5 t h . , and rose ag ain on the
6 t h . and 7 t h .
No c a s e s were observed in t h e 8 t h . day.
With t h e n e g a t i v e c a s e s th e i n c i d e n c e was 8 . 3 $ on the 1 s t .
d ay.
T h is r o s e t o 1 0 . 1 $ on the 2 n d . , f e l l t o zer o on the
3 r d . , r o s e t o 1 0 . 8 $ on th e 4 t h . day, and t h e r e a f t e r no c a s e s
were o b s e r v e d .
Of the v a r i o u s t y p e s o f C. Diphtherias , 1 . 4 $ of
g r a v i s , 4 . 8 $ o f i n t e r m e d i u s , 6 . 8 $ o f m i t i s and 7 . 1 $ of
n e g a t i v e e a s e s had r e c e i v e d serum w i t h i n the 1 s t . day o f
illn ess.
By the end o f t h e 4 t h . day th e f i g u r e s were 8 1 . 4 $
g r a v i s , 7 9 . 3 $ i n t e r m e d i u s , 8 5 . 4 $ m i t i s and 1 0 0 $ n e g a t i v e
oases..
-'• 3. 5 6 *
(5)
Day o f D i s e a s e c o r r e l a t e d w i t h t h e a g e group ( e x p r e s s e d
a s a p e r c e n t a g e o f c a s e s per day and s e c o n d l y a s a
p e r c e n t a g e o f t h e c a s e s i n e a ch age g r o u p ) •
Day o f
D isea se. 0-5
6-10
11-2 0
1
2
3
4
5
6
7
8
T otal.
1(8.3)
2(16.7) 4(33.3)
12(15.2) 48(60.7) 16(20.3)
1 6 (2 2 .2 )2 7 (3 7 .5 ) 20(27.8)
1 2 (2 6 .1 )2 6 (5 6 .5 ) 3(6.5)
4 (2 1 .0 )1 1 (5 7 .9 ) 3(15.8)
2 ( 1 1 .0 )1 0 (5 5 .7 ) 3(16.7)
—
1 (10 0 .0
3(100.0;
47
128
49
1
2
3
4
5
6
7
8
T otal•
1(2.1)
2(1.5)
12(25.5) 48(37.6)
16 (34 .1) 27 ( 2 1 .1 )
12(25.5)26(20.3)
4(8.5) 11(8.6)
2(4 .3 ) 10(7.8)
1(0.8)
3(2.3)
47
128
4(8.2)
16(32.7)
20 ( 40.8)
3(6.1)
3(6.1)
3(6.1)
49
2 1 -3 0
31-40
41-50
3(25.0)
2(2.5)
3(4.2)
3(6.5)
1(5.3)
1(5.6)
-
2(16.7)
1(1.3)
2(2.8)
1(2.2)
•
4(5.5)
1(2.2)
13
3(23.1)
2(15.3)
3 ( 2 3 .1 )
3(23.1)
1(7.7)
1(7.7)
13
—
-
6
51-60
-
2(11.0)
—
—
-
—
7
2(33.3)
1(16.7)
2(33.3) 4(57.1)
1 ( 1 6 .7 ) 1 ( 1 4 . 3 )
2(28.6)
6
-
-
-
7
Of the 250 o a s e s , 175 (70$) were aged 10 or under and o f t h i s
number 144 (8 2 .3 $ )
had r e c e i v e d serum b e f o r e the end o f the
4 t h . day o f i l l n e s s .
Pour p a t i e n t s who d id not c ome under
t r e a t m e n t u n t i l the 7 t h . and 8th • day o f i l l n e s s were i n the
6 - 1 0 age g r o u p .
Of t h e age groups most c a s e s came under t r e a t m e n t on
t h e 3 r d . day o f i l l n e s s w i t h th e e x c e p t i o n o f t h e 6 - 1 0 age
g r o u p , when i t was on the 2nd. da y, and f o r t h e 2 1 - 3 0 age
group when i t was t h e 3 r d . and 4 t h . d a y s .
.1 5 7 .
(6)
Day o f D i s e a s e c o r r e l a t e d w i t h the dose o f serum g i v e n
( e x p r e s s e d f i r s t a s a p e r c e n t a g e o f c a s e s per day and
s e c o n d l y s s a p e r c e n t a g e o f c a s e s r e c e i v i n g the d e f i n e d
d o ses) •
Day o f
D isease.
1
2
3
4
5
6
7
Under 8 ,0 0 0
U n its.
8,000-40,000
U n its.
8 (6 6 . 66)
16(20.3)
1 7 ( 2 3 .6 )
1 ( 2 . 2)
2(16.66)
46(58.2)
30(41.7)
24(52.2)
8(42.1)
8(44.4)
2 (1 6 .6 6 )
1 7 ( 2 1 .5 )
25(34.7)
21(45.6)
1 1 (5 7 .9 )
1 0(5 5.6)
1 ( 100.0 )
3(100.0)
42
118
90
8(19.0)
16(38.1)
17(40.5)
1(2.4)
2(1.7)
46(38.9)
30(25.4)
24(20.4)
2 (2 . 2)
17(18.9)
25(27.8)
21(23.3)
1 1 ( 1 2 .3 )
10 ( 11 . 1)
8
T otal.
1
2
3
4
5
6
7
8 (6 . 8)
8 ( 6 . 8)
1( 1. 1)
8
T otal.
40,000 U nits
and Over.
42
118
3(3.3)
90
The l o n g e r t h e p a t i e n t was i l l b e f o r e b e i n g t r e a t e d , the
l a r g e r was the amount o f serum which was r e q u i r e d .
The h i g h e s t number o f p a t i e n t s who r e c e i v e d l e s s than
8 , 0 0 0 u n i t s o f serum d i d so on the 3 r d. day o f i l l n e s s .
In
th e 8 , 0 0 0 - 4 0 , 0 0 0 u n i t s group, t h e h i g h e s t number o f p a t i e n t s
were g i v e n serum on the 2nd. day o f i l l n e s s and in t h e 4 0 ,0 0 0
u n i t s or o v e r , i t was on the 3 r d . day.
.,159 •
(7) Type o f C. D ip h t h e r i® r e c o v e r e d from th e i n d i v i d u a l
c a s e s c o r r e l a t e d w i t h t h e dose o f serum g i v e n ( e x p r e s s e d as
a p e r c e n t a g e o f Type o f C. D i p h t h e r i a s ) .
Type o f C.
Diphtherias.
Under 8 , 0 0 0
U n its.
G r a v is
In t e r m e d iu s
M itis
Aberrant
Negative
T otal.
6(8.6)
5(7.9)
27(26.2)
__ 4 ( 2 8 . 6 )
42
8,000-40,000
U n its.
4 0 ,0 0 0 U n i t s
and Over.
26(37.1)
31(49.2)
51(49.5)
10(71.1)
118
38(54.3)
27(42.9)
25(24.3)
I n t h e g r a v i s i n f e c t i o n s most c a s e s ( 5 4 . 3 ®
___ 90
r e q u ir e d over
4 0 , 0 0 0 u n i t s o f serum and 3 7 . 1 $ and 8 . 6 $ r e c e i v e d d o s es o f
8 , 0 0 0 - 4 0 , 0 0 0 u n i t s and l e s s than 8 ,0 0 0 u n i t s r e s p e c t i v e l y .
With i n t e r m e d i u s , m i t i s and n e g a t i v e i n f e o t i o n s the h i g h e s t
number o f p a t i e n t s r e d e i v e d between 8 ,0 0 0 and 4 0 , 0 0 0 u n i t s
o f serum.
(8) Type o f C. Diph theria s r e c o v e r e d from the d i f f e r e n t
c l i n i c a l t y p e s o f d i p h t h e r i a ( e x p r e s s e d as a p e r c e n t a g e o f the
c li n i c a l types.
C ervical a d e n i t i s i s expressed as a
p e r c e n t a g e o f the number o f c a s e s with each s t r a i n o f o .
d i p h t h e r ia s ) .
• 159*
C lin ical
..T yp e*
»
P auoial:
(a) Mild
(b) Moderate
(c) S ev ere
(d) Haemorrtaagie
Nasal
Laryngeal
F a u c i a l and
Nasal
C ervical
A d en itis
T otal.
Gravis *
In t e r m e d iu s
M itis
7(14.9)
23(22.5)
17(31.5)
5(10.6)
28(27.4)
18(33.3)
26(55.3)
50(49.1)
16(29.6)
7(53.8)
1(16.66)
-
4(30.8)
1(16.66)
2(15.4)
4(66.66)
-
15(55.6)
7(25.9)
6 2 ( 88.6)
70
40(63.5)
65
Aberrant
N e g a t iv e *
-
9(19.2)
1(1*0)
3(5.6)
1(100.0)
5(18.5)
_28(27.2)
103
-
6(42.9)
14
C. D i p h t h e r i a s g r a v i s and in te r m e d i u s were a s s o c i a t e d w i t h the
more s e v e r e c l i n i c a l c a s e s o f d i p h t h e r i a .
M i t i s and n e g a t i v e
c u l t u r e s were found m o st ly in the m ild er c l i n i c a l o a s e s .
C ervical a d e n itis
most o f t e n in
occurred w i t h a l l s t r a i n s o f d i p h t h e r i a , but
the c a s e s from which a g r a v i s s t r a i n was i s o l a t e d .
Death and C o m p lic a t io n R a t e s .
(a)
Type o f C. D iph theriae r e c o v e r e d from the o a s e s c o r r e l a t e d
w i t h the v a r i o u s c o m p l i c a t i o n s observed ( e x p r e s s e d a s a
percentage of
the number of th e v a r i o u s t y p e s f o u n d ) .
C o m p lic a tio n •G ravis
Albuminuria
Cardiac P a r e s i s
P alatal
,,
Ocular
,,
Death Rate
In ter m ed iu s
2(2.9)
2(2.9)
2(2.9)
1(1.6)
2(3.2)
3(3.2)
2(2.9)
1(1.6)
M itis
Aberrant
N egative•
1(1.0)
1(1.0)
-
With the e x c e p t i o n o f o c u la r p a r e s i s , a l l the c o m p l i c a t i o n s
mentioned above occu rred in e q u al fre q u en cy with the g r a v i s
strain.
With the i n t e r m e d i u s c a s e s , the ca rd ia c p a r e s i s and
p a l a t a l p a r e s i s r a t e were s l i g h t l y h i g h e r than t h a t f o r
g r a v i s i n f e c t i o n s , but the i n c i d e n c e o f albuminuria and the
.160.
d eath r a t e was l o w e r .
M i t i s i n f e c t i o n s were very m i ld ,
and i n t h e n e g a t i v e c a s e s no c o m p l i c a t i o n s were o b s e r v e d .
One o f t h e d e a t h s , w i t h g r a v i s i n f e c t i o n s , was due t o the
p a t i e n t ’ s d e v e l o p i n g an a c u t e m a s t o i d i t i s which was o p e r a te d
on but t h e p a t i e n t d e v e lo p ed s e p t i c m e n i n g i t i s and d i e d .
(b) Death and C o m p licatio n Rate s c o r r e l a t e d with the age of
the p a t i e n t ( e x p r e s s e d as p e r c e n t a g e s of the age g r o u p s ) .
Ige Group. Albuminuria
P alatal
P aresis
Cardiac
P aresis
1(2.1)
2(1.5)
2(4.1)
-
1(2.1)
2(1.5)
1(2.0)
-
1(2.1)
2(1.5)
1(2.0)
-
0-5
6-10
1 1 -20
21-30
3 1 -4 0
41-50
5 1 -60
T otal.
-
4
-
Ooular
P aresis
2(4.2)
1(0.7)
-
-
-
-
____ "
5
Death
Rate.
4
3
C o m p li c a t io n s were more f r e q u e n t in the 0 - 5 and the 11 -20
age g r o u p s .
The death r a t e was h i g h e s t in the 0 - 5 age group*
(c)
Death and C o m p lic a t io n Rates c o r r e l a t e d w i t h day o f
d i s e a s e ( e x p r e s s e d a s p e r c e n t a g e s o f day o f d i s e a s e ) •
Day o f
Disease
1
2
3
4
5
6
Albuminuria
1(1.3)
1(2.2)
2(10.5)
7
T otal.
4
P alatal
P aresis
Cardiac
Paresis
1(1.4)
2(4.4)
2(10.5)
1(1.4)
2(4.4)
1(5.3)
-
”
_
-
5
4
Ocular
P aresis
-
Death
Rate.
1(1.4)
x
2(10.5)
_3
No c o m p l i c a t i o n s were observed when the p a t i e n t was g i v e n
*X61 *
serum
013
th e f i r s t day o f i l l n e s s , and o n l y one e a s e which
was g i v e n serum on the second day o f i l l n e s s d e v e lo p ed a
com plication (album inuria)•
From th e t h i r d day o f i l l n e s s
c o m p l i c a t i o n s were more f r e q u e n t and rea ched t h e i r h i g h e s t
i n c i d e n c e on the 5 t h . day, a f t e r t h i s d s y no c o m p l i c a t i o n s
were r e c o r d e d .
(d)
Death and C om p licatio n Rates c o r r e l a t e d w i t h the
c l i n i c a l types of diphtheria (expressed as percentages of
c l i n i c a l ty p e s) .
C linical
Type.
Albuminuria
_____________
P alatal
P aresis
Cardiac
Paresis
Ocular
Paresis
Death
Rate.
F eudal:
(s) Mild
-
(b) Moderate
(c) Severe
1(1*8)
(d) Haemorrhsgic
2(15.4)
Nasal
Laryngeal
F a u c i a l and
N asa l
1(5.7)
4
-
1(1*8)
-
2(15.4)
2(15.4)
-
2(15.4)
2 ( 7 .4)
4
-
1(5.7)
3
2(7.4)
5
The more s e v e r e t h e c l i n i c a l t y p e , th e h i g h e r was the
incidence of co m p lica tio n s.
F a u c i a l - n a s a l c a s e s occu pied
an i n t e r m e d i a t e p o s i t i o n between s e v e r e and haemorrhagio
f a u c i a l d i p h t h e r i a when c o n s i d e r e d in terms o f c o m p l i c a t i o n s .
Doses o f Serum g i v e n .
The maximum
dose g i v e n was 3 1 2 , 0 0 0
u n i t s , the minimum 8 , 0 0 0 u n i t s , and the s v e r a g e 6 2 , 0 0 0 u n i t s .
148 c a s e s had one dose o f serum ( a c t u a l l y one i n t r a m u s c u l a r l y
and one i n t r a v e n o u s l y but t h e s e two d o s e s were c o n s i d e r e d as
one i n i t i a l dose).
separate d o ses.
76 had 2 , 21 had 3 d o s e s , and 5 had 4
.162.
Rate o f Disap pearan ce o f Membrane/ or D i s o h a p g e s / or
C ervical A d en itis.
The maximum time taken f o r the membrane/ or d i s c h a r g e s /
or g l a n d s to c l e a r up was 120 h o u r s .
The p a t i e n t , a woman
o f 26 y e a r s , was a d m itted on the 6 t h . day o f i l l n e s s w ith a
”b u l l n e c k ” membrane on both t o n s i l s , the hard and s o f t
p a l a t e and a p r o f u s e n a s a l d i s c h a r g e .
She was g iv en
1 4 4 , 0 0 0 u n i t s ( 7 2 , 0 0 0 i n t r a v e n o u s l y and 7 2,0 0 0 i n t r a m u s c u l a r l y ) .
The organism r e c o v e r e d was o f the in t e r m e d iu s s t r a i n .
The
minimum time was 12 hours and the a v e r a g e , 68 ho u rs .
Rate o f Disappearance o f Toxaemia.
20 p a t i e n t s were comatose on a d m i s s i o n , 110 had
s e v e r e to x a e m ia , 65 moderate, 46 mild and 10 showed no s i g n s
or symptoms o f t o x a e m i a .
The maximum time taken f o r the
toxaemia t o p a s s o f f was 160 hours and was in the case
mentioned a b o v e .
The minimum time was 24 h o u rs, the
a v e r a g e , 62 h o u r s .
Q
INTRAMUSCULAR.
The serum was i n j e c t e d i n t o t h e v a s t u s e x t e r n u s
muscle o f the t h i g h .
A n a l y s i s o f the 600 Ca s e s t r e a t e d •
(1)
Age and S e x .
Age Groups.
0-5
6 -10
Ma l e s
Females
T otal.
57
58
115
134
114
248
11-20
87
71
158
21-30
27
18
45
31-4 0
41-50
9
8
17
11
JL
12
Most of the c a s e s (421 or 70$) were under the age o f 2 0 .
Of th e 600 c a s e s , 330 (55$) were m a l e s , and 270 (45$) were
•1 6 3 .
fem ale s •
(2)
Age o f P a t i e n t
c o r r e l a t e d w i t h t h e Type o f C. D iphtheriae
r e c o v e r e d from each c a se ( e x p r e s s e d f i r s t a s a p e r c e n t a g e of
age groups and then as a p e r c e n t a g e of the Type o f C.
D iphtheriae) •
Age Group.
Gravis
In ter m ed iu s
0-5
6-10
11-20
21-30
31-40
41-5 0
51-6 0
T otal.
36(31.3)
78(31.5)
63(39.8)
3(6.6)
35(30.4)
74(29.8)
32(20.2)
9(20.0)
9(52.9)
3(25.0)
0-5
6-10
1 1 -2 0
21-30
31-40
41-50
5 1 -6 0
T otal.
-
-
162
180
36(20.0)
78(43.3)
63(35.0)
3(1.7)
-
35(21.6)
7 4 ( 4 5 .7 )
32(19.9)
9(5.5)
9(5.5)
3(1.8)
-
180
-
162
Of the 0 - 1 0 age group, 114 (19$)
and 109 (18$)
from i n t e r m e d i u s .
M itis
Aberrant
40(34.8)
3(2.6)
7 3 ( 2 9 .4 )
7(2.8)
54(34.2)
5(3.2)
31(68.9)
2(4.5)
4(23.55)
2(16.7)
5(100.0)
17
209
40(19.1)
73(34.9)
5 4 ( 2 5 .8 )
31(14.8)
4(1.9)
2(1.0)
5(2.5)
209
3(17.7)
7(41.2)
5(29.4)
2(11.7)
-
N e g a t iv e
1(0.9)
16(6.5)
4(2.6)
-
4(23.55
7(58.3)
-
32
1(3.1)
16(50.0)
4(12.5)
-
4(12.5)
7(21.9)
-
17
-
52
s u f f e r e d from g r a v i s i n f e c t i o n s
In the 0 - 5 and 6 - 1 0 age
groups th e i n c i d e n c e o f g r a v i s , i n t e r m e d i u s and m i t i s c u l t u r e s
occurred with f a i r l y equal frequency.
A l l f o u r t y p e s and t h e n e g a t i v e c a s e s had t h e i r
h i g h e s t i n c i d e n c e i n th e 6 - 1 0 age g r o u p .
found in p a t i e n t s over 3 0 .
No g r a v i s e a s e s were
In t e r m e d iu s and n e g a t i v e o u l t u r e s
were the most f r e q u e n t l y found i n the 3 1 - 4 0 and 4 1 - 5 0 s g e g r o u p s ,
but m i t i s was found most f r e q u e n t l y in t h e 5 1 - 6 0 age grou p.
.'164*.
(3)
Dosage o f Serum g i v e n c o r r e l a t e d w i t h the age groups
( e x p r e s s e d f i r s t as a p e r c e n t a g e o f t h e age groups and
s e c o n d l y a s a p e r c e n t a g e o f the number o f c a s e s r e c e i v i n g
the d e f i n e d d o s e s ) •
i Group.
Under 8 ,0 0 0
U n its.
0-5
6-10
11-20
2 1-3 0
31-40
4 1-5 0
51-60
T otal.
5(4.4)
9(3.6)
10(6.3)
3(6.7)
2(11.8)
3(25.0)
__ 2 ( 4 0 . 0 )
34
0-5
6-10
11-20
2 1-3 0
3 1-4 0
4 1-50
51-60
T otal.
8,000 -40 ,0 00
U n its.
90(78.2)
1 7 5 ( 7 0 .5 )
76 ( 4 8 .1 )
22(48.9)
10(58.9)
4(33.3)
3(60.0)
380
4 0 , 0 0 0 Units
and Over.
20(17.4)
64(25.9)
72(45.6)
20(44.4)
5(29.3)
5(41.7)
186
5(14.7)
9(26.5)
10(29,4)
3(8.8)
2(5.9)
3(8.8)
2(5.9)
90(23.7)
1 7 5 ( 4 6 .1 )
76(20.0)
22(5.8)
10(2.6)
4(1.1)
3(0.7)
20(10.7)
6 4 ( 3 4 .4 )
72(38.8)
20(10.7)
5(2.7)
5(2.7)
34
380
186
the 600 c a s e s t r e a t e d . 380 (63.3 $)
serutn between 8 ,0 0 0 and 4 0 , 0 0 0 u n i t s .
r e c e i v e d a dose o f
Doses o f over 4 0 ,0 0 0
u n i t s were used alm ost s i x t i m e s as o f t e n a s d o s e s o f under
8,000 u n i t s .
Doses o f serum between 8 , 0 0 0 and 4 0 ,0 0 0 u n i t s were
employed most o f t e n in c h i l d r e n between the a g e s o f 6 - 1 0 , but
d o s e s o f under 8 , 0 0 0 u n i t s and over 4 0 ,0 0 0 u n i t s were used
most o f t e n in the 11-20 age gro up.
(4)
Day o f D i s e a s e c o r r e l a t e d w i t h the typ e o f C. Diphtheriae
r e c o v e r e d from the c a s e ( e x p r e s s e d as a p e r c e n t a g e o f the c a s e s
o c c u r r i n g per day and s e c o n d l y as a p e r c e n t a g e o f the v a r io u s
.1 6 6 .
t y p e s o f C . D iph theria s ) •
Day of
D isease.
G ra v is
1
2
3
4
6
6
7
8
Total •
M itis
3(23.1)
51(34.4)
49(21.1)
28(24.4)
23(54.8)
8(18.2)
7(53.8)
41(27.7)
89(38.4)
43(37.4)
5(11.9)
24(54.6)
2(15.4)
35(23.6)
81(34.9)
34(29.6)
11(26.2)
11(25.0)
-
6(100.0)
160
2(1.1)
35(19.5)
81(45.0)
34(18.9)
11(6.1)
11(6.1)
1
2
3
4
5
6
>7
f
8
Total
In ter m ed iu s
180
3(2.0)
7(3.0)
3(2.6)
3(7.1)
1(2.2)
Negative
1(7.7)
18(12.3)
6(2.6)
7(6.0)
-
-
-
-
-
-
-
-
-
-
162
209
3(1.9)
51(31.4)
49(30.3)
28(17.3)
23(14.2)
8(4.9)
7(3.3)
41(19.6)
89(42.5)
43(20.5)
5(2.7)
24(11.4)
6(3.3)
Aberrant
-
162
Of t h e 600 o a s e s , 508 (8 4 .7 $ )
17
-
3(17.6)
7(41.3)
3(17.6)
3(17.6)
1(5.9)
1(3.1)
18(56.2)
6(18.8)
7(21.9)
-
-
-
209
32
17
-
32
had r e c e i v e d serum by the end
o f th e 4 t h . day o f t h e i r i l l n e s s .
G ravis i n f e c t i o n s reached
t h e i r h i g h e s t i n c i d e n c e i n p a t i e n t s who were a dm itt ed on the
3 r d . day o f i l l n e s s ,
i n t e r m e d i u s on the f i f t h day, m i t i s on
the s i x t h day, a b e r ra n t on the f i f t h and n e g a t i v e c a s e s on
the second d ay .
The h i g h e s t p e r c e n t a g e
o f g r a v i s , m i t i s and aberrant
c a s e s were a d m i t t e d on the 3 r d . day o f i l l n e s s .
With
i n t e r m e d i u s and n e g a t i v e c a s e s , the h i g h e s t p e r c e n t a g e was
on the 2nd. day o f i l l n e s s .
A sm a ll number o f c a s e s (6) ,
a d m itted on the 8 t h . day o f i l l n e s s were found t o be g r a v i s
in fectio n s.
.166.
(5)
Day o f D i s e a s e c o r r e l a t e d w i t h t h e age group ( e x p r e s s e d
f i r s t a s a p e r c e n t a g e o f c a s e s p e r day and s e c o n d l y a s a
p e r c e n t a g e o f th e c a s e s in each age group) •
Day o f
Disease •
0-5
1(7.7)
33(22.3)
32(13.8)
29(25.3)
8(19.0)
6(13.4)
1
2
3
4
5
6
7/
8
3(23.0)
58(39.2)
109(46.9)
47(40.9)
21(50.0)
10(22.7)
6(100.0 )
T otal.
115
1( 0 .9 )
33(28.7)
32(27.8)
29(25.3)
8( 6 .9 )
6( 5 .2 )
1
2
3
4
5
6
ri
I
8
>tal.
__ 6( 5.2)
115
11-20
6-10
-
21-30
4 (30 . 8)
2(15.4)
2( 1.4)
52(35.1)
44(18.9) 30(12.9)
2 2 ( 1 9 . 1 ) 10( 8 . 7 )
12(28.6)
24(54.6)
1( 2 . 3 )
-
1( 2 .3 )
-
-
248
2( 4 .4 )
2( 4 .4 )
30(66.7)
10(22.2)
158
45
1(7.7)
1(0.6)
5(2.2)
4(3.4)
-
4(1.8)
1(0.9)
-
-
1(2.3)
-
12
2(11.8)
2(11.8)
8(47.0)
2(11.8)
1( 5 .8 )
2(11.8)
-
51-60
-
17
4( 2 .5 )
52(32.9)
44(27.9)
22(13.9)
12( 7.6)
24(15.2)
41-50
-
158
3( 1.2 )
58(23.4)
1 0 9 ( 4 3 .9 )
47(18.9)
21 ( 8.5)
10( 4.1)
2(15.4)
2 ( 1.4)
8 ( 3 .5 )
2( 1.7)
K 2.4)
2 ( 4 .7 )
-
-
248
31 - 4 0
5
1(8.3)
1(8.3)
5(41.8)
4(33.3)
-
1( 8 . 3 )
-
17
12
had r e c e i v e d serum t r e a t m e n t b e f o r e
t h e end o f the 4 t h . day o f i l l n e s s .
S i x p a t i e n t s who d i d no t
r e c e i v e serum tr e a t m e n t u n t i l the 8 t h . day o f t h e i r i l l n e s s were
i n the 0 - 5 age group.
For the v a r i o u s age gr o u p s , t h e r e were d i f f e r e n t days on
which most p a t i e n t s r e c e i v e d t r e a t m e n t : - 0 - 5 and 11 -2 0 were
on th e 2nd. day, w h i l e a l l th e o t h e r s were on the 3 r d . day.
(6)
Day o f D i s e a s e c o r r e l a t e d w i t h th e dose of serum g i v e n
( e x p r e s s e d f i r s t as a p e r c e n t a g e o f c a s e s per day and then a s
a p e r c e n t a g e of the c a s e s r e c e i v i n g t h e d e f i n e d doses) •
-
-
Of th e 600 c a s e s , 363 (65$) were under the age of 11 y e a r s , and
o f t h i s number 312 ( 5 2 .0 $ )
_
<
4(80.0)
1( 20.0):
1
-
5
\
.1 6 7
Day o f
D isease •
1
2
3
4
5
6
7
8
Total
1
2
3
4
5
6
7
8
Total
Under 8 , 0 0 0
U n its.
9(69.2)
16(10.1)
8(3.6)
1(0.9)
1(2.4)
34
9(26.5)
15(44.1)
8(23.5)
1(2.95)
1(2.95)
34
8,000-40,000
U nits
40,000 U nits
and Over
2(15.4)
98(66.2)
172(74.1)
94(81.7)
10(23.8)
3(6.8)
2(15.4)
35(23.7)
52(22.4)
20(17.4)
31(73.8)
41(93.2)
1(16.7)
5(83.3)
380
186
2(0.5)
98(25.8)
172(45.4)
94(24.7)
1 0 (2 . 6 )
3(0.7)
2 ( 1 .1 )
35(18.9)
52(27.9)
20(10.7)
31(16.7)
41(22.0)
1 (0.3)
380
5(2.7)
186
D e la y in d i a g n o s i n g the d i s e a s e l e d to l a r g e r d o s e s o f serum
h a vin g t o be a d m i n i s t e r e d .
Of the c a s e s coming under t re atm en t
on t h e 8 t h . day, 16*7$ r e q u i r e d between 8 , 0 0 0 and 4 0 , 0 0 0 u n i t s ,
w h i l e 83*3$ r e q u i r e d d o s e s o f over 4 0 , 0 0 0 u n i t s .
The h i g h e s t number of p a t i e n t s who r e c e i v e d l e s s than
8 , 0 0 0 u n i t s did so on t h e 2n d. day of t h e i r i l l n e s s , t h o s e who
were g i v e n between 8 , 0 0 0 and 4 0 , 0 0 0 u n i t s , on t h e 3 r d . day and
t h o s e who r e c e i v e d over 4 0 , 0 0 0 u n i t s d id so a l s o on the 3 r d . day.
(7) Type o f C. Diphtheriae r e c o v e r e d from the c a s e s c o r r e l a t e d
w i t h t h e dose o f serum g i v e n ( e x p r e s s e d a s a p e r c e n t a g e o f Type
o f C . Diph theriae ) •
.1 6 8 .
Type o f C.
D lphtherise .
Under 8 ,0 0 0
U n its.
8,000-40,000
U n its.
7( 3 . 9 )
4( 2 . 5 )
3( 1.4)
3(17.6)
1 7 ( 5 3 .1 )
34
78(43.3)
75(46.3)
2 0 2 ( 9 6 .7 )
10(58.9)
1 5 ( 46.9)
380
Gravis
Interm edius
M itis
A berrant
Negative
Total •
40,000 U nits
and Over.
95(52.8)
83(51.2)
4( 1 .9 )
4(23.5)
186
The h i g h e s t number o f p a t i e n t s who had g r a v i s and i n t e r m e d i u s
i n f e c t i o n s r e c e i v e d over 4 0 , 0 0 0 u n i t s o f serum, w h i l e most o f
th e m i t i s and a b e r ra n t i n f e c t i o n s were g i v e n between 8 , 0 0 0
and 4 0 , 0 0 0 u n i t s .
Of the n e g a t i v e c a s e s , 5 3 . 1 ^ r e c e i v e d
l e s s than 8 , 0 0 0 u n i t s and 4 6 . 9 ^ between 8 ,0 0 0 and 4 0 , 0 0 0 u n i t s .
(8)
Type o f C. Diph therias r e c o v e r e d from th e v a r i o u s
c l i n i c e l t y p e s of d i p h t h e r i a
the c l i n i c a l t y p e s .
(expressed as a percentage of
C e r v i c a l a d e n i t i s i s e x p r e s s e d as a
p e r c e n t a g e o f the number o f c a s e s w it h each s t r a i n o f
C . Di phtheriae ) •
C lin ical
Ty pe.
F aucial:
(a) Mild
(b) Moderate
(c) Se vere
(d) Haemorrhagic
Na s a l
Laryngeal
F a u c i a l and
N asal.
C ervical
A d en itis•
T ot8l.
Gravis
In term ed iu s
M itis
Aberrant
5 1 ( 5 6 .7 ) 5 ( 5 . 5 )
75(31.1) 8(3.3)
12(14.3) 2(2 .4 )
9(10.0)
80(33.2)
41(48.8)
9(10.0)
68(28.2)
29(34.5)
8(47.1)
1( 9.1 )
3(17.6)
K 9 .1 )
6(35.3)
9(81.8)
1 3 ( 6 8 .4 )
41(29.5)
5 2 ( 3 7 .7 )
43(31.3)
1 2 6 ( 7 0 .0 )
180
1 0 0(6 1.7 )
162
_87(41.6)
209
N e g a t iv e
16(17.8)
10( 4.2)
6(31.6)
2(1.5)
6(55.3)
17
The g r a v i s s t r a i n was a s s o c i a t e d w i t h the most c l i n i c a l l y
s e v e r e c a s e s and had the h i g h e s t p e r c e n t a g e o f c e r v i c a l
4(12.5)
32
*169.
a d en itis.
The h i g h i n c i d e n c e o f m i t i s s t r a i n s
a s s o c i a t e d w i t h haemorrhagio c a s e s i s a f e a t u r e o f the
tab le.
The a b e r ra n t s t r a i n s were a s s o c i a t e d , i n the
m a j o r i t y o f c a s e s , w i t h a m odera tely s e v e r e o f m ild i l l n e s s .
Of t h e n a s a l d i p h t h e r i a s a high p e r c e n t a g e ( 8 1 . 8 ) were
m itis types.
C u l t u r e s from l a r y n g e a l d i p h t h e r i a were
e i t h e r m i t i s or n e g a t i v e .
Death and C om p lica tio n R a t e s .
(a)
Type o f C. Diph therias
r e c o v e r e d from t h e i n d i v i d u a l
c a s e s c o r r e l a t e d w i t h the v a r i o u s c o m p l i c a t i o n s observed
8nd the d e a t h rat© ( e x p r e s s e d as a p e r c e n t a g e o f the number
o f the Type o f C. D i p h t h e r i a s ) .
C o m p li c a t io n •
G rav is
Albuminuria
8(4.4)
Cardiac P a r e s i s l O ( 5 .6 )
P alatal
,,
7(3.9)
Ocular
,,
Death Rate
8(4.4)
In ter m ed iu s
4(2.5)
4(2.5)
7(4.3)
6(3.7)
3(1.9)
M itis
Aberrant
4(1.9)
1(0.5)
3(1.5)
2(1.0)
1(5.9)
N e g a tiv e
1(5.9)
1(5.9)
Prom th e t a b l e th e a b e r r a n t t y p e s would appear to have the
h i g h e s t alb u m in u r ia , p a l a t a l p a r e s i s and dea th r a t e s , b u t ,
a s p r e v i o u s l y e x p l a i n e d , . a l l t h e s e c o m p l i c a t i o n s occu rred in
one c a s e from which a Type t v organism was r e c o v e r e d .
The
p a t i e n t d i e d from s e p t i c m e n i n g i t i s f o l l o w i n g upon an
op eration f o r acute m a s t o i d i t i s .
The g r a v i s s t r a i n was a s s o c i a t e d w ith t h e h i g h e s t
com plication rate except for p a la t a l p a r e s i s .
most o f t e n in inte rm e d iu s c a s e s .
T h is occurred
.
(b) Death and C o m p lic a tio n Rates c o r r e l a t e d w i t h t h e age
o f t h e p a t i e n t ( e x p r e s s e d a s p e r c e n t a g e s o f t h e age g r o u p s ) .
;e Group.
0-5
6-10
11-20
21-30
3 1 -4 0
4 1-5 0
5 1-6 0
Albuminuria
4(3.5)
9(3.6)
1(0.6)
2(4.4)
1(5.9)
T otal.
P alatal
Paresis
Cardiac
Paresis
Ocular
Paresis
Death
Rate •
4(3.5)
5(2.0)
6(3.8)
2(4.4)
1(5.9)
5(4.4)
5(2.0)
4(2.5)
1(2.2)
3(2.6)
3(1.2)
5(4.4)
4(1.6)
5(3.0)
-
-
-
-
-
-
-
18
17
-
15
-
-
-
-
6
-
14
Albuminuria o ccu rred w i t h alm ost the same f r e q u e n c y in the 0 - 5
and 6 - 1 0 age g r o u p s .
The i n o i d e n c e f e l l in the 1 1 -2 0 group,
r o s e i n t h e 2 1 - 3 0 and the 3 1 -4 0 age g r o u p s , but was not
o b s e r v e d in any a g e s above 4 0 .
P a l a t a l p a r e s i s , with the
e x c e p t i o n o f a s l i g h t f a l l i n the 6 - 1 0 age group, tended to
become more f r e q u e n t i n the h i g h e r age g r o u p s .
Cardiac
p a r e s i s was h i g h e s t in the 0 - 5 age group, f e l l in the 6 - 1 0
age group and r o s e a g a i n s l i g h t l y in the two rem aining age
groups in which i t oc cu rred - 11-20 and 2 1 - 3 0 .
i
S ix cases of ocular p a r e s is occurred, 3 in the 0-5
age group and 3 in the 6 - 1 0 .
The death r a t e was h i g h e s t in
th e 0 - 5 age group, f e l l i n the 6 - 1 0 and r o s e a ga in i n the
1 1 - 2 0 age group*
age g r o u p s .
No d e a t h s were r eco rd ed i n any o f the o t h e r
-m .
(o)
Death and C o m p lic a tio n Rates c o r r e l a t e d w i t h day o f
disease
( e x p r e s s e d a s p e r c e n t a g e s o f day o f d i s e a s e ) •
Day o f
D i s e a s e • Albuminuria
1
2
3
4
5
6
*7(
8
Total
P alatal
Paresis
a.
3(1.3)
8(6.9)
4(9.5)
2(4.5)
3(2.0)
4(1.7)
4(3.5)
3(7.1)
4(9.1)
-
1(7.7)
1(0.6)
4(1.7)
4(3.5)
18
Ooular
P aresis
Death
Rate.
.
-
-
4(1.7)
2(1.8)
-
-
-
4(9.1)
1(16.7)
15
-
17
Cardiac
Paresis
3(1.3)
3(2.6)
2(4.8)
5(11.4)
1(16.7)
14
-
6
With the e x c e p t i o n o f c a rd iac p a r e s i s , where one p a t i e n t , who
was g i v e n serum on the f i r s t day o f h i s i l l n e s s , dev e lop ed
t h i s c o m p l i c a t i o n , the i n c i d e n c e o f a l l c o m p l i c a t i o n s and the
d e a t h r a t e i n c r e a s e d , as the time b e f o r e serum was g i v e n ,
was i n c r e a s e d .
(d)
Death and C om p lic a tio n Rates c o r r e l a t e d w i t h the
c l i n i c a l v a r i e t i e s o f d i p h t h e r i a ( e x p r e s s e d as a p e r ce n ta g e
o f the c l i n i c a l t y p e s ) .
C Jinical
Type
Albuminuria
Faucial:
(a) Mild
(b) Moderate
(e) Severe
(d) Haemorrhsgie
K g e « l
P8UCN a s . i nd
Total
1(1.1)
1(0.4)
2(2.4)
6(35.3)
P alatal
P aresis
Cardiac
P aresis
Ocular
P aresis
1(1.1)
2(0.8)
4(4.8)
-
6(7.2)
%
4(23.5)
3(17.7)
1
_ V ( 5 .1 )
17
"
18
_8(5.8)
15
6
Death
Rate.
-
„ .
7(41.2)
'
2 <1 0 ' 5)
_5(3.7)
14
With the e x c e p t i o n o f th e moderate o a s e s , t h e more s e v e r e
.17*2 •
t h e c l i n i c a l c a s e , the h i g h e r was the i n c i d e n c e of
com p lication s,
F a u o i s 1 - n a s a l o a s e s o c c u p i e d an i n t e r m e d i a t e
p l a c e between s e v e r e and haemorrhagic d i p h t h e r i a #
The
c a r d i a c p a r e s i s in the l a r y n g e a l c a s e s was h i g h , but t h i s
was due t o e x t r a s t r a i n on the he a r t caused by th e
d i f f i c u l t y in r e s p i r a t i o n .
Dosage o f Serum g i v e n #
The maximum dose g i v e n was
2 5 6 . 0 0 0 u n i t s , the minimum, 4 ,0 0 0 u n i t s and the average
54.000 units#
476 p a t i e n t s had only one i n j . e o t io n o f serum,
105 had two, 19 had t h r e e but none had a f o u r t h i n j e c t i o n .
Rate o f Disappearance o f Membrane/ or D i s c h a r g e s / or
C ervioal A d e n it is .
The maximum time was 108 ho u rs .
The case was a g i r l
o f 2 y e a r s , w i t h membrane on both t o n s i l s , s o f t and hard
p a l a t e , and w i t h a b i l a t e r a l c e r v i c a l a d e n i t i s .
She was i n
her f i f t h dsy o f i l l n e s s and was g i v e n 7 2 ,0 0 0 u n i t s o f serum.
The organism r ec o v er ed was of the g r a v i s s t r a i n .
The
minimum time was 16 hours , and the a v e r a g e , 44 hours#
Rate o f Disappearance o f Toxaemia.
On admission 30 p a t i e n t s were com atose, 156 had s e v e r e
to x a e m ia , 288 moderate, 108 mild and 18 showed no s i g n s or
symptoms o f to x a em ia .
The maximum time take n f o r the
toxaemia t o p a s s o f f was 120 h o u r s .
mentioned above.
a v e r a g e , 39 hours#
This was i n t h e c a s e
The minimum time was 12 h o u r s , the
•173*
Comparing t h e r e s u l t s o f treatm ent by the t h r e e d i f f e r e n t
methods o f a d m i n i s t e r i n g the serum.
R e s u l t s o f tre a tm en t are b e s t judged by the
c o m p l i c a t i o n s and death r a t e s in e a ch method, a f t e r t a k i n g
a c c o u n t o f the v a r i o u s f a c t o r s which might i n f l u e n c e t h e s e
resu lts*
(a)
Age (P e r c e n t a g e s) •
6 -1 0
11-20
2 1-30
Intravenous
1 9 .3
In tra m u sc u la r)
and
) 18.8
Intravenous )
In tra m u scular) 1 9 . 2
45.3
21.3
8.7
2.7
03
51.2
19.6
5.2
2.4
2 .8
41.3
26.3
7.5
2.8
2 .0
3 1 -4 0
41-50
51-60
r.
i
Age Groups*
0.9
The p e r c e n t a g e o f c h i l d r e n in the 0 - 5 age groups approximated in
a l l t h r e e methods.
Of the 6 -1 0 group the in t r a m u s c u la r
s e r i e s had the l o w e s t p e r c e n t a g e of t h i s age grou p, and the
i n t r a m u s c u l a r - i n t r a v e n o u s s e r i e s had the h i g h e s t *
In the
1 1 - 2 0 age group the intr am u sc u la r s e r i e s had the h i g h e s t
percentage of these*
The ages mentioned ( 0 -2 0 ) are the
a g e s i n which c o m p l i c a t i o n s and the death r a t e are h i g h e s t .
(F orbes 1932)*
Thus a l l three have a p p ro x im a te ly the same
p e r c e n t a g e o f c a s e s i n t h i s group*
(b)
P e r ce n ta g e o f Types o f C. Diphthe riae found in the
various groups.
Intravenous
Intram usc ular)
Intravenous )
In t r a m u sc u la r
G ravis
30.0
28.0
30.0
In term ed iu s
2 5 .3 3
25.2
27.0
M itis
41.33
41.2
34.8
Aberrant
2.8
N egative•
3.33
5.6
5.4
I n a l l t h r e e s e r i e s the p e r c e n t a g e o f the v a r i o u s t y p e s was
.1 7 4 .
f a i r l y even ly d is tr ib u te d .
The i n t r a m u so u la r s e r i e s
had a low i n c i d e n c e of m i t i s s t r a i n s .
(o)
S e v e r i t y o f Cases judged by amount o f serum g i v e n
( e x p r e s s e d a s p e r c e n t a g e s of number in each group) •
Dose o f Serum.
Under 8,000
U n its♦
8,000-40,000
U n its.
40,000 Units
and Over.
23.3
42.0
34.7
16.8
5.7
4 7 .2
63.3
36.0
31.0
Intravenous
I n t r a m u s c u l a r &)
Intravenous
)
In t r a m u s c u l a r
Judged by dosage of serum g i v e n , the i n t r a m u s c u l a r i n t r a v e n o u s c a s e s were most s e v e r e , as they had the h i g h e s t
p e r c e n t a g e o f c a s e s who were giv en over 4 0 , 0 0 0 u n i t s of
serum.
Next came the i n t r a v e n o u s , and l a s t l y the
In t r a m u sc u la r c a s e s .
However, the in t r a m u s c u l a r had the
h i g h e s t p e r c e n t a g e o f c a s e s in the 8 ,0 0 0 - 4 0 , 0 0 0 u n i t s group.
I f we c o n s i d e r the s e v e r i t y o f the c a s e s by the average dose
g i v e n , the order o f d e c r e a s i n g s e v e r i t y i s intram uscular-intravenous (62,000 units) ,
(54,000 units)
(d)
intram usou lar
and in t r a v e n o u s ( 4 2 ,5 0 0 u n i t s ) .
Day of D i s e a s e -
(expressed as a percentage of c a se s
i n each s e r i e s ) •
Day o f
Disease
Intravenous.
1
2
3
4
5
6
7
9 ( 6 . 0)
49(32.7)
53(35.3)
18(12.0)
8( 5 .3 )
7( 4 .7 )
3 ( 2 . 0)
3 ( 2 . 0)
8
I n t r a v e n o u s and
Intramusoular
12( 4 .8 )
79(31.6)
72(28.8)
46(18.4)
18( 7.6)
18( 7 .2 )
1( 0 .4 )
3 ( 1.2)
I n t r a m u s o u la r .
13( 2 . 2 )
1 4 8 ( 2 4 .7 )
232(38.7)
1 1 6 ( 1 9 .2 )
42( 7.0)
44( 7 .2 )
6 ( 1. 0)
Ths t h i r d day was th e day on which the h i g h e s t p e r ce n ta g e o f
c a s e s r e o e i v e d serum in the i n t r a v e n o u s and in the
In tra m u sou la r s e r i e s *
In the i n t r a v e n o u s - i n t r a m u s c u l a r
s e r i e s t h e h i g h e s t percenta ge occurred on the secon d day*
In t h e t h r e e s e r i e s 14*0$ of the i n t r a v e n o u s , 16*4$ o f
th e i n t r a v e n o u s - i n t r a m u s c u l a r and 1 5 . 2% o f the In tram usoular
c a s e s r e c e i v e d serum a f t e r the f o u r t h day o f i l l n e s s *
The
i n t r a m u s c u l a r s e r i e s in the t h i r d and f o u r t h days had the
h i g h e s t p e r c e n t a g e o f c a s e s r e c e i v i n g t re a t m en t on t h e s e
days*
The o t h e r two had alm ost the same p e r ce n tag e*
-.-I / r-) 1
I?’ •
r-f :
:3.r
K atos i r
j f 1-* T-.
o
0 ti
f
■
-* s * $
Viu?x t h r e e
m j"4
** a
m
s
e
r
t? *
»
■
>
12
rS\
•; - 1 - a gg - V
i
- LBr
, ;j . . . d .,r ■
« -x o;
'UO
r
;
2»3:% 5v
69co ^
ra £a f. j a r 3. r 3s^i/3;3^
y<*?
S -3
X■■t r e -f e ?:.x n-Y i r V $ £ i ■ -
«r.
---‘j v ';
S U M M A R Y *
In the thr ee s e r i e s there was l i t t l e
d i f f e r e n c e in
t h e p e r c e n t a g e o f p a t i e n t s per age group and o f
o • d ip h t h e r ia e
found*
types o f
Judged by the amount o f serum
g i v e n , the i n t r a v e n o u s - i n t r a m u s c u l a r s e r i e s was c l i n i c a l l y
the most s e v e r e , the intram uscular being n e x t , and the
i n t r a v e n o u s c a s e s the m i ld e s t *
The i n t r a v e n o u s -
in t r a m u s c u l a r s e r i e s had the h i g h e s t pe r ce ntag e o f c a s e s
r e c e i v i n g treatm en t a f t e r the f o u r t h day, th e In tra m usc ular
s e r i e s be in g second and the i n tr a v en o u s l a s t *
Thus the order o f c l i n i c a l s e v e r i t y i s : (1)
i n t r a v e n o u s - i n t r a m u s c u l a r c a s e s , (2)
c a s e s , and (3)
intram uso ular
In t r a v e n o u s.
Comparison o f Complication Rates i n the t h r e e s e r i e s
( e x p r e s s e d a s a p e r o en ts g e o f o a s e s in each s e r i e s ) *
Route o f
TMaAfinn
Albuminuria
Intravenous
Intravenous &
In tra m u sc u la r
In tra m u sc u la r
P a l a t a l Cardiac
Paresis P aresis
Ocular
Death
P a r e s i s Rate*
1 0 .0
12.7
11.3
e
8.0
1.8
2.7
2.0
3.0
1.8
2.5
1.0
1.2
2.3
The i n t r a v e n o u s - i n t r a m u s c u l a r s e r i e s o f c a s e s had the l o w e s t
percentage of com plications.
Next in order came the o a s e s
t r e a t e d by intramusoular i n j e c t i o n and l a s t l y t h o s e whioh
had r e c e i v e d the serum by in t r a v e n o u s i n j e o t i o n .
• 177.
C onclusions.
A combined in t r a v e n o u s and in t r a m u s c u l a r t h e r a p y
i s t h e b e s t treatm ent f o r d i p h t h e r i a .
Where t h i s cannot
be u s ed , the serum should be g iven by i n t r a m u sc u la r i n j e c t i o n .
I n t r a v e n o u s thera py alone i s not to be recommended.
Comparison o f C om plicatio ns and death r a t e s , c o r r e l a t e d w i t h
typ e o f C • Diphtheriae , when c o n c e n tr a t e d and r e f i n e d sera
were u s e d .
A u th or .
x Anderson
et al
1931.
Complication
Albuminuria
Paralysis
Death Rate
x J . F . Murray
Albuminuria
1935.
P aralysis
Death Rate
Gravis
44.4%
22.2%
17.6%
In term ed iu s
66.66#
50.0%
0
M itis
17.1%
0
0
0
0
0
7.8#
10.0#
11.1#
3.4%
6.8%
3.4%
x T annahill
1936.
Albuminuria
P aralysis
Death Rate
38.4%
20.8%
9.5%
40.4#
21.4#
13.8#
18.1%
11.3%
4.8%
# Present
series.
Albuminuria
P aralysis
Death Rate
5.4%
13.5%
5.4%
3.4#
12.9#
3.0#
2.1%
2.0%
0.8%
x
Aberrant N e g a t i v e .
-
-
5.9%
5.9%
5.9%
3.9%
2.0%
2.0%
Cone e n t r a t e d Serum.
Refined Serum •
McLeod, Murray and Tan n a h ill a l l found the i n c id e n c e of
/
a lbum in uria and p a r a l y s i s to be the h i g h e s t in i n te rm e d iu s
cases.
In the c a s e s t r e a t e d in B e lv i d e r e H o s p i t a l ,
al bum in uria had i t s h i g h e s t i n c id e n c e in aberra n t c a s e s and
p a r a l y s i s i t s h i g h e s t i n c id e n c e i n g r a v i s o a s e s .
The de at h
r a t e i n McLeod*s s e r i e s was h i g h e s t in g r a v i s s t r a i n s .
In
•iw .
Murray and T a n n a h i l l ! s s e r i e s i t was w i t h th e in t e r m e d i u s
s t r a i n s and i n the B e l v i d e r e o a s e s i t was with the
aberrant s t r a in s .
Comparison o f R e s u l t s o f Treatment.
Albuminuria
R olleston,1925
G oodall,
1928
Anderson e t a l
1931
Murray,
1935
Present Series
Paralysis
Death R a t e .
(1)
(1)
53.3#
20.7#
15.0#
1 0 . 1#
13.0#
(2)
(2)
(3)
3 6 .5 #
5.4#
3.6#
16 • j/o
7.8#
7.8#
1 0 . 6#
7.2#
2 .9#
(1) Whole Serum.
(2) Concentrated Serum. (3) R e f in e d
Serum*
C l a s s i f i e d i n order o f e f f i c a c y from the above t a b l e ,
r e f i n e d serum I s the b e s t , c o n c e n tr a t e d serum comes n e x t ,
and whole serum gave th e p o o r e s t r e s u l t s .
v -s r m t %to xi B
:• -o
■>1 ^ ' ■ &&*’m ':v y ':'' 1
; o f serum reaat* t m * - * '
"i;o
b f: a n t i
' - '•- -
. o- o. . .. ...
nzfAaut m l m
t
o
*
7
t o visa
CONCLUSIONS.
The d e a t h r a t e was h i g h e s t In the 0 - 5 age group.
The s e v e r e s t c l i n i c a l o a s e s were a s s o c i a t e d w it h t h e
gravis stra in .
The c a s e s where a g r a v i s s t r a i n was i s o l a t e d had the
h i g h e s t percentage of c o m p l i c a t i o n s .
As the number of
Type jLv s t r a i n s recovered was very sm a l l , t h e r e I s
I n s u f f i c i e n t data f o r a reaso n a b le comparison t o be made.
As the d u r a t i o n of the p a t i e n t * s i l l n e s s i n o r e a s e d b e f o r e
serum was g i v e n , so a l s o did the p e r ce n ta g e o f
com p lication s.
Haemorrhagio d ip h t h e r ia was the most se v er e type o f
d ip h th eria•
No hard and f a s t r u l e can be l a i d down on dosage o f serum
t o be g i v e n .
Each case should be reviewed s e p a r a t e l y .
I t i s b e t t e r t o g i v e e x c e s s serum than t o o l i t t l e .
Serum
should conti nu e to be given so long as the membrane i s
spreading.
Combined intramuscular and in t r a v e n o u s
t h e r a p y should be employed.
R e f i n e d d i p h t h e r ia a n t i t o x i n can be g iv en i n t r a v e n o u s l y
w i t h l i t t l e f e a r o f serum r e a c t i o n .
Given i n t r a m u s c u l a r l y
I t oausas s l i g h t discom fort t o the p a t i e n t owing t o the
l a r g e number o f u n i t s o f a n t i t o x i n per c . o .
The i n c i d e n c e o f serum r e a c t i o n s has been reduced*
The i n c i d e n c e o f o . d ip h t h e r ia s g r a v i s i s on the
upgrade i n the Glasgow a r e a .
a si.
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