Scarlet Fever: A Penicillin Therapy Trial
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SOAShST
A.
rEM IOIU.!»
FETÈR.
TOR-RiyT
IK lili
ProQuest Number: 27708415
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uest ProQuest 27708415 Published by ProQuest LLO (2019). C opyright of the Dissertation is held by the Author. All rights reserved. This work is protected against unauthorized copying under Title 17, United States C o d e M icroform Edition © ProQuest LLO. ProQuest LLO. 789 East Eisenhower Parkway P.Q. Box 1346 Ann Arbor, Ml 4 8 1 0 6 - 1346
P r e fa c e •
The work on t h i s t h e s i s was s t a r t e d in 1948 w h i l s t I w as a r e s i d e n t p h y s i c i a n a t K n igh tsw ood H o s p i t a l , G la sg o w . The s u h j e c t m a tte r c o n s i s t s l a r g e l y o f a r e v ie w o f c a s e s o f s c a r l e t f e v e r a d m itte d to t h a t h o s p i t a l d u r in g th e p e r io d J a n u a r y , 1 9 4 6 , to J u l y , 1 9 4 8 , i n c l u s i v e .
Prom N ovem ber,
1 9 4 7 , t o J u l y , 1 9 4 8 , a t h e r a p e u t ic t r i a l o f 5 0 0 ,0 0 0 u n i t s in t r a m u s c u la r P e n i c i l l i n o n ce d a i l y f o r s e v e n d a y s was c a r r i e d o u t on e a c h p a t i e n t w it h s c a r l e t f e v e r a d m itte d t o th e h o s p i t a l . My th a n k s a re due to D r. M cO rorie, P h y s ic ia n S u p e r in te n d e n t a t K n igh tsw ood H o s p i t a l , f o r p e r m is s io n t o r e p o r t t h i s t r i a l and to D r. T. A n d erso n , C o n s u ltin g p h y s i c i a n , f o r th e en cou ragem en t w h ic h he a f f o r d e d m e. I a l s o have t o th ank Mr. McLea&, L a b o r a to r y T e c h n ic ia n a t K n ig h tsw o o d H o s p i t a l , f o r b a c t e r i o l o g i c a l h e l p , and t h e v a r io u s r e s i d e n t p h y s i c i a n s and n u r s in g s t a f f who k e p t v e r y f u l l reco rd s o f th e in d iv id u a l c a s e s .
PABT
OHE
I n t r o d u c t io n C h a p ter 1.
The E p id e m io lo g y o f S c a r l e t F e v e r .
2.
The C a u sa l A gen t o f S c a r l e t F e v e r - th e H a e m o ly tic S tr e p to c o c c u s.
3*
The D i f f e r e n t i a t i o n o f t h e S t r e p t o c o c c u s b y V a r io u s M eans.
4.
P r e v e n t iv e I n o c u l a t i o n s in th e C o n tr o l o f S c a r l e t F e v e r
5.
The Serum T reatm en t o f S c a r l e t F e v e r .
6.
The Use o f t h e S u lp h o n a m id es i n S c a r l e t F e v e r .
7*
The Use o f P e n i c i l l i n
PAHT
in S c a r l e t F e v e r .
TtfO
The C l i n i c a l T r ia l u s i n g a O n c e -D a ily D osage o f 7 0 0 ,0 0 0 U n it s " P e n i c i l l i n f o r S even D a y s * 8.
The M ethod a d o p te d i n
th e C lin ic a l T r ia l.
9.
An S z p la n a t io n o f
t h e S t a t i s t i c a l M ethods u s e d .
10.
The G o h p a r isen o f
th e T hree P e r io d s u n d er B ev iew -
11.
The Com parison o f t h e Three P e r io d s u n d er Be v ie w H o s p ita l P r o g r e s s .
Admission pi##inga.
1 2 . C a ses o f A cute O t i t i s lifedia o c c u r r in g d u r in g th e 194 8 P e r io d . B e f e r e n c e s - O r ig in a l A r t i c l e s and A b s t r a c t s .
Ofaapter 1
qiHE
SPIDBMIOLOflY
QJ
SOiRLRT
TBITiaR
E a rly H is t o r y .
The e a r l y h i s t o r y o f s c a r l e t f e v e r i s d ou b t t h i s
o b sc u r e and no
i s due t o t h e d i f f i c u l t i e s w h ich p h y s ic i a n s o f
a n c i e n t t im e s e x p e r ie n c e d in d i f f e r e n t i a t i n g t h i s d i s e a s e from s m a llp o x and m e a s le s ,
H ir s c h (1 8 8 3 ) in h i s fam ous w ork s t a t e d ,
•The o r i g i n and n a t i v e h a b i t a t o f s c a r l a t i n a a re q u e s t io n s t h a t do n o t ad m it o f an answ er ;
we a r e e q u a lly u n a b le t o d e c id e as
t o th e tim e when th e d i s e a s e f i r s t a t t a in e d i t s g e n e r a l p r e v a le n c e on t h e C o n tin e n t o f E u r o p e ."
D ip h t h e r ia and s c a r l e t
f e v e r a re c o n s id e r e d t o g e t h e r by C r e ig h to n (1 8 9 4 ) b e c a u s e he c o n s id e r s t h a t c e r t a i n im p o r ta n t e p id e m ic s in th e U n it e d Kingdom and th e A m erican C o lo n ie s c a n n o t be p la c e d u nder one h e a d in g or th e o t h e r . E a r ly C o n t in e n t a l R e f e r e n c e s . I n g r a s s i a o f P a lerm o , i t i s r e c o r d e d , d e s c r ib e d a d i s e a s e r e s e m b lin g s c a r l e t f e v e r and d i f f e r e n t i a t e d t h i s d i s e a s e from m e a s le s . sta te s -
P o t h e r g i l l ( I 7 4 8 ) in h i s work on s c a r l e t f e v e r ,
«The d i s e a s e w h ich i s c a l l e d by th e S p a n ia r d s
G a r r o t i l l o , by th e I t a l i a n s and o t h e r n a t io n s Morbus S t r a n g u l a t o r ! u s , P e s t i l e n s Fauciurn A f f e c t u s , E p id em ic G u ttu r is L u es, and by d iv e r s o th e r a p p e l l a t i o n s ,
i s s a i d t o h ave ap peared
f i r s t in S p a in ab ou t t h e y e a r 1 6 1 0 , to have s p r e a d from t h e r e t o M a lta , S i c i l y , O tr a n to , A p u lia , C a la b r ia and th e Campagnia in th e s p a c e o f a few y e a r s , and t o h ave broken o u t in N a p le s in 1018
—
2
—
w here i t c o n t in u e d upw ards o f tw e n ty y e a r s r a v a g in g t h e d i f f e r e n t p a r t s o f t h e Kingdom". M o r t a l i t y r e f e r r e d t o th e and m e a s le s .
I n 1029 t h e London B i l l s
of
" p u r p y le s* i n company w ith s m a llp o x
By t h e « p u r p y le s • was m eant any f e v e r ev e n
m e a s le s or s m a llp o x in w h ich l i v i d o r d ark s p o t s o c c u r r e d . T h is term was th o u g h t by C r e ig h to n (1 8 9 4 ) n o t t o in c lu d e s c a r l e t fe v e r .
D a n ie l S e n n a r t, t h e P h y s ic ia n t o t h e E l e c t o r o f S a x o n y ,
o b s e r v e d m a lig n a n t s c a r l e t f e v e r a t t h e b e g in n in g o f th e S e v e n t e e n t h C en tu r y .
He m e n tio n e d s c a r l e t f e v e r d esq u a m a tio n
and r e f e r r e d t o c a s e s o f n e p h r i t i s and d r o p sy f o l l o w i n g a f t e r th e d i s e a s e . The F i r s t E n g l i s h D e s c r i p t i o n .
S c a r l e t f e v e r was d e s c r ib e d by Sydenham in l b 65 and t h i s i s u s u a l l y c o n s id e r e d t o be th e e a r l i e s t E n g lis h o b s e r v a t io n s on th e d i s e a s e .
He d e s c r ib e d th e r a s h and d esq u a m a tio n
b u t made no m e n tio n o f th e s o r e t h r o a t , d i s e a s e t o be o f a v e r y m ild n a t u r e .
and c o n s id e r e d th e He w r o te -
i n f a n t s m ost and t h a t to w a rd s th e end o f summer. c h i l l s a t th e commencement:
"This a t t a c k s S h iv e r s and
bu t no g r e a t d e p r e s s io n .
The w h ole
s k in i s marked w ith s m a ll r e d s p o t s more f r e q u e n t , more d i f f u s e d and more r e d th a n in m e a s le s . They th e n d is a p p e a r ;
T hese l a s t two or t h r e e d a y s .
l e a v i n g th e s k in c o v e r e d w ith brany
squam ulae as i f powdered w it h m ea l" .
-
)
-
AS i t o c c u r r e d in E d in b u rgh in 1 6 8 4 . A cc o rd in g t o C r e ig h to n (1 8 9 4 ) S i r Thomas S ib b a ld o f E d inb u rgh w ro te a book in 1684 i n w h ich he m en tio n ed s c a r l e t fev er.
He d e s c r ib e d t h e d e sq u a m a tio n , s a i d t h a t e x t r e m e ly fe w
d ie d o f th e d i s e a s e ,
and, l i k e Sydenham , o m itte d t o m e n tio n s o r e
t h r o a t and d r o p sy in h i s d e s c r i p t i o n .
" J u st a s th e lu x u r y o f
man i n c r e a s e s e v e r y day so t h e r e grow up new d i s e a s e s ,
i f not
unknown t o fo rm er g e n e r a t io n s y e t u n t r e a t e d o f by th em .
Nor
i s t h i s s u r p r is i n g s i n c e new d e p r a v a tio n s o f th e humors a r i s e fro m unw onted d i e t s and fro m v a r io u s m ix tu r e s o f th e sam e. Among t h e many d i s e a s e s w h ic h owe t h e i r
o r ig in to t h is
h a s b e e n m o s t r e c e n t l y o b s e r v e d a f e v e r w h ic h i s
age th e r e
c a lle d
S c a r l a t i n a , fr o m t h e c a r m in e c o l o u r w i t h w h i c h a l m o s t t h e w h o le sk in is
tin g e d .
of
t h i s d is e a s e th e o b s e r v a tio n s are n o t so
many t h a t an a c c u r a t e t h e o r y can be d e l i v e r e d o r a m e th o d o f cure c o n s tr u c te d ."
The D is e a s e a s D e s c r ib e d by Dover and M orton in th e L a te S e v e n te e n th C e n tu r y . M e t t l a r ( I 9 4 7 ) s t a t e s t h a t D ov er i n h i s w ork, A n c ie n t p h y s i c i a n ' s Legacy t o d ise a se
"The
h i s C o u n tr y " , d e s c r i b e d t h e
as v e r y m ild in th e l a t e s e v e n t e e n t h c e n t u r y .
By l b 89 in London th e c h a r a c t e r o f s c a r l e t f e v e r had ch an ged t o a much s e v e r e r d i s e a s e a c c o r d in g t o th e p h y s ic ia n M orton .
A q u o ta t io n i s ta k e n from W ith e r in g ( I 7 7 8 ) g i v i n g a s
- 4 M o rto n 's o p in io n - " I t i s
a p o i s o n d e f i l i n g t h e a n im a l s p i r i t s
w h o s e m a l i g n i t y d o e s n o t o n l y o v e r w h e lm t h e s p i r i t s
in i t s
f i r s t a t t a c k h u t b r e a k s down t h e m a s s o f b l o o d b y a g i t a t i o n in to
an a c r i d c o l l u v i e s m ore p o w e r f u l t h a n any o t h e r f e r m e n t . "
The N o r t h A m e r ic a n O u t b r e a k . C r e i g h t o n ( 1 8 9 4 ) s t a t e s t h a t i n E d in b u r g h i n J u n e , 1 7 3 3 , s c a r l e t f e v e r a n a s o r e t h r o a t w e r e f r e q u e n t and many f a t a l casés occurred.
I n t h e y e a r s 1 7 3 4 and 1 7 3 5 t h e r e w e r e
m any f a t a l c a s e s o f s c a r l e t f e v e r i n t h e N o r t h A m e rica n C o lo n ie s.
The d i s e a s e
s t a r t e d i n K i n g s t o n i n New H am p sh ire
a n d w as a new o c c u r r e n c e f o r t h i s
area.
I t came w i t h g r e a t
s u d d e n e s s and k i l l e d o f f many y o u n g p e o p l e .
The c o m p l i c a t i o n
o f n e p h r i t i s w as r e c o g n i s e d a s o c c u r r i n g d u r i n g t h e o u t b r e a k . T ra d e b e t w e e n N o r t h A m e r ic a and S p a i n , P o r t u g a l and G reat B r i t a i n w as a r e g u l a r o c c u r r e n c e a t t h a t t i m e .
S c a r le t fe v e r
w a s a t t h a t t im e p r e v a l e n t i n E n g la n d and S p a i n , and i t u n d o u b t e d l y f o u n d v i r g i n s o i l i n New H a m p s h ir e . p r o b a b ly broke lo o s e im m u n it y .
The d i s e a s e
a m o n g st a p o p u l a t i o n w i t h a p o o r n a t i v e
H o w e v er , a t t h a t t im e s c a r l e t f e v e r was o f a
m a lig n a n t n a tu re in E urope.
A D e s c r ip tio n o f th e D ise a se by P o t h e r g i l l . A cco rd in g to C r e ig h to n (1 8 9 4 )
s i m ila r s e v e r e e p id e m ics
o f t h r o a t d i s t e m p e r o c c u r r e d i n London i n 1 7 3 9 and i n 1 7 4 3 i n Ir e la n d .
Prom 1 7 4 6 to 1 7 4 8 u l c e r o u s
sore th r o a t o ccu rred in
- 3 London and was d e s c r ib e d by P o t h e r g i l l ( I 7 4 8 ) , a p h y s i c ia n o f t h a t t im e .
H is d e s c r i p t i o n o f t h e d i s e a s e i s an e x c e l l e n t one
"In t h i s c o u n tr y a s w e l l a s i n t h o s e w here t h e A n gin a M a lig n a was f i r s t ta k e n n o t i c e o f , c h i l d r e n andyoung p e o p le a r e more ex p S se d t o i t th a n a d u l t s ; th a n b o y s ;
a g r e a t e r number o f g i r l s h a r e i t
more women th a n men;
and th e in f ir m o f e i t h e r s e x
a re more l i a b l e t o h a v e t h e d i s e a s e and t o s u f f e r from i t th a n t h e h e a l t h y and v i g o r o u s .
I have s e e n v e r y fe w grown p e o p le
o f t h i s c l a s s who had i t and n o t one who d ie d o f i t .
If it
b r e a k s o u t in a f a m ily a l l t h e c h ild r e n a re commonly a f f e c t e d w it h i t ,
i f t h e h e a lt h y a re n o t k e p t a p a r t from th e s i c k ;
and
s u c h a d u lt s a s a r e f r e q u e n t l y w it h them and r e c e i v e t h e i r b r e a t h n e a r a t h a n d , o f t e n u n d ergo t h e same d i s e a s e .
It
g e n e r a l l y comes on w it h s u c h a g i d d i n e s s o f t h e h ead a s o f t e n p r e c e d e s f a i n t i n g and a c h i l l i n e s s or s h i v e r i n g l i k e t h a t o f an ague f i t .
T h is i s s o o n f o llo w e d by t h e g r e a t h e a t ;
and t h e s e
in t e r c h a n g e a b ly s u c c e e d e a c h o th e r d u r in g some h o u rs t i l l a t le n g t h t h e h e a t becom es c o n s t a n t and i n t e n s e .
The p a t i e n t th e n
c o m p la in s o f an a c u te p a in in t h e h ea d , o f h e a t and s o r e n e s s r a t h e r th a n p a in in th e t h r o a t , s t i f f n e s s o f t h e n e c k , commonly o f g r e a t s i c k n e s s w it h v o m it in g p u r g in g or b o t h .
The f a c e so o n
a f t e r lo o k s r e d and s w e l l e d , th e e y e s in fla m e d and w a te r y a s in t h e m e a s le s ;
w ith r e s t l e s s n e s s ,
a n x ie t y and f a i n t n e s s .
- 6 . " I f th e mouth and t h r o a t he exam ined s o o n a f t e r th e f i r s t a t t a c k th e u v u la and t o n s i l s ap p ear s w e l le d ;
and t h e s e
p a r t s t o g e t h e r w it h th e Velum Pendulum P a l a t i and th e c h e e k s on ea c h s i d e n e a r th e e n t r a n c e i n t o th e f a u c e s and a s much o f them and t h e ph aryn x b e h in d i t red c o lo u r .
can be s e e n ap p ear o f a f l o r i d
T h is c o lo u r i s commonly m ost o b s e r v a b le on t h e
p o s t e r i o r ed g e o f t h e p a l a t e , in th e a n g le s ab ove th e t o n s i l s and upon th e t o n s i l s t h e m s e lv e s .
In ste a d o f t h is red n e ss a
b road s p o t or p a t c h o f an i r r e g u l a r f i g u r e and o f a p a le w h it e c o lo u r i s so m etim es t o be s e e n su r ro u n d ed b y a f l o r i d r e d ; w h ich w h it e n e s s commonly a p p e a rs l i k e t h a t o f th e gums im m e d ia te ly a f t e r h a v in g b een p r e s s e d w it h t h e f i n g e r or as i f m a tte r r e a d y t o be d is c h a r g e d was c o n t a in e d u n d e r n e a th . " G e n e r a lly on th e s e c o n d day o f th e d i s e a s e
th e f a c e ,
n e c k , b r e a s t and hands to th e f i n g e r en d s a re become o f a deep e r y s i p e l a t o u s c o lo u r w it h a s e n s i b l e t u m e f a c t io n ;
th e f in g e r s
a re f r e q u e n t l y t in g e d in s o rem a rk a b le a manner t h a t from s e e in g them o n ly i t h as n o t b een d i f f i c u l t t o g u e s s a t th e d i s e a s e . g r e a t number o f s m a ll p im p le s o f a c o lo u r d i s t i n g u i s h a b l e more in t e n s e th a n t h a t w h ich su r ro u n d s them ap p ear on th e arms and o th e r p a r t s . "They a re l a r g e r and more p rom in en t in t h e s e s u b j e c t s and in t h e s e p a r t s o f th e same s u b j e c t w here th e r e d n e s s i s l e a s t in te n s e ;
w h ich i s g e n e r a l l y on th e arm s, th e b r e a s t and
t h e lo w e r e x t r e m i t i e s .
A
- 7 "The a p p ea ra n ce in th e f a u c e s c o n t in u e s t o be th e sam e; w h it e ;
e x c e p t t h a t t h e w h ite p l a c e s become o f a more opaque and i t
i s now d i s c o v e r a b l e t h a t what a t f i r s t m igh t
h a v e b een ta k e n f o r th e s u p e r f i c i a l c o v e r in g o f a su p p u r a te d tumour i s r e a l l y a s lo u g h o f th e same d im e n s io n ." "The p u ls e d u r in g t h e w h ole c o u r s e o f th e d i s e a s e i s g e n e r a l l y v e r y q u ic k f r e q u e n t l y 120 s t r o k e s or more a m in u te ; in some i t
i s hard and s m a l l ,
in o t h e r s s o f t and f u l l ;
b ut
w it h o u t th e s t r e n g t h and f ir m n e s s w h ich u s u a l l y a cco m p a n ies e q u a l q u ic k n e s s and h e a t in g e n u in e in fla m a to r y d i s o r d e r s . " The D is e a s e as D e s c r ib e d by W illia m W ith e r in g . A s im i l a r e p id e m ic was o b se r v e d by D r. C o tto n in S t . A lb an s in I 7 4 9 .
The e p id e m ic o f I 7 7 7 - 7 8 in Birm ingham
was r e c o r d e d by T fillia m W ith e r in g ( I 7 7 8 ) .
He n o ted t h e
o c c u r r e n c e o f s c a n t y u r in e and oedem a. "They f e l t a f t e r a fe w d a y s' amendment a s o m e th in g t h a t p r e v e n te d t h e i r f u r t h e r ap p roach t o h e a l t h ; u n a c c o u n ta b le la n g u o r and d e b i l i t y ,
an
t o g e t h e r w it h a s t i f f n e s s
in t h e i r lim b s , an a c c e l e r a t e d p u l s e , d is t u r b e d s l e e p , d i s r e l i s h t o fo o d and a p a u c i t y o f u r i n e . "These symptoms w ere so o n f o llo w e d by an u n i v e r s a l s w e l l i n g o f t h e a n a sa r cou s k in d and so m etim es an a s c i t e s . I n some p a t i e n t s t h e f e v e r i s h d i s p o s i t i o n ra n h ig h ; i t e x i s t e d o n ly in a m od erate d e g r e e .
in o t h e r s
i n some t h e d ro p sy
—8 —
a f f e c t e d th e b r a in p r o d u c in g coma v i g i l ,
d e lir iu m , b l in d n e s s ;
w ith th e m ost e n la r g e d e x p a n s io n o f th e i r i s , w h ic h was in c a p a b le o f c o n t r a c t i o n in t h e s t r o n g e s t l i g h t . " C r e ig h to n (1 8 9 4 ) s t a t e s t h a t th e London B i l l s
of
M o r t a lit y in I 786 show ed 19 d e a th s due t o s o r e t h r o a t and 793 d e a th s due t o m e a s le s . S c a r l e t F e v e r a s i t o c c u r r e d in I r e la n d in 1 8 3 4 . A c c o r d in g t o G raves (1 8 4 3 ), th e fam ous I r i s h p h y s i c i a n , fro m 1804 onwards t h e r e was a lo n g p e r io d o f im m unity from m a lig n a n t s c a r l e t f e v e r in I r e l a n d . E n glan d and S c o t la n d a f t e r I 8 0 5 .
T h is a l s o a p p lie d t o S c a r l e t f e v e r o f a m ild e r
form was common en ou gh a t t h a t t im e .
In 18 3 4 a d i s a s t r o u s
form o f th e d i s e a s e o c c u r r e d in D u b lin .
The e p id e m ic k i l l e d
o f f more p e o p le in th e c i t y th a n c h o le r a had done s e v e r a l y e a r s b e fo r e . The G lasgow F i n d i n g s . The f o l l o w i n g t a b l e g i v e s t h e t o t a l d e a th s from s c a r l a t i n a i n G lasgow in th e y e a r s 1835 t o 1839
(a fte r
C r e ig h to n 1 8 9 4 ) . Under 1 1835 1836 1837 1838 1 8 39
27 34 4 3 29
1 -2
2 -1
5 -1 0
30 37 9 13 43
89 136 34 42 104
73 86 22 17 74
1 0 - 2 0 2 0 -3 0 3 0 -4 0 4 0 up T o ta l 23 25 3 7
7 9 3 1
2 3 1 1
2 3 1 1
-
-
-
-
273 333 79 87 262
- 9 The p o p u la t io n o f th e C it y o f G lasgow a t t h a t p e r io d was — 1821 . . . 1 4 7 , 0 4 3 - C ensus o f G lasgow and L a n a r k s h ir e f i g u r e s I831 ••• 202,426 ,, ,, ,, ,, 1838 . . . 2 6 3 ,0 0 0 - M o r t a lit y B i l l s hy C le la n d . T aking th e p o p u la t io n o f th e C it y o f G lasgow a t t h a t tim e t o be 2 5 0 , 0 0 0 s o u l s t h e d e a t h r a t e s from s c a r l e t f e v e r p e r m i l l i o n w ere 1835
1836
1092
1 ,4 2 0
1837 318
1838
1839
348
1 ,0 4 8
F erg u so n (1 9 4 8 ) r e f e r s t o t h e s e v e r i t y o f th e d i s e a s e a t t h i s p e r io d . From t h e r e p o r t s o f th e M e d ic a l O f f ic e r o f H e a lth o f th e C ity o f G lasgow d e t a i l s o f th e s c a r l e t f e v e r c a s e r a t e p er m i l l i o n o f th e p o p u la tio n p e r annum in th e C it y s i n c e I 900 w ere o b t a in e d .
- 10 G lasgow ; Oase R a te s and D e a th R a te s from S c a r l e t F e v e r per M i l l i o n o f p o p u la t io n from 1 9 0 0 t o 1 9 4 9 .
Year
C ase B a te p er M illio n
1900 1 2 3 4 5 6 7 8 9 19 10 1 2 3 4 5 6 7 8 9 1920 1 2 3 4
6,355 4,353 3 ,2 8 9 2,660 2 ,0 5 8 1,667 1,770 2,253 3,576 5,634 5 ,3 8 2 4,019 3 ,6 8 2 4 ,0 4 6 5,479 6 ,2 0 0 3,910 1 ,8 5 8 1,259 2,567 3,526 3,272 3,233 3,321 2,965
D ea th R a te per M illio n
'
280 180 140 100 90 40 60 50 110 200 190 120 100 130 220 260 150 30 20 40 60 50 60 90 110
Year
Case R ate per M illio n
D ea th R ate per M illio n
1925 0 7 8 9 1930 1 2 3 4 5 6 7 8 9 1940 1 2 3 4 5 0 7 8 9
3,552 4,252 3,777 2,970 3,079 4,555 6,449 8 ,3 6 1 7 ,5 9 3 5 ,3 3 6 3,592 3 ,8 0 1 5 ,0 0 1 3 ,5 8 8 2,625 1,706 1,742 2 ,9 6 4 2 ,9 8 0 3,253 3,254 3,192 3 ,2 4 3 3,521 2 ,1 0 0
70 90 40 30 40 40 60 90 V 89 33 30 26 26 10 10 7 8 5 7 4 1 4 3 3
I n fo r m a tio n a b o u t th e d e a th r a t e p e r m i l l i o n in h a b it a n t s p e r annum f o r th e C it y s i n c e 1855 was in p a r t o b ta in e d from t h e R e g is t e r o f D ea th s and in p a r t from th e r e p o r t s o f t h e M e d ic a l O f f ic e r o f H e a lt h .
T h is in fo r m a t io n i s shown in th e
accom panying fr e q u e n c y p o ly g o n .
There h as b een a f l u c t u a t i n g
v a r i a t i o n in th e c a s e r a t e from y e a r t o y e a r .
In s p i t e o f
t h i s i t w i l l be n o te d t h a t s i n c e 1 8 8 1 t h e r e h a s b een a f a i r l y s t e a d y downward tr e n d in th e d e a th r a t e .
11
-Ê-f[— If m
Crd
aô
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12
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00
t o-
—-k'^(
oo oo
r2 3 l^ 7 t ' I
7^
9p^
-
1)
-
The D is e a s e as i t h a s o c c u r r e d i n G rea t B r i t a i n s i n c e th e E a r ly N in e t e e n th C e n tu r y . In 1 8 4 0 and f o r a w h o le g e n e r a t io n t h e r e a f t e r , s c a r l e t f e v e r was in G rea t B r i t a i n th e l e a d i n g c a u s e o f d e a th am ongst t h e i n f e c t i o u s d i s e a s e s o f c h ild h o o d .
G reat num bers o f
d e a th s o c c u r r e d due t o s c a r l e t f e v e r f o r some t h i r t y or f o r t y y e a r s in th e m id d le o f th e 1 9 th C e n tu r y .
T h is p e r io d had b een
p r o c e e d e d by a w h o le g e n e r a t io n w it h m od erate or s m a l l m o r t a l i t y from t h e d i s e a s e .
In t h e s e y e a r s th e m o r t a l i t y from s c a r l e t
fe V e r made from 4 t o 6% p e r c e n t , o f th e d e a t h s fro m a l l c a u s e s . The enorm ous m o r t a l i t y o f some y e a r s may be ta k e n t o have d ep en d ed in p a r t upon an i n c r e a s e d p r e v a le n c e o f t h e d i s e a s e b u t m a in ly upon an in c r e a s e d v i r u l e n c e o f th e c a s u a l o r g a n ism . The Change in R e l a t i v e Im p o rta n ce o f th e Common C h ild h o o d I n fe c tio u s D is e a s e s . The f o ll o w i n g t a b l e i s e x t r a c t e d from t h e L a n c e t, 1 9 4 9 , 1 , 3 1 7 - G a le . The number o f D ea th s p er M i l l i o n l i v i n g u n d er 15 y e a r s o f age i n E n g la n d and W a le s . Y ea rs
S c a r le t F ever
1 8 5 6 -6 0 1939
“Whooping Cough
2 ,2 0 1 17
1 ,3 9 8 145
M e a s le s 1 ,1 8 5 55
D ip h t h e r ia and Croup 1 ,3 9 7 231
D u rin g th e l a s t 1 0 0 y e a r s i n G reat B r i t a i n t h e r e h as b een l i t t l e
change in th e i n c i d e n c e o f s c a r l e t f e v e r b u t a g r e a t
d e c l i n e in i t s m o r t a l i t y . f o u r common d i s e a s e s i s
The o rd er o f im p o rta n ce o f t h e s e
c h a n g in g .
C ru ik sh an k in 1943 gave t h e
- 14 o r d e r o f p r e c e d e n c e a t t h a t tim e as w h ooping c o u g h , m e a s le s , d i p h t h e r i a and s c a r l e t f e v e r .
S in c e th e n and ow ing t o th e
s u c c e s s o f d i p h t h e r i a im m u n isa tio n , w hooping cou gh and m e a s le s a re
now c o n s id e r e d o f e v e n g rea ter im p o r ta n c e . H ild a Woods in 1955 r e p o r t e d on an e p i d e m i o l o g i c a l
s tu d y o f s c a r l e t f e v e r in E n g lan d and W ales d u r in g t h e p e r io d 19 0 0 t o 1955»
D u rin g t h i s p e r i o d th e d e a th r a t e s from s c a r l e t
f e v e r h a v e s t e a d i l y d im in is h e d and th e d i s e a s e h a s becom e o f r e l a t i v e u n im p o r ta n c e .
She s t a t e s t h a t th e p r e s e n t low l e v e l
o f th e d e a th r a t e may be b u t th e tr o u g h o f th e
wave and t h a t a
much s e v e r e r form o f s c a r l e t f e v e r m ig h t o c c u r a g a in .
The
p r e v io u s h i s t o r y o f s c a r l e t f e v e r s h o u ld be ta k e n as a w a rn in g a g a i n s t undue o p tim ism as r e g a r d s t h e f u t u r e . e p id e m io lo g y o f th e d i s e a s e a s i t
By s t u d y in g th e
a f f e c t e d f o u r o f th e l a r g e s t
tow ns i n E n glan d - London, L i v e r p o o l , Birm ingham and M a n ch ester - s h e show ed t h a t c o n s id e r a b le v a r i a t i o n h a s o c c u r r e d in th e d e c l i n e o f m o r t a l i t y d u r in g t h i s p e r i o d .
In th e p e r io d
1 9 0 I - I 9 1 3 , r e l a t i v e l y th e g r e a t e s t im provem ent in m o r t a l i t y o c c u r r e d in L iv e r p o o l. o c c u rr ed in Birm ingham .
S in c e I 9 I 8 th e g r e a t e s t d e c l i n e h as She s t a t e s t h a t a lth o u g h s c a r l e t f e v e r
has ta k e n a d e c r e a s in g t o l l o f l i f e
d u r in g t h e p e r io d 190 0 - 1 9 3 5 ,
i t h a s n o t g e n e r a l l y d im in is h e d in p r e v a l e n c e . The p r o b a b le R ea so n s f o r th e C hanging S e v e r i t y are D i s c u s s e d . The e p i d e m i o l o g i c a l h i s t o r y o f s c a r l e t f e v e r show s t h a t d u r in g th e a g e s g r e a t v a r i a t i o n s i n th e m o r t a l i t y r a t e have
- 15 occurred.
In some c a s e s i t m ig h t he s a i d t h a t t h e o c c u r r e n c e
o f v i r u l e n t s c a r l e t f e v e r h a s b e e n due t o t h e in t r o d u c t i o n o f / t h e c a s u a l org a n ism i n t o a new com m unity. com m unity had l i t t l e
B e c a u se t h i s
or no p r e v io u s e x p e r ie n c e o f th e d i s e a s e ,
t h e i r n a t i v e o r r a c i a l im m u n ity t o i t was s l i g h t and t h e y w ere s e v e r e l y a f f l i c t e d by t h e d i s e a s e .
T h is e x p la n a t io n m igh t
e x p l a i n th e o c c u r r e n c e o f v i r u l e n t s c a r l e t f e v e r i n Few H am pshire i n 1 7 5 4 .
On th e o t h e r h an d, s c a r l e t f e v e r h a s b een
r e g u l a r l y r e p o r t e d as o c c u r r in g in th e U n it e d Kingdom s i n c e th e 1 7 t h C en tu ry and d u r in g t h i s p e r io d th e i n t e n s i t y o f th e d i s e a s e h a s v a r ie d im m e n se ly .
The h y p o t h e s is o f p o o r n a t iv e
im m unity due t o l a c k o f e x p e r ie n c e o f th e d i s e a s e b y a community f o r many y e a r s w ould n o t ap p ear t o h o ld good h e r e . T h is l e a d s one t o r a i s e th e q u e s t io n as t o w h e th e r or n o t th e d i s e a s e o rg a n ism v a r i e s in i t s p a t h o g e n i c i t y a t d i f f e r e n t t im e s . I t i s known t h a t many d i f f e r e n t t y p e s o f h a e m o ly t ic s t r e p t o c o c c i o c c u r , and i t may be t h e c a s e t h a t c e r t a i n t y p e s have l e s s i n v a s i v e and t o x i c e f f e c t s th a n o t h e r s .
A n oth er e p i d e m i o l o g i c a l
p e c u l i a r i t y o f s c a r l e t f e v e r n o t p r e v i o u s l y m e n tio n e d i n t h i s resum e i s
t h e f a c t , a c c o r d in g t o H ir s c h (1 8 8 3 ), t h a t t h i s d i s e a s e
v e r y r a r e l y o c c u r s i n A s ia or A f r i c a and i f
c a s e s a r e in tr o d u c e d
in t o e i t h e r o f t h e s e c o n t in e n t s from s h i p s no w id e sp r e a d o u tb r e a k occu rs.
A c c o r d in g t o an a n n o t a t io n in th e L a n cet ( I 9 3 I ) P a t e l
o f Bombay d e n ie s t h i s and s t a t e s t h a t th e r a s h i s e a s i l y o v e r
_ i6 lo o k e d i n d ark e k in a . im m u n ity.
The q u e s t io n a g a in a r i s e s o f n a t i v e
Have t h e A s i a t i c s and A f r ic a n s a n a t u r a l im m unity
t o t h i s d i s e a s e or a re c l i m a t i c c o n d i t i o n s im p o r ta n t; fe v e r is
S c a r le t
s t a t e d t o o c cu r i n t r o p i c a l S o u th A m erica am ongst
E u rop ean s and a l s o n a t i v e s o f t h a t a r e a .
The d i s e a s e a l s o
o c c u r s am ongst th e n e g ro p o p u la t io n o f th e U n it e d S t a t e s o f A m erica w it h a s g r e a t a m o r b id it y . r a t e a s i t h a s f o r th e E uropean r a c e s .
In th e p r e s e n t s t a t e o f our k n o w led g e th e
an sw er t o th e q u e s t io n i s
o b scu re.
When s e v e r e c l i n i c a l o u tb r e a k s o f s c a r l e t f e v e r o ccu r t h e y appear t o happen a t i r r e g u l a r i n t e r v a l s and u s u a l l y w it h 30 or 4 0 y e a r s b etw een them . sev ere s ta te is
S c a r l e t f e v e r when in i t s
s a id to a f f l i c t a l l c l a s s e s e q u a l l y .
The f a c t
t h a t s c a r l e t f e v e r h as become a m ild d i s e a s e r e c e n t l y m ig h t be a t t r i b u t e d by some t o th e b e t t e r h o s p i t a l i s a t i o n and c a r e o f th e se p a t ie n t s .
The s t a t i s t i c a l e v id e n c e t h a t i s o l a t i o n h a s
had any e f f e c t upon e i t h e r th e p r e v a le n c e o r m o r t a l i t y i s u n c o n v in c in g .
A cco rd in g t o C ru ik sh an k , p r o b a b ly th e r e a l
r e a s o n f o r th e d e c l i n e in th e m o r t a l i t y r a t e l i e s
in
th e
b e t t e r a l l rou n d s o c i a l c o n d i t i o n s o f t h e p e o p le b u t t h i s t h e o r y aw aits? th e t e s t o f t im e .
The new er form s o f th e r a p y
h ave c o n s id e r a b ly b u t t o a l e s s e r e x t e n t h e lp e d t o a c c e l e r a t e s t i l l f u r t h e r t h i s downward tr e n d in th e d e a th r a t e .
' .f
C h ap ter 2
THE
CAUSAL THE
AGENT
HAEMOLYTIC
OP
SCARLET
FEVER
STREPTOCOCCUS
-
17
-
E a r ly I n v e s t i g a t i o n s . In 1887 L o e f f l e r n o t e d t h e p r e s e n c e o f s t r e p t o c o c c i on th e mucous membrane o f th e t h r o a t in c a s e s o f s c a r l e t f e v e r c o m p lic a te d by d i p h t h e r i a .
K u rth , B a g in sk y and Mervyn
Gordon a l s o a b o u t t h i s tim e c o n s id e r e d t h a t th e s t r e p t o c o c c u s was th e c a u s a l o rg a n ism o f t h e d i s e a s e . An O utbreak o f M ilk -b o r n e S c a r l e t F ev e r in L ondon. An o u tb r e a k o f m ilk -b o r n e s c a r l e t f e v e r o c c u r r in g in London in 1885 and t r a c e d t o a farm in Hendon as a s o u r c e a r o u se d c o n s id e r a b le i n t e r e s t a t t h a t t im e .
Power (1 8 8 6 ) in
a s s o c i a t i o n w it h K le in ( 1 8 8 6 ) , t h e b a c t e r i o l o g i s t t o t h e l o c a l govern m en t b o a r d , i n v e s t i g a t e d t h i s o u tb r e a k .
I t had u s u a l l y
b een r e g a r d e d as n e c e s s a r y t o p ro v e t h a t i n f e c t i o n s h o u ld p r im a r ily have r e a c h e d th e m ilk from a human c a s e o f th e d is e a s e .
C e r ta in m ilk -b o r n e o u tb r e a k s had o c c u r r e d p r e v i o u s l y
and t h e s o u r c e o f t h e i n f e c t i o n had rem a in ed u n t r a c e d .
The
Hendon o u tb r e a k o f 1885 show ed t h a t th e s o u r c e o f th e i n f e c t i o n , th o u g h n o t p r e s e n t in th e m ilk i t s e l f as fo u n d in th e u d d e r , g a in e d e n tr a n c e b y th e i n t r o d u c t io n o f s t r e p t o c o c c i from le s io n s
on th e t e a t s o f t h e cows and t r a n s f e r r e d t o th e m ilk
by t h e hands o f t h e m il k e r . d e s ig n ;
The farm in q u e s t io n was o f good
was n o t in an i n s a n i t a r y c o n d it io n ;
w ere in good h e a l t h .
and th e w o rk ers
The few c a s e s o f s c a r l e t f e v e r a t Hendon
d u r in g th e y e a r had l i v e d some d i s t a n c e away and had o c c u r r e d i n f a m i l i e s w it h no c o n n e c tio n w it h t h e fa rm .
Ho c a l v i n g was
- 18 d one a t t h i s farm and o n ly m ilk was p ro d u ced i h e r e . had b een b o u g h t in some tim e b e f o r e . v e s i c u l a r l e s i o n s on t h e i r u d d e r s .
S e v e r a l o f th e cows had K le in show ed t h a t t h i s
d i s e a s e c o u ld be com m unicated from cow t o cow . a s t r e p t o c o c c u s from t h e s e l e s i o n s .
Few cows
He i s o l a t e d
K le in f u r t h e r r e p o r t e d
t h a t he was a b le t o p ro d u ce by i n o c u l a t i o n o f s t r e p t o c o c c i from c a s e s o f s c a r l e t f e v e r t h i s v e s i c u l a r d i s e a s e on th e u d d er o f cow s.
He a l s o r e p o r t e d t h a t he had i s o l a t e d th e same o r g a n ism
w h ich he had fo u n d in th e Hendon cow s from th e b lo o d s o f f o u r ca ses of s c a r le t fe v e r .
O ther o b s e r v e r s a t t h a t tim e co n
s id e r e d t h a t th e d i s e a s e o f cows r e p o r t e d by K le in was in a c t u a l f a c t cow pox. M ilk -b o r n e S c a r l e t F e v e r in G lasgow in 1 8 9 2 . R u s s e l l and C h alm ers, a t t h a t tim e t h e M e d ic a l O f f i c e r s o f H e a lth f o r G lasgow , r e p o r t e d in 1893 on th e o c c u r r e n c e o f an o u tb r ea k o f s c a r l e t f e v e r in th e C it y c o n n e c te d w it h an e p id e m ic t e a t e r u p t io n on m ilk cows a t J a a p sto n Farm in R e n f r e w s h ir e . T h is o u tb r e a k had o c c u r r e d in A u g u st, 1 8 9 2 , th e t o t a l number o f p a t i e n t s in v o lv e d b e in g 2^4 p e o p le in v o l v i n g 139 f a m i l i e s . S am p les o f p a t h o l o g i c a l m a t e r i a l from th e cows w ere s e n t t o D r. K le in i n London.
He r e p o r t e d t h e p r e s e n c e o f an organ ism
s i m i l a r in p r o p e r t i e s t o t h a t o b t a in e d in th e Hendon o u tb r e a k . The m a t e r i a l p rod u ced on i n o c u l a t i o n i n t o cows s i m i l a r s o r e s to t h o s e fo u n d in th e Hendon o u tb r e a k . o f v a c c in ia in th e s p e c im e n s .
He a l s o d e t e c t e d th e v i r u s
In c o n t r a s t t o t h e Hendon o u tb r e a k
_ 19 t h e s e J a a p s to n c a t t l e p r e s e n t e d no d esq u a m a tin g c o n d it i o n o f th e s k i n and no c o n s t i t u t i o n a l i l l n e s s . The C laim s o f o th e r O rg a n ism s. A bout t h i s p e r io d and s u b s e q u e n t ly th e c la im s o f o th e r o rg a n ism s w ere p u t fo r w a r d .
S e v e r a l w r i t e r s h ave d e s c r ib e d
t h e p r e s e n c e o f d i p l o c o c c i in th e b lo o d , u r in e and t h r o a t o f ca ses o f s c a r le t fe v e r . w o rk er s in t h i s f i e l d .
Di C r i s t i n a and C a ro n ia w ere t h e m ain A v i r u s h a s b een d e s c r ib e d a s b e in g th e
ca u sa l a g e n t. The Case f o r th e H a e m o ly tic S t r e p t o c o c c u s i s s t r o n g . H ow ever, th e c a s e p u t fo rw a rd f o r t h e h a e m o ly t ic str e p to c o c c u s i s
a s tr o n g one and th e f u r t h e r d e v e lo p m e n ts in
th e p r o o f o f t h i s o rg a n ism a s th e ca u se w i l l now be c o n s id e r e d . In 1 9 0 3 , S c h o ttm u lle r d i f f e r e n t i a t e d b etw een th e h a e m o ly t ic s t r e p t o c o c c u s and t h e s t r e p t o c o c c u s w h ich p ro d u ced a g r e e n p ig m e n t on b lo o d a g a r .
F o llo w in g t h i s work t h e
h a e m o ly t ic s t r e p t o c o c c u s was d e s c r ib e d a s o c c u r r in g i n e r y s i p e l a s , p u e r p e r a l s e p s i s and in p y o g e n ic i n f e c t i o n .
I t was
c o n s id e r e d by th e o b s e r v e r s o f t h a t tim e t h a t t h e s e f i n d i n g s th rew d o u b t a s t o w h eth er t h e h a e m o ly t ic s t r e p t o c o c c u s was in f a c t th e c a u se o f s c a r l e t f e v e r .
A p a t i e n t c o u ld s u f f e r from
s c a r l e t f e v e r and y e t l a t e r d e v e lo p e r y s i p e l a s .
I t was u s u a l l y
h e ld t h a t a f t e r an a t t a c k o f s c a r l e t f e v e r a s e c o n d a t t a c k was a r a r e o c c u r r e n c e , w here a s i t was r e c o g n is e d t h a t a p e r s o n c o u ld have r e p e a t e d a t t a c k s o f e r y s i p e l a s .
The argum ent .was r a i s e d
- 20 t h a t i f th e h a e m o ly t io s t r e p t o c o c c u s was in d e e d th e c a u s e o f b o th s c a r l e t f e v e r and e r y s i p e l a s ,
an a t t a c k o f one or o th e r
o f t h e s e d i s e a s e s s h o u ld p r o d u c e an im m unity a g a i n s t b o t h . I t became a c c e p t e d f o r a c o n s id e r a b le tim e a f t e r I 9 0 ) t h a t th e h a e m o ly t ic s t r e p t o c o c c u s was no more th a n an im p o r ta n t s e c o n d a r y in v a d e r . The E a r ly Work o f th e D i c k s . The m odern v ie w on t h e c a u s a t io n o f s c a r l e t f e v e r d a t e s from 1 9 1 4 , t h e y e a r t h a t th e f i r s t work o f th e D ic k s was p u b lis h e d .
In t h e i r f i r s t p a p er t h e y r e p o r t e d on t h e i r c a r e f u l
b a c t e r i o l o g y done on th e b lo o d , u r in e and t h r o a t s e c r e t i o n s o f cases o f s c a r le t fe v e r .
In b lo o d c a l t u r e s from 24 c a s e s made
a n a e r o b i c a l l y p o s i t i v e r e s u l t s w ere o b t a in e d i n 20 c a s e s .
They
fo u n d t h a t d u r in g th e a c u te s t a g e o f s c a r l e t f e v e r o rg a n ism s e n t e r e d th e b lo o d s tr e a m i n c o n s id e r a b le num bers and w ere e x c r e t e d in p a r t in a v i a b l e c o n d it io n th r o u g h t h e k id n e y s .
A
number o f o rg a n ism s w ere d e s c r ib e d w h ic h t h e y fo u n d commonly a s s o c i a t e d w it h c a s e s o f s c a r l e t f e v e r .
The v a r io u s b a c t e r i a
fo u n d were i n o c u l a t e d i n t o s e v e r a l a n im a ls i n c lu d in g g u in e a p i g s b u t i t was fo u n d im p o s s ib le t o s a y t h a t any one o f t h e s e a n im a ls r e a l l y had s c a r l e t f e v e r . L ater, in 1 9 1 6 , t h e y r e p o r t e d t h a t com plem ent d e v i a t i o n and c u ta n e o u s t e s t s f a i l e d t o d e m o n str a te i n c a s e s o f s c a r l e t f e v e r any s p e c i f i c s c a r l a t i n a l v ir u s or a n t ig e n in th e b lo o d
-
21
serum o r in th e e x t r a c t s o f s p le e n o r lym ph g l a n d s .
F ix a tio n
t e s t s w it h t h r o a t mucu© a s a n t ig e n g a v e i n one in s t a n c e a weak f i x a t i o n o f com plem ent w ith th e serum o f a c o n v a le s c e n t s c a r l a t in a l p a tie n t.
S k in t e s t s w ere p e r fo r m e d on s c a r l a t i n a l
c o n v a le s c e n t o a s e s and h a v in g a s c o n t r o l s c o n v a le s c e n t d ip h th e r ia p a t i e n t s .
S c a r l e t f e v e r t h r o a t a n t ig e n , s t r e p t o
c o c c u s a n t ig e n and t o n s i l l i t i s b e f o r e u se were h e a t k i l l e d .
a n t ig e n were u s e d .
The o r g a n is m s
The r e a c t i o n o f th e s k in in c o n
v a le s c e n t s c a r le t f e v e r p a t ie n t s to
a l l t h r e e a n t ig e n s was much
more m arked th a n th e r e a c t i o n o f th e s k in s i n th e d i p h t h e r i a c o n v a le s c e n t c a s e s .
The s i g n i f i c a n c e o f t h i s f in d i n g was n o t
u n d ersto o d . The i n t r a d e m a l T e s t o f S c h u ltz and C h a r lt o n . I n 1 9 I 8 , S c h u lt z and C h a r lto n d is c o v e r e d t h a t t h e i n t r a d e m a l i n j e c t i o n o f c o n v a le s c e n t s c a r l e t f e v e r serum i n t o a s c a r l e t f e v e r r a sh p ro d u ced b la n c h in g . t h i s t e s t was shown by M air in 1 9 2 3 .
The s i g n i f i c a n c e o f He c o n s id e r e d t h a t th e
r e a c t i o n w as on e b e tw e en t o x i n and a n t i t o x i n .
I t w as p o in t e d
o u t t h a t th e f a i l u r e o f th e serum from a p a t i e n t in th e a c u te s t a g e to b la n c h th e r a s h w as b e c a u se th e a n t i t o x i n had n o t a s y e t become e v i d e n t .
T h is b la n c h in g pow er o f t h e serum
i n v a r i a b l y f o llo w e d on an a t t a c k o f s c a r l e t f e v e r .
Som etim es
t h e serum o f a p e r s o n who had n e v e r had s c a r l e t f e v e r had t h i s pow er and t h i s p r o b a b ly showed t h a t t h i s p e r so n had a n a t u r a l im m u n ity.
- 22 _ The fu r t h e r Work o f th e D ic k s . The D icks f i n a l l y p roved t h a t th e h a e m o ly tic s t r e p t o c o cc u s was th e c a u s a l a g en t o f th e d i s e a s e .
They r e a l i s e d
t h a t th e f i n a l o b s t a c le to th e p r o o f o f th e h a e m o ly tic s t r e p t o c o c c u s as a c a u s a l a g e n t was th e f a i l u r e to produce e x p e r im e n ta l s c a r l e t f e v e r in a n im a ls. They had in o c u la t e d la b o r a to r y an im als on th e t h r o a t , s u b c u ta n e o u sly , i n t r a p e r i t o n e a l l y and in tr a v e n o u s ly w ith f r e s h b lo o d serum , b lo o d p lasm a, w hole b lo o d , t h r o a t mucus and u r in a r y sed im en t from c a s e s o f s c a r l e t f e v e r and a l l w ith n e g a t iv e r e s u lts .
Erasmus Darwin had many y e a r s p r e v io u s ly s u g g e s te d
th e in o c u la t io n o f th e human s u b j e c t w ith s c a r l e t f e v e r m a t e r ia l as a p r e v e n tiv e on th e same b a s is as v a c c in a t io n a g a in s t sm a llp o x . B e fo re th e D ick s ( 1 9 2 I ) d id t h e i r human in o c u la t io n t e s t s th e y perform ed immune r e a c t i o n s t o d eterm in e where th e organism s were p r e s e n t in g r e a t e s t number in c a s e s o f th e d is e a s e .
The c u lt u r e s from th e th r o a t gave p o s i t i v e r e s u l t s
w ith Complement F ix a t io n T e s t s .
E xp erim en ts were perform ed
on human s u b j e c t s in o c u la te d su b c u ta n e o u sly w ith w hole b lo o d from s c a r l e t f e v e r c a s e s w ith n e g a t iv e r e s u l t .
The serum
Was p a in te d on th e th r o a t and a g a in t h i s gave n e g a tiv e r e s u l t s . The c a u s a l organ ism , i t was assum ed, was n o t p r e s e n t in th e b lo o d stream in th e e a r ly s t a g e s o f s c a r l e t f e v e r .
Throat
s e c r e t i o n s o b ta in e d e a r ly in th e d is e a s e were shaken in b ro th
- 23 _ and t h i s m a t e r i a l p a s s e d th r o u g h a B e r k e f e ld F i l t e r .
The
v o lu n t e e r s i n o c u l a t e d on th e t h r o a t w it h t h i s m a t e r ia l rem a in ed w e l l . The Use o f B a e m o ly tic S t r e p t o c o c c i I s o l a t e d from a L e s io n on th e F in g e r o f a N u r s e . In 1923 th e y i n o c u l a t e d th e t h r o a t s o f f i v e v o lu n t e e r s w ith f i v e c u l t u r e s o f a h a e m o ly t ic s t r e p t o c o c c u s i s o l a t e d from a le s io n
on th e f i n g e r o f a n u r s e .
T h is n u r s e had a c q u ir e d
th e d i s e a s e w h ile c a r in g f o r a c o n v a le s c e n t s c a r l e t f e v e r p a t ie n t.
T hree o f t h e s e p e o p le rem ain ed w e l l , one had a s o r e
t h r o a t b u t no r a s h and th e f i f t h fe v e r .
d e v e lo p e d d e f i n i t e s c a r l e t
O ther v o l u n t e e r s w ere in o c u la t e d on th e t h r o a t w it h a
c u lt u r e o f t h e same o rg a n ism a f t e r p a s s a g e th r o u g h a B e r k e f e ld V C a n d le.
T h is f i l t r a t e had no e f f e c t
on th e f i v e v o l u n t e e r s .
A f t e r e le v e n d a y s t h e y w ere i n o c u l a t e d w ith t h e u n f i l t e r e d c u ltu r e .
One o f th e c a s e s had m a la is e and s o r e t h r o a t b u t no
r a s h 34 h o u rs a f t e r i n o c u l a t i o n , one had a s o r e t h r o a t d e v e lo p in g on t h e f i f t h day a f t e r i n o c u l a t i o n and l a s t i n g f o r one d ay, and two rem a in ed w e l l .
The o th e r v o lu n t e e r o f th e s e r i e s , a
woman aged 23 y e a r s , was i n o c u l a t e d w it h an u n f i l t e r e d c u lt u r e o f th e h a e m o ly tic s t r e p t o c o c c u s on th e 1 3 th d ay a f t e r in o c u l a t i o n w ith th e f i l t e r e d
c u ltu r e .
F o r t y - e i g h t h o u rs l a t e r sh e
had d e v e lo p e d d e f i n i t e s c a r l e t f e v e r . The D evelop m en t o f th e D ic k T est . The n e x t q u e s t io n t o be an sw ered was why o n ly two o u t o f th e t e n v o lu n t e e r s d e v e lo p e d s c a r l e t f e v e r .
They d e v e lo p e d a
- 24 t e s t w h ich i s now known a s th e D ick T e s t ( 1 9 2 4 ) .
H a e m o ly tic
s t r e p t o c o c c i w ere fo u n d i n th e t h r o a t and v e r y r a r e l y i n th e b lo o d o f c a s e s o f th e d i s e a s e .
T h is s u g g e s t e d t h a t a t o x i n
Was p ro d u ced by th e o rg a n ism i n th e t h r o a t and t h i s t o x i n w as r e s p o n s i b l e f o r th e r a s h .
I n tr a d e r m a l i n j e c t i o n s o f th e
B e r k e f e ld iff f i l t r a t e w ere c a r r i e d o u t . 1 ,0 0 0 ( i n s t e r i l e
0 .1 c . c . o f a 1 in
s a l t s o l u t i o n ) f i l t r a t e when i n j e c t e d in t o
t h e s k in o f p e o p le w it h no h i s t o r y o f s c a r l e t f e v e r g a v e s k in r e a c t i o n s w it h in f i v e h o u r s i n 4 1 .6 p e r c e n t , o f o a s e s .
In
a l l t h e c o n v a le s c e n t s c a r l e t f e v e r p a t i e n t s t e s t e d , n e g a t iv e o r o n ly s l i g h t l y p o s i t i v e r e s u l t s o c c u r r e d .
P e o p le g i v i n g a
n e g a t i v e D ick T e s t a re u s u a l l y c o n s id e r e d immune t o t h e d i s e a s e . N abarro and S ig n y ( 1 9 3 1 ) s t a t e t h a t i n e a r l y c a s c s o f s c a r l e t f e v e r o n ly a b o u t 40 p e r c e n t , o f p a t i e n t s a r e D ick p o s i t i v e . They e x p l a i n t h a t th e s k in h a s a d im in is h e d r e a c t i v i t y t o a l l t o x i n s i n th e e a r l y s t a g e s o f an a c u te i n f e c t i o u s d i s e a s e . B o th i n s c a r l e t f e v e r and in m e a s le s t h e r e i s a le s s e n e d r e a c t i v i t y t o t u b e r c u li n and s t r e p t o c o c c u s t o x i n s . The U se o f H on-M annite F e rm e n tin g S t r e p t o c o c c i . The f i r s t t e s t s p r o d u c in g s c a r l e t f e v e r by t h r o a t i n o c u l a t i o n u s e d m a n n ite fe r m e n tin g h a e m o ly t ic s t r e p t o c o c c i . N on-m an n ite fe r m e n tin g o r g a n ism s ta k e n from th e t h r o a t o f a s c a r l e t f e v e r p a t i e n t w ere u s e d t o i n o c u l a t e th e t h r o a t o f tw o v o lu n t e e r s ( D ic k s 1 9 2 4 ) .
The v o l u n t e e r who show ed th e
n e g a t i v e s k in t e s t rem ain ed w e l l and d id n o t d e v e lo p a s o r e
- 23 th r o a t, fe v e r or a ra sh .
The v o l u n t e e r who show ed a p o s i t i v e
s k i n t e s t d e v e lo p e d s c a r l e t f e v e r .
The h a e m o ly t ic s t r e p t o c o c c u s ,
t h e D ic k s c o n s id e r e d , had f u l f i l l e d
a l l t h e r e q u ir e m e n ts o f
K o c h 's p o s t u l a t e .
K och c o n s id e r e d t h a t b e f o r e an o r g a n ism
c o u ld b e h e ld t o be th e c a u s a l a g e n t th e f o ll o w in g r u l e s s h o u ld be o b se rv ed . d is e a s e .
The o r g a n ism s h o u ld a lw a y s be a s s o c i a t e d w it h th e
I t m ust be i s o l a t e d in p ure c u l t u r e and s h o u ld in
p u re c u lt u r e rep ro d u ce th e d i s e a s e i n a h e a lt h y s u s c e p t i b l e a n im a l.
The o rg a n ism m ust b e i s o l a t e d i n p u re c u lt u r e from
t h e l e s i o n s o f th e i n o c u l a t e d a n im a l.
The work o f th e D ic k s
h a s b ee n c o n fir m e d by v a r io u s o t h e r a u t h o r i t i e s .
Chapter 3
THE
DIFFEREMIATION BY
OF
VARIOUS
THE
STfiBPTOCOCCUS
MEA2SS
— 26 —
The D i f f e r e n t i a t i o n by M o r p h o lo g ic a l C h a r a c t e r i s t i c s . The f i r s t a tte m p ts t o d i f f e r e n t i a t e t h e s t r e p t o c o c c u s w ere b a se d on m o r p h o lo g ic a l c h a r a c t e r i s t i c s .
S tr e p to c o c c i
w ere d iv id e d i n t o s t r e p t o c o c c u s lo n g u e and b r e v i s , a c c o r d in g t o th e l e n g t h o f c h a in s e e n u n d er th e m ic r o s c o p e .
L a te r
a tte m p ts w ere made u s i n g f e r m e n t a t io n t e s t s on s u g a r t o d i f f e r e n t i a t e t h e o r g a n ism . D i f f e r e n t i a t i o n by H a e m o ly sis o f B lood A g a r. S c h o ttfflu lle r in 1903 d i f f e r e n t i a t e d th e o rg a n ism in t o two t y p e s u s in g a s t h e t e s t t h e c a p a c it y t o p rod u ce h a e m o ly s is on b lo o d agar p l a t e s . d e fin ite l y s i s
The s t r e p t o c o c c u s h a e m o ly tic u s p ro d u ced
and th e s t r e p t o c o c c u s v i r i d a n s p rod u ced c o l o n i e s
su rro u n d ed by a g r e e n i s h z o n e .
U s in g th e c l a s s i f i c a t i o n o f
S m ith and Brown ( I 9 1 9 ) w h ich i s an advan ce on th e o r i g i n a l work o f S c h o t t m u lle r , s t r e p t o c o c c i can be d i f f e r e n t i a t e d i n t o t h r e e d i s t i n c t t y p e s when grown in p ou red p l a t e s o f b lo o d a g a r .
The
f i r s t t y p e i s t h e a lp h a t y p e in w h ich th e c o l o n i e s a re u s u a l l y su rro u n d ed b y a zon e o f g r e e n c o l o r a t i o n , on th e o u t s id e o f w h ich can be s e e n a t h i n c l e a r zone o f c o m p le te l y s i s . s tr e p to c o c c u s v ir id a n s i s
o f t h is ty p e .
The
The se c o n d ty p e i s
th e b e t a ty p e around c o l o n i e s o f w h ich can be fo u n d a d e f i n i t e c l e a r zone o f h a e m o ly s is .
T h is t y p e i s
th e h a e m o ly tic s t r e p t o
c o c c u s a s f i r s t d e s c r ib e d by S c h o t t m u lle r .
The t h i r d ty p e i s
th e gamma t y p e , around th e c o l o n i e s o f w h ich no change o c c u r s i n th e m ed ia .
The s t r e p t o c o c c u s f a e c a l i s b e lo n g s t o t h i s t y p e .
- 27 D i f f e r e n t i a t i o n o f t h e H a e m o ly t ic S t r e p t o c o c c u s i n t o T y p es b y A g g lu tin a tio n T e s t s .
U s in g a g g l u t i n a t i o n and a g g l u t i n i n a b s o r p t io n t e s t s , S m ith ,
J o n e s , G r i f f i t h (1 9 3 4 )
and o t h e r s show ed t h a t th e
h a e m o ly t ic s t r e p t o c o c c i i s o l a t e d from c a s e s o f s c a r l e t f e v e r c a n n o t be clum ped t o g e t h e r i n t o on e g ro u p .
G r iffith
(1 9 3 4 )
h a s i s o l a t e d 30 s e r o l o g i c a l l y d i f f e r e n t t y p e s o f h a e m o ly t ic s tr e p to c o c c i.
The com m onest G r i f f i t h ty p e s fo u n d in s c a r l e t
f e v e r a r e 1 , 2 , 3 and 4 .
The a n t i s e r a f o r t h e G r i f f i t h t e s t
a re o b t a in e d by i n j e c t i n g r a b b i t s w it h k i l l e d ty p e s t r a i n s o f h a e m o ly t ic s t r e p t o c o c c i .
c u l t u r e s o f known
A n t is e r a u s u a l l y show
c r o s s r e a c t i o n and h ave t o be p u r i f i e d by a b s o r p t io n w it h o th e r ty p es.
In p e r fo r m in g th e t e s t a p r e lim in a r y t r i a l i s u s u a l l y
c a r r ie d o u t u s i n g p o o le d a n t i s e r a , e a c h r e p r e s e n t i n g f i v e t y p e s , ^ en
an a g g l u t i n a t i o n r e a c t i o n i s fou n d w it h a p o o le d s e r a th e
i n d i v i d u a l ty p e s e r a a r e th e n t r i e d .
The a g g l u t i n a t i o n t e s t
i s done b y a s l i d e m eth o d , th e a g g l u t i n a t i o n b e in g v i s i b l e t o t h e naked e y e in a fe w m in u t e s . fo u n d i t
B urton and B alm ain (1 9 2 9 )
im p o s s ib le t o c o r r e l a t e th e ty p e o f h a e m o ly t ic s t r e p t o
co c c u s w it h t h e c l i n i c a l ty p e o f s c a r l e t f e v e r . D iffe r e n tia tio n
i n t o G roups b y p r e c i p i t a t i o n R e a c t i o n s .
L a n c e f i e l d ( s e e M ack ie and M cC artney 1 9 4 8 ) by means o f p r e c ip it a t i o n r e a c t io n w ith a n t is e r a has d is c o v e r e d v a r io u s groups o f s t r e p t o c o c c i. a g ro u p s p e c i f i c
The p r e c i p i t a t i o n r e a c t i o n d e p e n d s on
a n tig e n o f th e n a tu r e o f a c a r b o h y d r a te .
It
- 28 h a s b een fo u n d p o s s i b l e t o c o r r e l a t e t h i s g r o u p in g t o a c e r t a i n e x t e n t w it h w h e th e r or n o t t h e o r g a n ism i s p a t h o g e n ic t o man or t o t h e v a r iô u s a n im a ls .
L a n c e f ie l d Group A i s
fo u n d t o g i v e b e t a h a e m o ly s is when grown upon b lo o d a g a r and t h i s grou p in c l u d e s a l l G r i f f i t h t y p e s w it h t h e e x c e p t io n o f t y p e s 7 , 1 6 , 20 and 2 1 .
I t i s th e m ost im p o r ta n t group from
th e m e d ic a l p o in t o f v ie w and s t r a i n s b e lo n g in g t o i t p a t h o g e n ic t o man.
are
The g r e a t m a j o r it y o f h a e m o ly t ic s t r e p t o
c o c c i c a u s in g d i s e a s e in man b e lo n g t o Group A L a n c e f ie ld c la s s ific a tio n .
She h a s shown t h a t t h r e e w e l l d e f in e d
im m u n o lo g ic a l com ponents in h a e m o ly t ic s t r e p t o c o c c i a r e im p o r ta n t.
T here i s a t y p e s p e c i f i c p r o t e i n M, w h ic h , in th e
c a s e o f Group A s t r a i n s , d i f f e r e n t i a t e s t y p e s i n a g reem en t w it h th e G r i f f i t h a g g l u t i n a t i o n t e s t s .
T here i s
a ls o a n o n -s p e c ific
p r o t e i n p and a group s p e c i f i c c a r b o h y d r a te C.
L a n c e f ie ld
u s i n g group s p e c i f i c c a r b o h y d r a te C in h e r p r e c i p i t a t i o n t e s t s was a b le t o d i f f e r e n t i a t e h e r v a r io u s g r o u p s o f s t r e p t o c o c c i . The U n it a r ia n H y p o t h e s is . F o llo w in g upon t h e work o f G r i f f i t h and L a n c e f ie ld i t h a s now come t o be c o n s id e r e d t h a t t h e r e i s no s e r o l o g i c a l d i s t i n c t i o n b etw een th e s c a r l a t i n a l s t r a i n s o f h a e m o ly tic s t r e p t o c o c c i and h a e m o ly t ic s t r e p t o c o c c i fro m o th e r l e s i o n s in th e human s u b j e c t ( O k e ll 1 9 3 2 ) .
p r io r t o t h i s ,
ow ing t o th e
work o f Gordon (1 9 2 1 ) i t had been c o n s id e r e d t h a t s e r o l o g i c a l l y
- 29 th e str e p to c o c c u s s c a r la t in a s tr e p to c o c c u s p yogen es. t h i s v ie w .
was q u i t e d i s t i n c t from t h e
T u n n i c l i f f and B l i s s a l s o h e ld
The modern b e l i e f r e g a r d in g human s t r e p t o c o c c a l
i n f e c t i o n s i s b a se d on t h e s o - c a l l e d U n it a r ia n H y p o t h e s is . The v a r io u s c e llu litis ,
s t r e p t o c o c c a l d i s e a s e s , su c h as e r y s i p e l a s , p u e r p e r a l s e p s i s , s c a r l e t f e v e r and s o r e t h r o a t ,
a re a l l c a u se d by th e one s p e c i e s o f h a e m o ly t ic s t r e p t o c o c c u s . The g r e a t d i v e r s i t y o f a c t i o n i s e x p la in e d by t h e v a r i a b i l i t y i n th e s t r e n g t h o f th e t h r e e p a t h o g e n ic com ponents o f t h e h a e m o ly t ic s t r e p t o c o c c u s .
T h ese com ponents a r e t h e t o x i g e n i c ,
t h e p y o g e n ic and th e i n v a s i v e e le m e n t s .
The t o x i c a c t i o n o f
th e o rg a n ism i s due t o th e e r y t h r o g e n ic f a c t o r .
In s c a r l e t
f e v e r t h e t o x i c com ponent i s t h e im p o r ta n t f a c t o r , in p u e r p e r a l s e p s i s th e p y o g e n ic e le m e n t i s more p r o m in e n t, and in s e p t ic a e m i a t h e i n v a s i v e f a c t o r .
S e r o lo g ic a lly id e n t ic a l
s t r a i n s h ave b een i s o l a t e d from c a s e s o f s c a r l e t f e v e r , s o r e t h r o a t , e r y s ip e la s and th e o th e r s t r e p t o c o c c a l i n f e c t i o n s . In s c a r l e t f e v e r th e t o x i c com ponent i s r e s p o n s i b l e f o r th e v o m it in g , t h e h ea d a ch e and t h e r a s h . e n t i s d e m o n str a te d by th e t o n s i l l i t i s
The p y o g e n ic compon
and s e p t i c c o m p lic a t io n s ,
s u c h a s o t i t i s m ed ia , a d e n i t i s and s i n u s i t i s , w h ich may o c c u r . In s c a r l e t f e v e r t h e i n v a s i v e f a c t o r i s v e r y v a r i a b l e b u t d o e s n o t u s u a l l y p la y a b i g p a r t . I t w ou ld ap p ear t h a t t h e v a r io u s s t r a i n s o f h a e m o ly t ic s t r e p t o c o c c i p ro d u ce t h e same e r y t h r o g e n ic f a c t o r b u t c e r t a i n
- 30 s t r a i n s p rod u ce g r e a t e r q u a n t i t i e s th a n o t h e r s .
A ls o i t
a p p ea r s t h a t t h e e r y t h r o g e n ic f a c t o r v a r i e s in i n d i v i d u a l s t r a in s a t d if f e r e n t t im e s .
E it h e r o f t h e s e two f a c t s m igh t
e x p la i n th e v a r i a t i o n i n t h e t o x i c i t y o f s c a r l e t f e v e r a t d i f f e r e n t p e r io d s o f t im e .
On t h e o th e r hand t h e t r u e
e x p la n a t io n o f th e v a r i a b i l i t y o f t h e d i s e a s e a t d i f f e r e n t p e r io d s may w e l l r e s t w it h t h e h o s t and h i s v a r i a b le r e s i s t a n c e o r , as i s more p r o b a b le , on a c o m b in a tio n o f a l l t h e s e f a c t o r s .
C h a p ter 4 .
PBBTearTIVB
IHQQIJLATIOHS OF
SQABLBg
IH
(ESS
FSTBR.
COlfTBOL
- 31 "* E a r ly S u g g e s t io n s on P r e v e n t i o n . H ektoen i n 1 9 2 3 r e v ie w e d t h e h i s t o r y o f e x p e r im e n ta l s c a r l e t f e v e r i n man.
Erasm us D arw in , th e f a t h e r o f C h a r le s
D a rw in , s t a t e d - "No one c o u ld do an a c t more b e n e f i c i a l t o s o c i e t y o r g l o r i o u s t o h i m s e l f th a n b y t e a c h in g h u m a n ity how t o in o c u la te t h i s d is e a s e ; m a lig n ity .
and t h u s t o d e p r iv e i t o f i t s
M a tte r m ig h t b e ta k e n from t h e u l c e r s i n t h e
t h r o a t w h ich w o u ld p r o b a b ly co n v ey t h e c o n t a g io n .
Or warm
w a t e r m ig h t be p u t on th e e z iip tio n and s c r a p e d o f f a g a in b y t h e ed g e o f a l a n c e t .
T hese e x p e r im e n ts c o u ld be a t t e n d e d by
no d a n g e r and s h o u ld be t r i e d f o r th e p u b l i c b e n e f i t and t h e h o n o u r o f th e m e d ic a l s c i e n c e . ” S tr u v e i n 1802 h e ld t h a t th e s u r e s t m eans o f p r e v e n t io n w as t o d e s t r o y th e r e c e p t i v i t y b y an a t t a c k o f t h e d i s e a s e i t s e l f and he em p h a sise d th e s u c c e s s s a id t o have b e e n o b t a in e d b y t h e i n o c u l a t i o n o f m e a s le s .
He s a i d t h a t in a l l p r o b a b i l i t y
t h e i n o c u l a t i o n o f s c a r l e t f e v e r w o ia d a c c o m p lis h j u s t a s m uch a s t h e i n o c u l a t i o n o f sm a llp o x and t h a t i t p r o b a b ly w o u ld b e a cco m p a n ied w i t h d a n g e r s o f th e same k in d .
V a c c in a t io n w as
c l e a r l y d e s i r a b l e w it h b lo o d , s a l i v a , s c a b s o r m a t e r ia l from u l c e r s i n th e t h r o a t o f s c a r l e t f e v e r p a t i e n t s and c a r e m ust b e t a k e n to p r e v e n t t h e n a t u r a l ^ tr a n s m is s io n o f t h e d i s e a s e . Salm an Hudson o f W h it t le s a y , O h io , i n 1862 d e s c r ib e d t i e a c c i d e n t a l i n o c u l a t i o n o f s c a r l e t f e v e r w i t h s m a llp o x v a c c i n e . T w e n ty -th r e e o f t h i r t y c h i l d r e n v a c c in a t e d w it h th e same v a c c in e m a t t e r d e v e lo p e d s c a r l e t f e v e r .
The d e t a i l s o f t h i s p a r t i c u l a r
- 32 in c id e n t a r e , how ever, v ery v a g u e. be
The above m eth od s a p p e a r t o
very d r a s t i c p r o c e d u r e s , a t te m p tin g t o p ro d u ce im m u n ity t o
t h e d i s e a s e b y a c t u a l l y i n o c u l a t i n g th e l i v e h a e m o ly tio a tr e p to c o c c u s. The P r e v e n t iv e V a c c in e o f G & b ritso h ew sk y . In 1907 G a b r itsc h e w sk y p ro d u c e d a v a c c in e u s in g h a e m o ly t ic s t r e p t o c o c c i f o r p r e v e n t iv e i n o c u l a t i o n .
H is v a c c in e c o n s i s t e d
o f h e a t k i l l e d b r o t h c u l t u r e s o f h e a r t b lo o d from f a t a l c a s e s o f s c a r le t fe v e r .
A c e r t a i n p e r c e n ta g e o f c h i l d r e n i n o c u l a t e d w it h
t h i s v a c c in e d e v e lo p e d a r a s h s i m i l a r t o s c a r l e t f e v e r b u t w i t h o u t d e sq u a m a tio n . v o m it e d .
S e v e r a l d e v e lo p e d a s o r e t h r o a t and o t h e r s
C h ild r e n who had a lr e a d y had s c a r l e t f e v e r had v e r y
s li g h t r e a c tio n s . se v e r e r e a c tio n .
The se co n d and l a t e r d o s e s d id n o t p ro d u ce G a b r itsc h e w sk y and h i s c o -w o r k e r s im m unised
i n t h e p e r io d 1906 to 1910 more them 5 0 ,0 0 0 p e o p le i n B u s s ia . F i f t e e n p e r c e n t , o f t h e s e c a s e s d e v e lo p e d r a s h e s a f t e r in o c u la tio n .
He c o n s id e r e d t h a t he had p r o v e d t h a t th e s t r e p t o c o c c u s
w as th e c a u se o f s c a r l e t f e v e r .
R u s sia n w o rk ers b e l i e v e d t h a t
t h i s v a c c in e m a t e r i a l l y r ed u ced t h e in c id e n c e o f t h e d i s e a s e . H i k i t i n in 19 2 6 gave d e t a i l s i n an A m erican J o u r n a l o f t h e t r i a l s w it h t h i s v a c c in e p erfo rm ed i n B u s s ia i n 1 9 0 6 . The
i n o c u l a t i o n Method u s in g S c a r l e t F e v e r T oxin d e v e lo p e d b y th e D i c k s . p r e v e n tiv e
The D ic k s ( 1 9 2 4 ) d e v e lo p e d a m ethod o f a c t i v e p r e v e n t iv e iB 00u l » t i 0B . t o x ia la to
I h i . t h e y a c h ie v e d h y i a j e o t l B g n a i l d o a e . o f
s u a o e p t ib le i a d i T i d u a l a ,
Some o f t h e i r e a p e r im e a t a l
- 33 s u b j e c t s d e v e lo p e d t h e s i g n s and symptoms o f s c a r l e t f e v e r .
The
u s u a l reg im e recommended was t o s t a r t w it h 250 s k in t e s t d o s e s and t o g i v e t h e r e a f t e r a t w e e k ly i n t e r v a l s 5 0 0 , 1 , 0 0 0 , 2 ,5 0 0 and 5 ,0 0 0 s k in t e s t d o s e s .
A th o u sa n d s k in d o s e s a s a f i r s t
i n o c u l a t i o n i n a s u s c e p t i b l e i n d i v i d u a l (D ic k p o s i t i v e p e r s o n ) w o u ld p ro d u ce i n m ost c a s e s a s c a r l e t f e v e r r a s h , h ea d a ch e and v o m it in g .
T h is i s u n d e s ir a b le and t h e r e f o r e a s m a ll f i r s t d o se
is
There a r e o t h e r m eth od s u s in g d i f f e r e n t d o s e s b u t
g iv e n .
a l l a re b a se d e s s e n t i a l l y on th e same t e c h n iq u e . A h ig h p e r c e n t a g e o f D ick p o s i t i v e to
a D ick n e g a t iv e s t a t e b y t h i s m eth o d .
r e a c t o r s a re ch a n g ed Those c a s e s w ere
t h e r e f o r e c o n s id e r e d t o have d e v e lo p e d im m u n ity.
The d u r a t io n
o f t h i s im m unity i s v e r y v a r i a b l e and i s b etw een e i g h t m on th s and s i x y e e ir s .
T h is m ethod h a s b e e n t o a g r e a t e x t e n t r e s t r i c t
e d t o t h e im m u n isa tio n o f n u r s in g and m e d ic a l s t a f f s i n f e v e r h o s p ita ls .
Owing to th e v e r y m ild form o f s c a r l e t f e v e r
p r e v a l e n t a t th e p r e s e n t tim e th e m ethod i s
r a r e l y p r a c t i s e d now.
A M ethod o f P a s s iv e Im m u n isa tio n . A m ethod o f p a s s i v e im m u n isa tio n i s
a v a i l a b l e w hereby
a s m a ll d ose o f s c a r l e t f e v e r a n t i t o x i n i s g iv e n in t r a m u s c u la r ly s o o n a f t e r ex p o su r e t o a c a s e o f th e d i s e a s e .
T h is m ethod
p r e v e n t s th e o n s e t o f t h e d i s e a s e b u t t h e im m unity o n ly l a s t s up t o t e n d a y s .
T h is m ethod i s a l s o r a r e l y p r a c t i s e d to d a y
b e c a u s e o f th e m ild n e s s o f th e i l l n e s s .
Cowie ( 1 9 3 0 ) gave
2 ^ t o 5 c .b m s . o f s c a r l e t F e v e r A n t it o x in a s p a s s i v e im m unisa t i o n to c a s e s a d m itte d a s s c a r l e t f e v e r b u t w it h no r a s h on
- 34 a d m is s io n w i t h g o o d r e s u l t .
Graham ( 1 9 2 5 } u s in g D oohez S c a r l e t
F e v e r A n t i t o x i n w as o f t h e o p in io n t h a t p a s s i v e im m u n isa tio n c o u l d he e s t a b l i s h e d i f th e tr e a tm e n t w as g iv e n on th e f i r s t d a y . J o n e s ( 1 9 2 8 ) , K irk h op e ( 1 9 2 6 ) , H a in e s ( I 9 2 6 ) and c o w o r k e r s , J o e and sw y er ( 1 9 2 9 ) , and many o t h e r o b s e r v e r s r e p o r t e d f a v o u r a b ly on th e p r e v e n t i v e a c t i o n o f s c a r l e t f e v e r a n tito x in .
G a r r e tt ( I 9 2 6 ) , th e M .O.H. f o r C h elten h am , w as o f
t h e o p in io n t h a t t h e work o f l a i n e s w as n o t c o n c l u s i v e , a s s c a r l e t f e v e r d o e s n o t a lw a y s s p r e a d .
C h a p ter 5 .
TTTR
SBHDM
THBAPMEEfT
S O A B IS T J ir a
OF
-
33
-
E a r ly A ttem p ts t o p ro d u c e a C u r a tiv e Serum . The f i r s t e f f o r t t o p rod u ce a c u r a t i v e serum f o r s t r e p t o c o c c u s i n f e c t i o n w as made h y Maxmorek i n 1 8 9 5 . p r o d u c e d an a n tis e r u m h y i n j e c t i n g l i v i n g c u lt u r e i n t o a h o r s e .
I n 1902 M oser
s tr e p to e o o c i in b r o th
The s t r e p t o c o c c i u s e d i n t h i s e x p e r im e n t
w ere o b t a in e d from c a s e s o f s c a r l e t f e v e r . t o g i v e V a r ia b le r e s u l t s .
T h is serum was fou n d
I t w as w id e ly u s e d f o r a c o n s id e r a b le
t im e b u t i t l a t e r f e l l in t o d is r e p u t e b e c a u s e o f t h i s f a c t .
In
1 9 0 5 , S a v ch en k o , a R u s sia n i n v e s t i g a t o r , p r o v e d t h a t M o s e r 's serum c o n t a in e d b o t h a n t i t o x i c and a n t i b a c t e r i a l s u b s t a n c e s . He s e p a r a t e d o f f by f i l t r a t i o n from b r o t h c u l t u r e s o f s t r e p t o c o c c i a p o ten t t o x in .
The f a i l u r e o f M o s e r 's serum to g i v e
un.jfQ rm r e s u l t s was c o n s id e r e d t o b e due to th e f a c t t h a t t h e seru m w as i n p a r t a n t i b a c t e r i a l and in pax*t a n t i t o x i c .
The a n t i —
^ o x ic f a c t o r was c o n s id e r e d to be v e r y v a r i a b l e i n d i f f e r e n t b a tch es. The
^ n t i - g t r e p t o o o c o a l Serum o f P och ez and Sherm an. P o ch ez and Sherman i n 1924 p ro d u ced an a n t i - s t r e p t o c o c c a l
seru m .
They i n j e c t e d a g a r in t o h o r s e s .
A f t e r th e a g a r had
s o l i d i f i e d , h a e m o ly tic s t r e p t o c o c c i i s o l a t e d from o a s e s o f s c a r l e t f e v e r w ere i n j e c t e d i n t o t h i s m a t e r i a l . fo rm ed a s t h e r e s u l t o f t h i s o p e r a t i o n .
An a b s c e s s
They th o u g h t t h a t th e
h a e m o ly t ic s t r e p t o c o c c i w ou ld p ro d u ce an a b s o r b a b le t o x i n and t h a t t h e in o c u l a t e d h o r s e w o u ld resp o n d b y t h e p r o d u c t io n o f a n tito x in .
The P ic k s ( 1 9 3 8 ) s u g g e s t e d t h a t i n f a c t th e p r o d u c t
w a s an a n t i - s t r e p t o c o c c a l a n t ib o d y .
H ow ever, i t i s u s u a l l y
—
36
—
c o n s i d e r e d t h a t b y t h e m eth od o f D ooh ez a c o n s i d e r a b l e
q u a n tity
o f a n t i t o x i n i s p r o d u c e d a s w e l l a s an a n t i - s t r e p t o c o c c a l f a c t o r . P a r k ( I 9 2 5 ) c o n s i d e r e d t h a t t h e a n t i - s c a r l a t i n a l seru m o f M o ser and S a v ch en k o p r o d u c e d th e same t h e r a p e u t i c r e s u l t s a s t h a t p r o d u c e d b y t h e D o ch ez m e th o d .
The v a lu e o f th e
e a r l i e r p r o d u c t s w a s g r e a t l y h a n d ic a p p e d b y t h e l a c k o f any m e a n s s u c h a s th e S c h u l t z C h a r lto n and D ic k m eth o d f o r e s t i m a t i n g th e a n t i t o x i c p o t e n c y . in
B ecau se o f t h i s la c k ,
serum weak
a n t i t o x i n w as u n d o u b te d ly f r e q u e n t l y u s e d w i t h d i s a p p o i n t i n g
r e s u lts . B ir k h a u g ( I 9 2 5 ) r e p o r t e d on t h e u s e o f c o n v a l e s c e n t s c a r le t
f e v e r serum and D och ez s c a r l a t i n a l a n t i - s t r e p t o c o c c i c
seru m i n th e t r e a t m e n t o f t h e d i s e a s e . b y 15 t o 85 c . c . fe v e r.
He t r e a t e d e a c h p a t i e n t
o f serum from c o n v a l e s c e n t c a s e s o f s c a r l e t
T h i r t y - s e v e n c a s e s in a l l w ere t r e a t e d and t h e r e w as a
r a p i d im p ro v em en t i n th e g e n e r a l sy m p to m s, w i t h a s l i g h t f a l l in
te m p e r a tu r e and p u l s e r a t e b u t no e f f e c t on t h e g e n e r a l r a s h
w as n o t ic e d .
The c o n v a le s c e n c e w as n o t s h o r t e n e d n o r was t h e
in c id e n c e o f s e p t ic
c o m p lic a tio n s r e d u c e d .
He t r e a t e d 31 c a s e s
o f s c a r l e t f e v e r u s i n g a s th e i n d i v i d u a l d o s a g e 40 c . c . D o o h ez seru m .
T here w as a r a p id d is a p p e a r a n c e o f t h e t o x a e m ia ,
a c r i t i c a l f a l l i n te m p e r a tu r e and p u l s e ra sh .
of
r a t e and f a d i n g o f t h e
G la n d u la r e n la r g e m e n t r a p i d l y d is a p p e a r e d an d s e p t i c
c o m p l i c a t i o n s w ere f e w .
The serum w a s g i v e n e a r l y and t h i s
w a s s t r e s s e d a s b e in g an im p o r t a n t f a c t o r .
-
37 -
B la k e i n 1 9 2 4 r e p o r t e d f a v o u r a b ly on th e u s e o f D oohez i n t i - s t r e p t o c o o o a l Serum. fiv e
I n 12 e a r l y c a s e s o f s c a r l e t f e v e r ,
o f w h ic h w ere s e v e r e l y t o x i c , a d m in is t r a t io n o f th e serum
w as f o ll o w e d b y r a p id and c o m p le te r e c o v e r y w i t h in 12 t o h o u rs.
36
I n a l l b u t th e two m ost s e v e r e o a s e s , a s i n g l e i n t r a
m u s c u la r i n j e c t i o n o f from 40 t o 6o c . c . o f serum s u f f i c e d . I n t h e two e x tr e m e ly t o x i c o a s e s , a p p r o x im a te ly 200 c . c . w ere r e q u ir e d .
D ochez serum w as a l s o fou n d t o p o s s e s s t h e c a p a c it y
t o b la n c h c o m p le t e ly and p e z m a n e n tly t h e exan th em i n a l o c a l a r e a a b ou t th e s i t e o f an in t r a o u t a n e o u s i n j e c t i o n i n p a t i e n t s w ith s c a r le t fe v e r .
That t h i s w as a s p e c i f i c p r o p e r t y o f t h e
serum w as i n d i c a t e d b y th e n e g a t iv e c o n t r o l t e s t s u s i n g norm al h o r s e serum and a p o l y v a l e n t a n t i - s t r e p t o c o c c u s h o r s e serum . K irk h o p e ( 1 9 2 6 ) , Robb ( 1 9 2 6 ) , L in d s a y ( 1 9 2 6 ) , Z in g h e r (1 9 2 6 ) and many o t h e r w o rk ers had s a t i s f a c t o r y r e s u l t s u s in g th e serum p r e p a r e d by D o ch ez.
On th e o t h e r h an d , T henebe ( 1 9 2 5 ) , Graham
( 1 9 2 5 ) , and S c o t t ( 1 9 2 8 ) fo u n d t h a t th e t h e r a p e u t ic i n j e c t i o n o f t h i s serum g a v e l i t t l e The
A n tito x ic
r e lie f.
serum p r e p a r e d by t h e D i c k s .
The D ic k s ( 1 9 3 8 ) , h o w e v er, c o n s id e r e d t h a t th e r e s u l t s d e s c r i b e d i n th e m e d ic a l l i t e r a t u r e a s h a v in g b e e n o b t a in e d w i t h t h e Doohez and Shezman serum w ere a c t u a l l y o b t a in e d w it h serum p r e p a r e d b y a com bined m ethod t h a t in c lu d e d i n j e c t i o n o f s c a r l e t f e v e r t o x in a s w e l l a s l i v i n g s t r e p t o c o c c u s a g a r c u ltu r e s .
They a l s o
s t a t e t h a t D ochez and Shezman d e n ie d th e
-
38
-
e x i s t e n c e o f b o t h th e s c a r l e t f e v e r t o x i n and a n t i t o x i n d e s c r i b e d b y th em .
The D ic k s ( 1 9 2 4 ) d e v e lo p e d a m ethod o f
p r e v e n t i v e i n o c u l a t i o n and an a n t i t o x i c c u r a t i v e seru m .
The
m eth od o f m a n u fa ctu re o f t h e serum w as t h a t f l a s k s o f b r o t h and o n e p e r o e n t . d e f i b r i n a t e d s h e e p ' s b lo o d w ere in o c u l a t e d w it h h a e m o ly t ic s t r e p t o c o c c i and in c u b a te d f o r s i x d a y s .
The
m a t e r i a l w as th e n f i l t e r e d th r o u g h a B e r k e f e ld N o r W f i l t e r . T h is f i l t r a t e was i n o c u l a t e d i n t o h o r s e s s u b o u ta n e o u s ly in g r a d u a l l y i n c r e a s i n g d o s e s b e g in n in g w it h 20 c . c . and in c r e a s i n g u n t i l one l i t r e
d o s e s w ere b e in g i n o c u l a t e d .
The h o r s e w as th e n
b l e d and th e serum o b t a in e d . The D ick a n t i t o x i n p o te n c y can be d e t e m i n e d b y . t h r e e m eth o d s ( 1 ) The a b i l i t y t o p rod u ce th e S c h u ltz C h a r lto n r e a c tio n . ( 2 ) N e u t r a l i s a t i o n o f t h e D ick t e s t t o x i n . ( 3 ) The r e v e r s a l o f D ick p o s i t i v e
r e s u l t s when a n t i
t o x in i s in j e c t e d in to a s u s c e p t ib le p e r s o n . M ethods ( 2 ) and ( 3 ) w ere u s e d b y t h e D ic k s t o s ta n d a r d is e
t h e ir a n tito x in .
A s k in t e s t d o e s o f t o x in w as d e f in e d a s
t h e minimum amount o f t o x i n w h ich when i n j e c t e d in t o th e s k in o f a s u s c e p t i b l e s u b j e c t p ro d u ced i n 24 h o u rs an e r y th e m a to u s r e a c t i o n o f a t l e a s t 1 cm. d ia m e t e r .
An amount o f s c a r l e t
f e v e r t o x i n , c o r r e s p o n d in g t o 1 ,0 0 0 s k in t e s t d o s e s , i s
c a p a b le
o f c a u s in g g e n e r a l m a l a i s e , n a u s e a , v o m itin g and f e v e r o f 1 0 1 ° P. an d a g e n e r a l i s e d s c a r l e t f e v e r r a s h i n s u s c e p t i b l e a d u l t s .
“ 39 “ The s t r e n g t h o f th e s c a r l e t f e v e r a n t i t o x i n h a s b een m ea su red b y t h e p ow er o f th e p r o d u c t t o n e u t r a l i s e
s c a r le t f e v e r t o x in
a s ju d g e d by th e S c h u lt z C h a r lto n r e a c t i o n i n e a r l y c a s e s o r a f t e r i n j e c t i o n o f s c a r l e t f e v e r t o x in in t r a d e z m a lly i n t o s u s c e p tib le in d iv id u a ls .
One c u b ic cm. o f serum s h o u ld
n e u t r a l i s e a t l e a s t 1 ,0 0 0 s k in t e s t d o s e s o f t o x i n . To p r o t e c t an e x p o s e d s u s c e p t i b l e p e r s o n from t a k in g t h e d i s e a s e 1 2 0 ,0 0 0 s k in t e s t d o s e s o f a n t i t o x i n a re s t a t e d t o b e r e q u ir e d and s h o u ld be g iv e n a s so o n a s p o s s i b l e a f t e r e x p o s u r e to i n f e c t i o n . l a s t s 10 d a y s .o r s o .
The im m unity d e v e lo p s i n 24 h o u rs and F o r c u r a t iv e p u r p o s e s , h a l f - a - m i l l i o n
s k i n t e s t d o s e s a re r e q u ir e d .
P a r is h and O k e ll (1 9 2 7 ) d ev elq p -
e d a m ethod o f t i t r a t i o n o f s c a r l e t f e v e r a n t i t o x i n i n r a b b it s By t h i s m ethod s c a r l e t f e v e r a n t i s e r a can be com pared am ongst th e m s e lv e s . The D ick a n t i t o x i n b r in g s down th e te m p e r a tu r e , d im in i s h e s th e r a s h , d im in is h e s c o m p lic a t io n s and i s u s e f u l i n t o x i c o a s e s when g i v e n e a r l y .
I t h a s , h o w ev er, l i t t l e
on s e p t i c o a s e s o f s c a r l e t f e v e r .
e ffe c t
B la k e and T rask ( 1 9 2 6 ) fo u n d
t h a t s c a r l e t f e v e r a n t i t o x i n i n p r o p e r am ounts w as a s p e c i f i c and prompt cu re f o r u n o o n ç )lio a te d s c a r l e t f e v e r .
They s t a t e d
t h a t i t d i r e c t l y b e n e f i t t e d th e s e p t i c c o n q p lic a tio n d u r in g th e a c u t e s t a g e o f s c a r l e t f e v e r , p re su m a b ly b y c u r in g t h e s p e c i f i c t o x a e m ia .
The a n t i s e r a was fo u n d t o be o f no v a lu e a f t e r th e
r a s h had fa d e d .
Ora i g ( 1 9 2 8 ) r e p o r t e d f a v o u r a b ly on th e t r e a t
m en t and p r o p h y la x is o f s c a r l e t f e v e r w it h s p e c i f i c a n t i t o x i c
- 40 seru m .
A nderson and L eon ard ( I 9 2 6 ) , C u sh in g ( 1 9 2 6 ) and o t h e r s
a l s o had g o o d r e s u l t s . Hunt ( 1 9 3 3 ) s t u d i e d 2 ,3 o 3 o a s e s o f s c a r l e t f e v e r , o f w h ic h number 882 w ere t r e a t e d w it h a n t i t o x i n ; d ay o f i l l n e s s ,
184 on th e f i r s t
245 on t h e seco n d d a y , 213 on th e t h i r d d a y ,
1 1 8 on th e f o u r t h d a y , and 122 a f t e r th e f o u r t h d a y .
He com pared
t h e in c id e n c e o f c o m p lic a t io n s i n e a c h group w it h t h a t i n 1 ,4 2 1 o a s e s t r e a t e d w it h o u t a n t i t o x i n and he fo u n d a p r o g r e s s i v e i n c r e a s e i n c o m p lic a t io n s w it h e a c h day o f d e la y in g i v i n g th e a n tito x in .
The D ic k s (1 9 3 8 ) on r e f e r r i n g to t h i s work s t a t e
t h a t t h e r e i s no a s p e c t o f s c a r l e t f e v e r w h ic h i s n o t pronqptly b e n e f i t t e d b y e a r l y a d m in is t r a t io n o f t h e a n t i t o x i n .
O th er
a u t h o r s have had fa v o u r a b le r e s u l t s u s in g th e D ick a n t i s e r a , an d i t
i s g e n e r a l l y a g r e e d th a t th e a n t i s e r a d o e s com bat
s u c c e s s f u l l y t h e t o x i c e f f e c t s o f th e d i s e a s e i f g iv e n e a r l y . On r e a d in g t h e l i t e r a t u r e on t h i s s u b j e c t one i s f o r c e d t o t h e c o n c l u s i o n t h a t many o b s e r v e r s d id n o t c a r e f u l l y r e p o r t w h ic h ty p e o f c u r a t iv e a n t i s e r a w as u s e d . to
I t i s th u s d i f f i c u l t
g e t a c l e a r c u t p i c t u r e o f th e r e l a t i v e m e r it s o f t h e s e r a
p r o d u c e d by th e D oohez m ethod and t h a t p r o d u c e d by th e D ick m e th o d . An I n c r e a s e o f D ic k P o s i t i v e R e a c t o r s i n C o n v a le s c e n c e a m o n g st O a se s t r e a t e d b y S e r o t h e r a p y .
B u rto n and B a lm ain (1 9 2 9 ) r e p o r t e d t h a t a c o n s id e r a b le p r o p o r t io n o f D ick p o s i t i v e ( s u s c e p t i b l e ) r e a c t o r s o c c u r r e d i n c o n v a le s c e n t s c a r l e t f e v e r p a t i e n t s .
The number o f D ick
- 41 p o s i t i v e r e a c t o r s w as fo u n d to be in c r e a s e d when a n t i s c a r l a t i n a l serum had b een u s e d f o r t h e r a p y .
B u rto n and
B a lm a in ( 1 9 2 8 ) fo u n d t h a t r e l a p s e s i n s c a r l e t f e v e r c o n v a l e s c e n t s w ere more common a f t e r a n t i t o x i n t h e r a p y .
The r e la p s e
r a t e w as 4 .1 6 p e r c e n t , i n t h e s e c a s e s com pared w it h th e a c c e p t e d f i g u r e o f 1 to 2 p e r c e n t , f o r c a s e s n o t so t r e a t e d . T hey f u r t h e r p u t fo rw a r d th e v ie w t h a t c a s e s o f s c a r l e t f e v e r i n i s o l a t i o n h o s p i t a l s s h o u ld be D ick t e s t e d a t th e en d o f t h e t h i r d w eek and t h a t D ick p o s i t i v e
r e a c t o r s s h o u ld be i s o l a t e d
i n c u b i c l e s o r p a s s i v e l y im m u n ised . I n t r a v e n o u s A n t ito x in in S c a r l e t F e v e r . Banks and M ack en zie ( 1 9 2 9 ) fo u n d t h a t in t r a v e n o u s a n t i t o x i n a d m in is te r e d in th e a c u te s t a g e o f s c a r l e t f e v e r s to p p e d t h e a c u te p r o c e s s w i t h in a few h o u r s and p r e v e n t e d c o n ç l i c a t i o n s and p erm an en t damage to h e a l t h . h o s p i t a l w as g r e a t l y r e d u c e d .
The p e r io d o f r e s id e n c e in They fo u n d , h o w e v e r , t h a t p r o t e i n
s h o c k o c c u r r e d and t h e y c o n s id e r e d t h a t c e r t a i n c a s é s s h o u ld b e e x c lu d e d from t h i s t r e a t m e n t .
When c o m p lic a t io n s had o c c u r r e d
t h e a n t i t o x i n had no e f f e c t as a c u r e .
Twenty c .c m s . o f a
c o n c e n t r a t e d serum w ere u s e d f o r th e s e v e r e a d u lt c a s e and 10 c .c m s . f o r a c h i l d o r a m od erate c a s e .
Be rum r e a c t i o n s o c c u r r e d
i n 60 p e r c e n t , o f c a s e s . s e p t i c a e m i a t r e a t e d b y S c a r l e t F e v e r A n t is e r u m .
Lord and H olm es ( 1 9 3 0 ) t r e a t e d one c a s e o f c l i n i c a l s e p t ic a e m ia w it h 10 c c . a n t i s c a r l a t i n a l serum g iv e n i n t r a m u s c u la r ly w it h g ood r e s u l t .
- 42 The U se o f G o n v a le s o e n t Serum and W hole B lo o d . In 1897 W e ie e b e e k e r t r e a t e d o a s e s o f s o a r l e t f e v e r by i n j e o t i o n s o f serum o b t a in e d b y b l e e d i n g p a t i e n t s r e c o v e r e d from t h e d i s e a s e .
The r e s u l t s , h o w e v e r , w ere n o t g o o d .
L a n g er
i n 1925 r e p o r t e d on t h e u se o f c o n v a l e s c e n t serum and i n an i m p e r f e c t l y c o n t r o l l e d s e r i e s fo u n d a r e d u c e d d e a t h r a t e . d o sa g e u s e d w as b etw ee n 30 and 70 c .c .
The
Bode i n t h a t y e a r a ls o
g a v e a f a v o u r a b le r e p o r t , th e d o sa g e he u s e d b e in g b e tw e e n 40 a n d 100 c . c .
The serum o f t h e c o n v a le s c e n t p a t i e n t w as s t a t e d
t o be e f f e c t i v e
i f w ith d ra w n b e tw een th e t h i r d and s i x t h w eek s
a f t e r th e a t t a c k .
P a r a f (1 9 2 3 ) had a f a v o u r a b le r e s u l t i n a
c a s e o f m a lig n a n t s c a r l e t f e v e r .
W e isse n b a c h ( I 9 2 5 ) u s e d
c o n v a l e s c e n t b lo o d in d o sa g e o f 23 o . c . w it h f a v o u r a b le r e s u l t s i n one v e r y t o x i c c a s e .
D a n ie l ( I 9 2 3 ) a l s o had f a v o u r a b le
r e s u l t s w it h c o n v a l e s c e n t w h o le b lo o d . Bhoads and G azul ( 1 9 3 4 ) have shown b y t i t r a t i o n m eth o d s t h a t 12 l o t s o f p o o le d c o n v a le s c e n t serum c o n t a in e d an a v e r a g e p o t e n c y o f o n ly 300 n e u t r a l i s i n g u n i t s o f a n t i t o x i n p e r c u b ic c . m . , a s com pared to 1 3 ,0 0 0 u n i t s p e r c u b ic c .m . in com m ercial a n tito x in .
H oyne, L e v in s o n and T h a lim e r ( 1 9 3 5 ) r e p o r t e d fa v o u r -
a b le r e s u l t s u s i n g d o s e s o f 40 c . c . o f c o n v a le s c e n t seru m . Some o b s e r v e r s s u g g e s t t h a t human c o n v a l e s c e n t serum h a s an a n t i b a c t e r i a l e f f e c t a s w e l l a s an a n t i t o x i c a c t i o n .
I t has a
g r e a t a d v a n ta g e o v e r h o r s e serum w i t h r e s p e c t to s a f e t y when e i t h e r h as t o be u s e d i n t r a v e n o u s l y . T hese m eth od s u s i n g c o n v a le s c e n t b lo o d o r serum demand
- 43 *“ h o w e v e r a v e r y l a r g e d o s e and t h e u s e o f h o r s e a n t i s e r a i s m uch t o he p r e f e r r e d .
The o r i g i n a l o b j e c t i o n t o h o r e e aerum
b e c a u s e o f many a n t i s e r a i s k i n and g e n e r a l i s e d r e a c t i o n s h a s now b e e n l a r g e l y m et b y t h e u s e o f c o n c e n t r a t e d and p u r i f i e d g lo b u lin a n t ito x in s .
The m eth o d o f m a n u fa c tu r e o r i g i n a l l y
d e s c r i b e d b y t h e D ic k s i s
com m only u s e d .
In o rd er to en su re
t h a t t h e i r t o x i n w a s a lw a y s m a n u fa c tu r e d c o r r e c t l y t h e D ic k s p a te n te d th e ir p r o c e s s .
T hey d id n o t , h o w e v e r , r e c e i v e a n y
r o y a l t i e s f o r th e u se o f t h e i r t e c h n iq u e s .
Chapter 6 .
ÆHË
USE
Qg
SULPHDBiMl.DB3 IBf
scABLHiT
# y sa.
- 44 The I n t r o d u c t io n o f th e S u lp h o n e a tid e s . B e fo r e th e i n t r o d u c t i o n o f t h e su lp h o n a m id e s i t w as b e l i e v e d t h a t o n ly th e P r o to z o a w ere s u s c e p t i b l e to chemo th e r a p y .
The i n t r o d u c t i o n o f t h e su lp h on am id e group o f d ru gs
i n t o t h e r a p e u t i c s was on e o f th e m ost im p o r ta n t e v e n t s in t h e h i s t o r y o f m e d ic in e .
The e v o l u t i o n o f th e su lp h o n a m id e s was
d u e to th e German dye c h e m is t s and t h e i r s e a r c h f o r i n t e r n a l a n t i s e p t i c s and a n t i - m a l a r i a l d r u g s .
F ren ch r e s e a r c h w o rk ers
p u t fo rw a r d th e h y p o t h e s is t h a t th e t h e r a p e u t i c a l l y a c t i v e p a r t o f S u lp h o n a m id e-c ry s o i d in ( r e d p r o n t o s i l ) w as th e su lp h o n a m id e m o r d a n t.
à dye to be o f v a lu e m ust c o lo u r t h e t e x t i l e
a l s o m ust h o ld f a s t .
and
The c o lo u r in g p a r t and th e f i x i n g p a r t
(m o r d a n t) may be com bined a s one c h e m ic a l o r be s e p a r a t e .
One
o f th e m o st v a lu a b le m ordant g ro u p s i s th e S u lp h o n ic Group (-S 0 2 0 H ). I n 1 9 3 3 Domagh u s in g m ice p r o v e d t h a t p r o n t o s i l ( 2 : 4 d ia m in o azo b en zen e - 4 - su lp h o n am id e) had m arked p r o t e c t i v e an d t h e r a p e u t ic v a lu e i n e x p e r im e n ta l s t r e p t o c o c c i c i n f e c t i o n s . He fo u n d t h a t i f m ic e w ere i n o c u la t e d i n t rap e r i to n e a l l y w it h t e n minimum l e t h a l d o s e s o f s t r e p t o c o c c u s p y o g e n e s t h e y s u r v iv e d if
t h e y w ere g iv e n ^ /lO to ^ /3 0 o f th e maximum t o l e r a t e a d o se o f
p r o n to s il.
P r o n t o s i l w as fo u n d to have no a c t io n upon b a c t e r i a
in v itr o .
L a te r i t w as shown t h a t p r o n t o s i l was b rok en down i n
t h e t i s s u e s i n t o t r i amino b en zen e and p a r a amino b e n z e n e su lp h o n a m id e ( s u lp h a n ila m id e ) .
T h is s u b s t a n c e , s u lp h a n ila m id e ,
-
43
_
w a s fo u n d to be e f f e c t i v e t h e r a p e u t i c a l l y and a c t i v e ev en in v itr o .
Demagh b e l i e v e d t h a t t h e d ru g ( p r o n t o s i l ) had i t s
e f f e c t b y an en h an cem en t o f th e p h a g o c y t o s is o f th e s t r e p t o c o c c i b y th e l e u c o c y t e s .
There have b een many o t h e r t h e o r i e s
a s to th e m ethod o f a c t i o n o f th e d r u g .
I t i s now f a i r l y
g e n e r a l l y a c c e p t e d t h a t t h e a c t io n o f th e su lp h o n a m id e s upon s u s c e p t i b l e o r g a n ism s i s b a c t e r i o s t a t i c r a t h e r th a n b a c t e r i o c id a l.
The r a t e o f r e p r o d u c tio n o f t h e o rg a n ism i s red u ced
and n o m a l p h a g o c y t o s i s i s g iv e n a b e t t e r ch an ce o f d e a li n g w i t h th e in v a d in g o r g a n is m . ly tic
F lem in g show ed t h a t th e haem o-
s t r e p t o c o c c i , w h ic h w ere n o t k i l l e d b y s u lp h a p y r id in e
a l o n e , w ere r a p i d l y d e s t r o y e d i n th e p r e s e n c e o f l e u c o c y t e s . The su lp h o n a m id e group o f d r u g s, w it h one e x c e p t io n m a r f a n i l , a re a n t a g o n is e d by th e p r e s e n c e o f sm a ll c o n c e n t r a t i o n s o f p a r a amino b e n z o ic a c i d .
I t i s h e ld b y some t h a t
t h e su lp h o n a m id e s and p a r a amino b e n z o ic a c id com pete f o r an en zym ic sy ste m a s s o c i a t e d w it h th e R e p r o d u ctio n o f o r g a n ism s (Beaum ont and D odds, 1 9 4 8 ) . Q l i n i c a l T r i a l s u s in g th e S u lp h o n a m id e s. P e t e r s and H avard ( 1 9 3 7 ) u s e d p r o s e p t a s i n e
(p a r a
b e n z l amino b e n z e n e s u lp h o n a m id e ) i n t h e t r e a t m e n t o f 1 3 0 o a se s o f s c a r le t fe v e r .
T here w ere 1 3 0 c o n t r o l s .
T hey a l s o
t r i e d t h e d ru g on 47 c a s e s o f e r y s i p e l a s and 18 o t h e r h a e m o ly t ic str e p to c o c c a l in fe c tio n s . to
a g e from 0 . 7 3 gm. t o
The d o s a g e g i v e n v a r i e d a c c o r d in g
6 gm s. p e r d a y b y m outh and in t a b l e t
fo r m d iv id e d in t o f o u r - h o u r ly d o s a g e .
F u ll d osage w as g iv e n
- 46 f o r two d ays and h a l f d o sa g e f o r a f u r t h e r p e r io d o f two to fo u r d a y s.
The maximum q u a n t it y g iv e n was 2 2 .3 gm s. The
a d m in i s t r a t i o n o f P r o s e p t a s i n e t o s c a r l e t f e v e r p a t i e n t s r e d u c e d t h e number o f p a t i e n t s h a v in g c o m p lic a t io n s from 30 p e r c e n t , i n th e c o n t r o l s e r i e s t o 33 p e r c e n t , i n th e t r i a l . a ls o
They
r e p o r t e d t h a t i n e r y s i p e l a s th e s p r e a d o f th e d i s e a s e w as
a r r e s t e d in 24 h o u r s i n a l l o f 47 c a s e s . H o g a rth (1 9 3 7 ) i n h i s p a p e r d i s c u s s e d th e f a c t t h a t th e c u r a t i v e a c t i o n o f P r o n t o s i l ( 4 sulp h am id o 2 - 4 diamimo azo ben^oL) o n i n f e c t i o n s c a u s e d b y th e h a e m o ly tic s t r e p t o c o c c i was due t o t h e r e d u c t io n p r o d u c t s o f th e su lp h o n a m id e s.
He fo u n d t h a t in
a c o n t r o l l e d s e r i e s o f 114 p a t i e n t s w it h s c a r l e t f e v e r d u r in g t h e p e r io d J u l y , 1 9 3 6 , t o May, 1 9 3 7 , t h e a d m in is t r a t io n o f P r o s e p t a s i n e (p a r a b e n z l amino b en zen e su lp h o n a m id e) had no s i g n i f i c a n t e f f e c t upon th e d u r a t io n o f th e i n i t i a l p y r e x i a , t h e i n i t i a l to x a e m ia o r th e in c id e n c e o f c o m p lic a t io n s .
He
p u t fo r w a rd t h r e e s u g g e s t e d c a u s e s f o r th e f a i l u r e o f th e drug in h is t e s t .
The m ild n e s s o f t h e i l l n e s s m ig h t h e th o u g h t h a v e
a r e la tio n s h ip .
He a l s o p u t fo rw a rd th e v ie w t h a t a h a e m o ly t ic
s t r e p t o c o c c u s r e s i s t a n t to sulp h on am ide m ig h t be th e c a u s e . He t h i r d l y s t a t e d t h a t w h i l s t i t
i s l e s s t o x i c th e p a r a b e n z l ^ ^ / amino b en zen e su lp h on am id e i s a l s o l e s s a c t i v e th a n i t s
com panion r e d u c t io n p r o d u c t .
He u se d a s a d o sa g e f o r c a s e s
u n d e r f i v e y e a r s 0 .3 gm. t w ic e d a i l y f o r t h r e e d a y s and th en 0 . 3 gm. once d a i l y f o r f o u r d a y s .
From t h e l 6 t h day o f th e
i l l n e s s he gave 0 ; 3 gm* o n ce d a i l y f o r s e v e n d a y s .
O ver th e
- 47 age o f f i v e y e a r s he g a v e 0*3 gm» t h r e e t im e s a day f o r t h r e e d a y s , th e n 0*3 gm. t w io e p e r day f o r f o u r d a y s , and from th e l 6t h
day 0 . 3 gm. t w ic e a day f o r s e v e n d a y s .
The o b j e c t o f
g i v i n g th e d o sa g e i n th e two p e r io d s o f th e i l l n e s s was t o c o v e r th e t o x i c p e r i o d and a l s o th e tim e when c o m p lic a t io n s m o st commonly o c c u r due to r e - i n f e c t i o n . S a k o , Dwan and P l a t o u (1 9 3 8 ) t r e a t e d 100 c a s e s o f s c a r l e t f e v e r w it h s u lp h a n ila m id e (p a r a amino b en zen e s u lp h o n a m id e ) and c o n t r o l l e d th e t e s t by a 100 c a s e s n o t so t r e a t e d , ju aon g st tn e s u lp h a n ila m id e group c o m p lic a t io n s d e v e lo p e d in e i g h t c a s e s , w h e r e a s 41 o c c u r r e d in th e c o n t r o l g r o u p .
The
r a t e o f r e c o v e r y from th e a c u te t o x i c p h a se o f th e d i s e a s e am on gst th e t r e a t s a sam p le a s com pared w it h t h e c o n t r o l s w as n o t a c c e le r a te d .
T h e ir d o sa g e w as 0 .0 3 gm. p e r l b . body w e ig h t
i n i t i a l d o se and a m a in te n a n c e d o se o f 0 .0 3 gm. p e r l b . i n 24 h ou rs.
T h is d o sa g e was c o n t in u e d f o r an a v e r a g e o f 12 d a y s .
C y a n o s is w it h o u t su lp h -h a e m o g lo b in e m ia was o b s e r v e d i n s e v e r a l ca ses.
Strom ( 1 9 3 9 ) u s i n g P r o n t o s i l Bubrum c o n s i d e r e d t h a t th e drug s h o r t e n e d t h e d u r a t io n o f t h e p r im a r y s c a r l e t f e v e r , r e d u c e d t h e f r e q u e n c y o f c o m p l i c a t i o n s and p r o b a b ly a l s o c o n f e r r e d some p r o t e c t i o n a g a i n s t new e x o g e n ic i n f e c t i o n s .
Gordon e t a l .
(1 9 4 1 ) u s in g s u lp h a n ila m id e had s u c c e s s f u l
r e s u l t s a g a i n s t s e p t i c c o m p li c a t io n s .
The f e b r i l e p e r io d was
h o w ev e r th e same a s in th e c o n t r o l g r o u p .
- 48 P f a f f e h b i c k l e r t r e a t e d 130 s c a r l e t f e v e r c a s e s w it h P r o n t o s i l f o r e i g h t d a y s and u s e d a s i m i l a r number o f c a s e s as c o n tr o ls . ra te.
He had go o d r e s u l t s i n r e d u c in g th e c o m p lic a t io n
Of th e t r e a t e d , 4 6 . 6 p e r c e n t , had an u n c o m p lic a te d
c o n v a le s c e n c e com pared w it h 2 6 . 6 p e r c e n t , o f t h e c o n t r o l s . B o z a l i s ( 1 9 4 0 ) e t a l . u s in g s u lp h a n ila m id e fo u n d an a p p a r e n t r e d u c t io n i n th e number o f s e p t i c c o m p li c a t io n s . Benn ( 1 9 3 9 ) u s i n g s u lp h a n ila m id e had f a v o u r a b le r e s u lts .
Two hundred and f i f t y - t h r e e c a s e s o f s c a r l e t f e v e r
i n c h i l d r e n u n d er t e n y e a r s w ere t r e a t e d i n a l l and t h e r e w ere 261 c o n t r o ls .
The d o sa g e was 0 .7 3 gm. f o r c h ild r e n u n d er two
y e a r s , 1 . 3 gm. f o r c h i l d r e n t h r e e to s e v e n y e a r s , and 3 gm s. f o r c h i l d r e n o v e r e i g h t y e a r g , in 24 h o u r s .
The d a i l y amount
w as d i v i d e d i n t o t h r e e e q u a l d o s e s and i t w as c o n t in u e d u n t i l t h e te m p e r a tu r e w as n o im a l f o r one week i n th e u n c o m p lic a te d case.
The e a r l y a c u te s t a g e o f th e d is e a d e w as u n in f lu e n c e d
b y t h e su lp h o n a m id e .
O f t ^ s e who r e c e i v e d th e sulp h on am ide
d r u g , 15 p e r c e n t , show ed c o m p lic a t io n s a s com pared w it h 2 3 . 3 p e r c e n t , i n th e c o n t r o l s . He was o f th e o p in io n t h a t th e m ain v a lu e o f su lp h o n a m id e s i n s c a r l e t f e v e r was a s a p r o p h y l a c t i c a g a i n s t c o m p lic a t i o n s o f a s e p t i c n a tu r e and he t h e r e f o r e in tr o d u c e d a p r o p h y l a c t i c d o sa g e sch em e.
T h is schem e was a ls o l i m i t e d to
c h i l d r e n u n d er t e n y e a r s .
P a t i e n t s w ere g iv e n 0 . 2 3 gm.
s u lp h a n ila m id e f o u r t im e s p e r day f o r 14 d a y s a f t e r a d m is s io n a n d a g a in from th e 2 1 s t to th e 2 8 th day o f th e i l l n e s s .
-
49
-
S e v e n t y - n in e p e o p le w ere t r e a t e d b y t h i s m ethod w it h good r e s u lts .
The c o m p lic a t io n r a t e in t h i s u n c o n t r o lle d s e r i e s
w as 1 1 . 4 p e r c e n t . I n Eue h i 11 H o s p i t a l , G la sg o w , i n 1937 and 1 9 3 8 , F ren ch o b s e r v e d 340 c a s e s o f s c a r l e t f e v e r .
One hundred and s e v e n t y
o f t h e s e w ere t r e a t e d w it h s u lp h a n ila m id e and 170 w ere u s e d as c o n tr o ls .
The c a s e s f o r t h e s e r i e s w ere ta k e n d u r in g two
p e r i o d s - J u l y t o A u g u st, 1 9 3 7 , and J a n u a r y , F eb ru a ry and M arch , 1 9 3 8 .
T h is was t o o b v i a t e s e a s o n a l v a r i a t i o n .
S c a r le t
f e v e r a n t i t o x i n , b e c a u s e o f i t s p r o v e d v a l u e , w as g iv e n to €l11 p a t i e n t s i f r e q u ir e d , i r r e s p e c t i v e o f w h e th e r su lp h on am id e was g iv e n o r n o t .
The d r u g s u s e d w ere s u lp h a n ila m id e and b e n z l
s u lp h a n ila m id e .
T w e n ty -e ig h t d a y s ’ tr e a tm e n t w as g i v e n .
P a t i e n t s o v e r th e age o f f i v e y e a r s r e c e iv e d a t o t a l d o sa g e o f 112 gm s. o f t h e drug and t h o s e u n d er f i v e y e a r s , 56 gm s. o f th e d ru g.
The r e s u l t s o f t h e t r i a l show ed t h a t su lp h a n
ila m id e had no e f f e c t upon t h e i n i t i a l symptoms o f s c a r l e t f e v e r o r upon t h e k i n d , in c id e n c e o r d u r a t io n o f l a t e r com p lic a tio n s .
S u lp h a n ila m id e had no e f f e c t i n h a s t e n in g th e
f a d in g o f th e r a s h . t h e u se o f t h e d r u g s . m en t and from i t little
A l a r g e number o f t o x i c e f f e c t s f a llo w e d T h is was a v e r y w e l l c o n t r o l l e d e x p e r i
i t w o u ld seem t h a t th e su lp h o n a m id es a r e o f
v a lu e i n th e r o u t in e tr e a tm e n t o f s c a r l e t f e v e r . W e s s e lh o e f t ( 1 9 3 8 ) u s in g s u lp h a n ila m id e had p o o r
r e s u lts .
Top and Young (1 9 4 1 ) fou n d no g r e a t d i f f e r e n c e in
t h e t h e r a p e u t i c e f f e c t s i n c a s e s o f m o d e r a te ly s e v e r e s c a r l e t
— 30 f e v e r when s u lp h a n ila m id e ,
c o n v a le s c e n t serum and a n t i t o x i n w ere
a d m in is t e r e d . E a s c o f f and Nussbaum ( 1 9 4 0 ) , and S i l v e m a n ( 1 9 4 0 ) had s i m i l a r f i n d i n g s to F r e n c h .
O th er w r i t e r s fou n d t h a t th e
su lp h o n a m id e d ru g s r e d u c e d th e in c id e n c e o f s e p t i c c o m p lic a t i o n s . A n d erso n ( 1 9 ) 8 ) b e l i e v e d t h a t s u lp h a n ila m id e d ru g s s h o u ld be r e s e r v e d f o r c a s e s w it h s e p t i c c o m p lic a t io n s . The work o f F r e n c h , h o w ev er, w as v e r y w e l l c o n t r o l l e d an d i s to d a y u s u a l l y c o n s id e r e d th e in f o r m a t iv e a r t i c l e on t h e su lp h o n a m id e s i n s c a r l e t f e v e r .
Ohapter 7.
Tm
W8B
OF
PIMLQILLIN
SCADLST
IS
FSTEH.
Y. l ;.1
-
51
-
The P i 800v e r y and D ev elo p m en t o f p e n i c i l l i n . The g r e a t s u c c e s s o f p e n i c i l l i n
i n th e tr e a tm e n t o f
w a r w ou n d s, i n c l u d i n g wounds c o n ta m in a te d b y th e h a e m o ly t ic s t r e p t o c o c c u s , m eant t h a t th e t r i a l o f p e n i c i l l i n
in s c a r le t
f e v e r w as e s s e n t i a l when t h e drug becam e p l e n t i f u l . P e n i c i l l i n was d i s c o v e r e d b y F lem in g in I 9 2 9 .
He
r e c o g n i s e d i t s e f f e c t upon v a r io u s o r g a n ism s b u t w as u n a b le t o p r o c e e d f u r t h e r f o r w ant o f a d e q u a te c h e m ic a l h e l p .
In 1930,
E a i s t r i c t e t a l . e x p e r im e n te d a s t o th e c h e m ic a l s t r u c t u r e o f p e n ic illin .
They d e m o n str a te d t h a t i t c o u ld be e x t r a c t e d from
t h e c u lt u r e d f l u i d b y e t h e r in a c i d s o l u t i o n b u t in t h e i r p r o c e s s a l a r g e p a r t o f t h e p e n i c i l l i n w as d e s t r o y e d .
They had
d i f f i c u l t i e s o v e r b a c t e r i o l o g i c a l c o - o p e r a t io n and d id n o t p roceed fu r th e r . F lo r e y and C hain a t O xford c o n c e n t r a t e d t h e o r i g i n a l p e n i c i l l i n one th o u s a n d t im e s o r more and d r ie d i t .
They
o b t a in e d b a c t e r i o s t a t i c d i l u t i o n s o f a s much a s one in one m illio n .
The p ow er o f p e n i c i l l i n , t h e y d e m o n s tr a te d , w as n o t
i n t e r f e r e d w it h by th e p r e s e n c e o f b lo o d a s w ere t h e o l d e r a n t i s e p t i c s and u n lik e t h e su lp h o n a m id es i t s
a c t i o n i s m a in ta in e d
i n p u s (F le m in g 1 9 4 6 ) . The C l i n i c a l A p p l i c a t i o n o f P e n i c i l l i n in many t y p e s o f I n f e c t i o n K e e fe r e t a l .
( 1 9 4 3 ) t r e a t e d many t y p e s o f i n f e c t i o n
i n c l u d i n g 33 c a s e s o f h a e m o ly tic s t r e p t o c o c o i. i n f e c t i o n w h ich w ere su lp h o n a m id e r e s i s t a n t . o r g a n s w ere i n c l u d e d .
I n f e c t i o n s o f many p a r t s and
Good r e s u l t s w ere o b t a in e d from
-
p e n ic illin
52
-
i n t o t a l d o sa g e o f 5 0 0 ,0 0 0 to 1 , 0 0 0 ,0 0 0 u n i t s ,
e i t h e r i n j e c t e d c o n t in u o u s ly o r a t f r e q u e n t i n t e r v a l s . M ajor Champ L yons ( 1 9 4 3 ) in an a r t i c l e o f v e r y w id e s c o p e r e p o r t e d on c a s e s o f s u r g i c a l i n f e c t i o n due to v a r io u s o r g a n is m s h u t in some o a s e s due to th e h a e m o ly t ic s t r e p t o c o c c u s . P e n i c i l l i n w as g iv e n by th e in tr a m u s c u la r r o u t e .
The d o sa g e
u s e d w as 9 0 ,0 0 0 u n i t s p e r day f o r s t r e p t o c o c c a l i n f e c t i o n s . F o r s t a p h y lo c o c c a l i n f e c t i o n s th e d o sa g e u s e d was b etw een 2 0 0 ,0 0 0 and 4 0 0 ,0 0 0 u n i t s p e r d a y .
P e n i c i l l i n w as p r o v e d t o be
an e f f e c t i v e t h e r a p e u t i c a g e n t in s u r g i c a l i n f e c t i o n s due to t h e s t a p h y lo c o c c u s , t h e h a e m o ly tic and n o n -h a e m o ly tic s t r e p t o c o c c u s and m ix e d i n f e c t i o n s due to gram p o s i t i v e b a c t e r i a and a c t in o m y c e s . The T h e r a p e u tic E f f e c t o f P e n i c i l l i n P h a r y n g itis .
in T o n s i l l i t i s and
Plum er and h i s c o -w o r k e r s i n 1945 r e p o r t e d t h a t a f t e r tr e a tm e n t w it h f o u r - h o u r ly p e n i c i l l i n in d osage o f 1 5 , 0 0 0 u n i t s , t h e h a e m o ly t ic s t r e p t o c o c c u s w as no lo n g e r fo u n d i n t h r o a t c u l t u r e s from p a t i e n t s w it h p h a r y n g i t i s and t o n s i l l i t i s .
The
o r g a n is m , h o w ev er, f r e q u e n t l y r e a p p e a r e d and symptoms r e la p s e d if
th e tr e a tm e n t w as c a r r i e d o u t f o r l e s s th a n s i x d a y s .
S u lp h a d ia z in e , on th e o t h e r h an d , a c c o r d in g to t h i s r e p o r t , r e d u c e d th e number o f o r g a n ism s in th e c u l t u r e s from th e t h r o a t w h ilB t th e tr e a tm e n t was b e in g g i v e n , b u t t h e y w ere a g a in fo u n d i n l a r g e num bers a f t e r th e tr e a tm e n t w as s to p p e d . U eads e t a l .
i n 1945 r e p o r t e d th e r e s u l t s o f s t u d i e s
-
53
-
o f c a s e s o f p h a r y n g i t i s and t o n s i l l i t i s
in f o u r s i m i l a r
g r o u p s o f n in e c a s e s e a c h . Group A, t h e c o n t r o l g r o u p , w it h no t r e a tm e n t show ed t h e f i r s t n e g a t iv e sw abs f o r t h e h a e m o ly t ic s t r e p t o c o c c u s on t h e 1 5 t h , 19 t h , 2 8 t h and 29t h d a y s . • Group B Was t r e a t e d b y t h r e e - h o u r ly in tr a m u s c u la r p e n i c i l l i n i n d o sa g e o f 1 0 ,0 0 0 u n i t s f o r s e v e n d a y s .
W ith
t h i s t r e a tm e n t th e t h r o a t c u l t u r e s becam e and rem ain ed f r e e o f t h e h a e m o ly t ic s t r e p t o c o c c u s i n 24 h o u rs in one c a s e and i n 48 h o u r s i n s i x o t h e r s . Group C Was t r e a t e d by s u lp h a d ia z in e o r a l l y i n d o sa g e o f 0 . 0 6 gm. p e r l b . bod y w e ig h t p e r d a y .
The c u l t u r e s i n t e r
m i t t e n t l y showed th e h a e m o ly tic s t r e p t o c o c c u s d u r in g t r e a t m en t b u t th e o r i g i n a l h a e m o ly t ic s t r e p t o c o c c u s was fou nd in t h e t h r o a t a t th e en d o f t r e a t m e n t . Group D w as t r e a t e d by s p r a y in g t h e n o se and t h r o a t W ith p e n i c i l l i n p e r c u b ic mm.
s o l u t i o n c o n t a in in g 1 ,0 0 0 u n i t s p e n i c i l l i n The r e s u l t s i n t h i s grou p w ere s i m i l a r t o
t h o s e o f th e c o n t r o l g r o u p . The r e s u l t s from t h i s e x p e r im e n t i n d i c a t e t h a t t h e e a r l y tr e a tm e n t w it h p e n i c i l l i n g iv e n s y s t e m i c a l l y in a d eq u a te d o sa g e and c o n t in u e d f o r a t l e a s t s e v e n d a y s may e lim in a t e t h e h a e m o ly tic s t r e p t o c o c c a l c a r r i e r s t a t e and p r e v e n t th e o n s e t o f c o m p li c a t i o n s . p e n ic illin
in S c a r l e t F e v e r .
P a u l A s h le y i n 1 9 4 6 r e p o r te d t h a t th e tr e a tm e n t o f
- 54 _ s o a r l e t f e v e r w tth c o n v a le s c e n t serum p l u s p e n i c i l l i n i s muoh b e t t e r th a n w it h c o n v a l e s c e n t serum o r w it h a n t i - s t r e p t o c o c c a l h o r s e serum a l o n e . p e n ic illin
I n t h i s t r i a l th e p a t i e n t s who w ere g iv e n
r e c e i v e d t h e a n t i b i o t i c i n an i n i t i a l d o sa g e o f
3 0 .0 0 0 u n i t s and t h e r e a f t e r 1 5 , 0 0 0 u n i t s t h r e e - h o u r l y u n t i l th e te m p e r a tu r e had b e e n n orm al f o r f i v e d a y s .
He a l s o fo u n d t h a t
t h e in c id e n c e o f c o m p lic a t io n s o f s c a r l e t f e v e r t r e a t e d w it h c o n v a l e s c e n t serum and p e n i c i l l i n w as much s m a lle r th a n in p a t i e n t s t r e a t e d b y c o n v a le s c e n t serum o r a n t i - s t r e p t o c o c c a l h o r s e serum a l o n e .
From t h i s r e p o r t i t w ould a p p ea r t h a t
p e n i c i l l i n g i v e n i n s u f f i c i e n t do sa g e t h r e e o r f o u r —h o u r ly and c a r r i e d on f o r s e v e n d a y s d o e s red u ce th e in c id e n c e o f c o m p lic a tio n s . Hoyne and Brown (1 9 4 7 ) w ere n o t f a v o u r a b ly im p r e sse d b y th e a c t i o n o f p e n i c i l l i n b u t th e y do s t a t e t h a t t h e y th o u g h t f e w e r c p m p lic a t io n s f o ll o w e d th e u se o f p e n i c i l l i n th a n w it h t h e o t h e r form s o f th e r a p y t r i e d .
They u s e d 1 0 ,0 0 0 u n i t s
p e n i c i l l i n i n t r a m u s c u la r ly e v e r y t h r e e h o u r s u n t i l th e te m p e r a t u r e had b e en norm al f o r 24 h o u r s . Torben J e r s i l d
( 1 9 4 8 ) i n Denmark t r e a t e d 2 ,0 0 0 c a s e s
o f s c a r l e t f e v e r b etw een D ecem ber, I 9 4 3 , and th e d a te o f h i s g o in g t o p r e s s .
He s t a t e s t h a t th e in tr a m u s c u la r i n j e c t i o n o f
9 0 . 0 0 0 to 1 5 0 , 0 0 0 u n i t s o f p e n i c i l l i n t w ic e a day (d e p e n d in g upon th e a g e ) w i l l r i d th e n o se and t h r o a t o f h a e m o ly tic s t r e p t o c o c c i i n 48 h o u r s .
He a ls o
s ta te s th a t i t i s
u n n e c e s s a r y t o m a in t a in a b a c t e r i o s t a t i c c o n c e n t r a t io n o f
- 55 p e n ic illin
i n th e b lo o d by g i v i n g i n j e c t i o n s t h r e e - h o u r ly o r
b y i n j e c t i n g t h e p e n i c i l l i n in a p e a n u t o i l b a s e . h i s tr e a tm e n t f o r s i x d a y s . i n any o f h i s c a s e s . d a y s.
He c o n t in u e d
Ho o t i t i s o r n e p h r i t i s d e v e lo p e d
The a v e r a g e s t a y in h o s p i t a l w as e i g h t
Good r e s u l t s f o r h i s m ethod o f t r e a tm e n t w ere a ls o
c la im e d f o r c a s e s a d m itte d w it h c o m p li c a t i o n s .
In t h i s
c l i n i c a l t r i a l a l l p a t i e n t s w ere p u t i n i n d i v i d u a l w ards f o r t h e f i r s t f i v e d a y s in h o s p i t a l .
T h is m eant in e f f e c t t h a t
t h e r e was no c r o s s i n f e c t i o n to c o n te n d w i t h . J u s t in - B e s a n c o n e t a l .
( 1 9 4 7 ) had f a v o u r a b le r e s u l t s
i n f i v e c a s e s o f m a lig n a n t s c a r l e t f e v e r t r e a t e d w it h d o s e s a v e r a g in g 2 0 0 ,0 0 0 u n i t s d u r in g t h r e e t o f o u r d a y s .
W eis and
M anheims (1 9 4 7 ) r e v ie w e d t h e i r o b s e r v a t io n s o f 239 o a s e s o f s c a r le t fe v e r .
They fo u n d p e n i c i l l i n g r e a t l y s u p e r io r to
s u lp h a d ia z in e n o t o n ly in th e p r e v e n t io n o f a c u te o t i t i s m ed ia b u t a l s o i n th e tr e a tm e n t o f a c u t e o t i t i s
s u p p u r a t io n .
They
recom m ended 2 0 ,0 0 0 u n i t s t h r e e - h o u r ly f o r f i v e t o s e v e n d a y s . B reeze e t a l .
( 1 9 4 6 ) had a good r e s p o n s e i n a l l c a s e s .
H ir s h e t a l* ( 1 9 4 7 ) r e p o r t e d on th e tr e a tm e n t o f 86 s c a r l e t f e v e r p a t i e n t s w it h e i t h e r 2 3 , 0 0 0 u n i t s in tr a m u s c u la r o r 1 2 5 , 0 0 0 u n i t s o r a l p e n i c i l l i n g iv e n t h r e e - h o u r l y f o r f i v e d a y s. it
T h e ir comment on th e f i n d i n g s was t h a t g iv e n e i t h e r way
was fou n d t h a t p e n i c i l l i n d e c r e a s e d t h e t o x i c i t y , g r e a t l y
d im in is h e d th e in cid en ce o f p y o g e n ic c o m p lic a t io n s and p r a c t i c a l l y e l i m i n a t e d th e c a r r i e r s t a t e .
They had t h r e e c r i t e r i a
t o be s e t t l e d b e f o r e i n c lu d in g c a s e s in t h e i r s e r i e s . w ere -
T h ese
—
36
—
( 1 ) T em perature o f 102®P. o r o v e r ; ( 2 ) E v id e n c e o f p ro n o u n ced t o x i c i t y r e g a r d l e s s o f h e i g h t o f te m p e r a tu r e ; and ( 3 ) The p r e s e n c e o f p y o g e n ic c o m p li c a t i o n s . They a l s o
s t a t e d t h a t p e n i c i l l i n g iv e n by e i t h e r o f t h e s e
m eth o d s was more e f f e c t i v e th a n s c a r l e t f e v e r a n t i t o x i n o r eym p to m a tio tr e a tm e n t i n th e p r e v e n t io n o f coix% )lication s and i n r e d u c in g th e number o f c a r r i e r s .
The a n t i t o x i n , h o w ev er,
c a u s e d a more r a p id d e c l i n e in th e te m p e r a tu r e th an th e p e n ic illin . Baybaud (1 9 4 7 ) had good r e s u l t s i n th e tr e a tm e n t o f la te
a c u te n e p h r i t i s a s s o c i a t e d w it h s c a r l e t f e v e r .
Two-
h u n d red - th o u sa n d u n i t s o f p e n i c i l l i n w ere a d m in is te r e d d a i l y and c o a ^ le t e r e c o v e r y r e s u l t e d from p r o lo n g e d tr e a tm e n t w it h a t o t a l d o se o f 3 ,4 0 0 ,0 0 0 u n i t s . The E f f i c a c y o f O ra l P e n i c i l l i n . F i nl a n d , M a x w e ll, Meads ( I 9 4 3 ) r e p o r t e d on th e e f f e c t i v e a b s o r p t io n o f p e n i c i l l i n
a f t e r o r a l a d m in is t r a t io n a s i n d i c a t e d
b y t h e l e v e l s in th e b lo o d .
A d o se o f 9 0 ,0 0 0 u n i t s p e n i c i l l i n
g i v e n by m outh h a l f - a n - h o u r b e f o r e b r e a k f a s t w as fo u n d t o g iv e r e g u l a r l y serum l e v e l s com parable w it h t h o s e o b t a in e d from 1 5 , 0 0 0 o r 2 0 ,0 0 0 u n i t s g iv e n in t r a m u s c u la r ly .
The l e v e l s
o b t a in e d in th e serum when th e same amount o f p e n i c i l l i n w as g i v e n h a lf - a n - h o u r a f t e r b r e a k f a s t w as v e r y i r r e g u l a r and u n p r e d ic ta b le .
When coagpared w it h n orm al p e o p l e , a c h lo r h y d r ic
i n d i v i d u a l s have more s u s t a in e d serum l e v e l s from o r a l p e n i c i l l i n ta k e n b e f o r e a m eal and h ig h e r a s w e l l a s b e t t e r
- 57 s u s t a i n e d l e v e l s from th e p o s t - p r a n d i a l d o s e . o b t a in e d w i t h o r d in a r y p e n i c i l l i n
The serum l e v e l s
i n s a l i n e s o l u t i o n w ere a t
l e a s t a s h ig h and a s w e l l s u s t a i n e d a s w it h any o f th e s p e c i a l o r a l p r e p a r a t io n s t e s t e d .
They r e p o r t e d t h a t e f f e c t i v e
p e n i c i l l i n l e v e l s c o u ld be f a i r l y w e l l m a in ta in e d w i t h a d o sa g e o f 9 0 , 0 0 0 o r 1 0 0 ,0 0 0 u n i t s e v e r y two h o u r s . B o s s , B urke and McLendon ( 1 9 4 5 ) o b t a in e d a d eq u a te t h e r a p e u t i c b lo o d c o n c e n t r a t i o n s o f p e n i c i l l i n a f t e r o r a l a d m i n i s t r a t i o n , t h e a n t i b i o t i c b e in g p r o t e c t e d from th e g a s t r i c a c i d i t y by th e u s e o f d o u b le g e l a t i n c a p s u l e s h a rd en ed b y fo r m a ld eh y d e im m e r sio n .
A d m in is tr a tio n o f 1 0 0 ,0 0 0 u n i t s e v e r y
t h r e e h o u rs by t h i s m ethod p r o v id e d c o n s t a n t t h e r a p e u t ic p e n i c i l l i n l e v e l s w e l l w i t h in o r ab ove th e e f f e c t i v e a n t i b a c t e r i a l ran ge o f m o st s u s c e p t i b l e o r g a n is m s . Gyorgy (1 9 4 3 ) e t a l . fo u n d t h a t p e n i c i l l i n g iv e n b y m ou th i n c o m b in a tio n w it h a s u i t a b l e b u f f e r s a l t , su c h a s t r i sod iu m c i t r a t e , was e f f e c t i v e i n a number o f c a s e s o f g o n o r r h o e a and o t h e r d i s e a s e s .
The e f f e c t i v e d o se w as
com p arab le to t h e a p s e s r o u t i n e l y u s e d i n p a r e n t e r a l a d m in is tr a tio n . I t w o u ld th u s a p p ea r t h a t p e n i c i l l i n g iv e n b y e i t h e r ( 1 ) 2 3 , 0 0 0 u n i t s in t r a m u s c u la r ly f o u r - h o u r ly f o r f i v e to sev en d a y s; o r ( 2 ) o r a l p e n i c i l l i n g iv e n i n d o sa g e o f 1 2 3 , 0 0 0 u n i t s f i v e h o u r ly f o r f i v e d a y s; o r ( 3 ) 1 2 3 ,0 0 0 u n i t s t w ic e p e r d ^ f o r 48 h o u r s ( p r o v id e d c a s e s a r e n u r se d i n c u b i c l e w a r d s ) , is
e f f i c i e n t a s a m ethod o f tr e a tm e n t o f s c a r l e t f e v e r .
—38 — p e n i c i l l i n g i v e n b y any o f t h e s e m e th o d s r e d u c e s th e d u r a t i o n o f t h e h a e m o ly t ic
s tr e p to c o c c a l c a r r ie r s t a t e
and
r e d u c e s th e in c id e n c e o f c o m p lic a t io n s . I n C o n c lu s io n . In s c a r l e t fe v e r th e s e a t o f in f e c t io n t h r o a t and a t o x i n i s sy m p to m s.
i s u s u a l l y th e
e la b o r a t e d th e r e t h a t c a u s e s m ost o f th e
S t r e p t o c o c c i a r e fo u n d o n l y r a r e l y i n t h e b lo o d
str ea m o f c a s e s .
The t o x i n c a u s e s t h e
r a sh , h ead ach e, s ic k n e s s
a n d v o m i t i n g , b u t t h e s t r e p t o c o c c u s c a u s e s th e s o r e t h r o a t a n d th e
s e p tic
c o m p l i c a t i o n s , s u c h a s d t i t i s m e d ia .
The a n t i t o x i n , w h e th e r a s s c a r l e t f e v e r h o r s e a n t i s e r a o r c o n v a l e s c e n t se r u m , s h o u ld r a p i d l y d e a l w i t h t h e t o x i c e ffe c ts.
The d u r a t io n o f th e r a s h and t h e te m p e r a tu r e s h o u ld
an d a r e c u r t a i l e d b y i t s little th u s i t
a d m in is tr a tio n .
The a n t i t o x i n h a s
o r no e f f e c t on t h e a c t u a l h a e m o ly t ic s t r e p t o c o c c u s and s h o u ld n o t p r e v e n t s e p t i c c o n ^ l i c a t i o n s .
Some a u t h o r s
c l a i m t h a t Do c h e z ’ s seru m h a s an a n t i b a c t e r i a l e f f e c t a s w e l l a s an a n t i t o x i c o n e .
S u lp h o n a m id e r e d u c e s t h e r a t e o f r e p r o
d u c t i o n o f s u s c e p t i b l e b a c t e r i a and i s r a t h e r th a n b a c t e r i o c i d a l .
I t s fa ilu r e
th u s b a c t e r io s t a t ic in
s c a r le t fe v e r i s
p r o b a b ly due t o t h e p e r s i s t e n c e o f s m a ll n u m b ers o f t h e o r g a n is m i n t h e t h r o a t i n o r g a n is m s p r o l i f e r a t e
s p ite
o f in t e n s iv e tr e a tm e n t.
T h ese
a g a in when t h e d r u g i s w ith d r a w n and
t h e y i n many c a s e s g i v e
r is e to s e p t ic
c o m p lic a tio n s .
t h e o r y , a t l e a s t , h o w ev e r, th e b a c t e r i o s t a t i c
In
a c t i o n o f th e
d r u g i f g i v e n i n s u f f i c i e n t d o s a g e guad f o r s u f f i c i e n t tim e
- 39 s h o u ld r ed u c e th e s e p t i c c o m p lic a t io n s and a l s o t h e c r o s s in fe c tio n r a te .
The a u t h o r i t a t i v e work o f F r e n c h , h o w e v e r ,
s t a t e s t h a t t h e d e p t ic c o m p lic a t io n s a r e n o t r e d u c e d . B e c a u s e th e su lp h o n a m id e s do n o t work e f f i c i e n t l y in t h e p r e s e n c e o f p u s t h e drug s h o u ld he o f l i t t l e
v a lu e when
s e p t i c c o m p lic a t io n s h ave o c c u r r e d . P e n ic illin
i s a b a c te r io c id a l a g e n t.
In t h e o r y i t
s h o u ld have d e f i n i t e a c t i o n in c u r t a i l i n g th e s e p t i c c o m p lic a t i o n s and in p r e v e n t in g c r o s s i n f e c t i o n i f g iv e n in a d eq u a te d o sa g e f o r a s u f f i c i e n t t im e . i n th e p r e s e n c e o f p u s .
P e n ic illin a c ts e f fic ie n t ly
P e n i c i l l i n i s fo u n d in p r a c t i c e to
b e o f v a lu e i n p r e v e n t in g th e s e p t i c c o m p lic a t io n s o f s c a r l e t fev er.
Chapter 8
THS
METHOD
ADOPTED
IH
THE
CLIHICAL
TRIAL
- 6o The M ethod o f T r e a tm e n t. There have b een num erous r e p o r t s a b o u t th e e f f i c a c y o f P e n i c i l l i n g i v e n i n i n t e m i t t e n t t h r e e - o r f o u r - h o u r ly d o sa g e o f 2 0 ,0 0 0 to 3 0 ,0 0 0 u n i t s .
M ost o b s e r v e r s have had
f a v o u r a b le r e s u l t s b o t h i n th e p r e v e n t io n and tr e a tm e n t o f th e p y o g e n ic c o m p lic a t io n s o f s c a r l e t f e v e r .
B e c a u se o f th e
m il d n e s s o f th e d i s e a s e and t h e f a c t t h a t i f s u c c e s s f u l i t w o u ld be a g r e a t s a v in g on n u r s in g t im e , i t
was d e c id e d to t r y
f'
a o n c e - d a i l y d o sa g e o f 3 0 0 ,0 0 0 u n i t s P e n i c i l l i n . D uring th e p e r i o d November 1947 t o J u ly 1948 a l l c a s e s o f s c a r l e t f e v e r a d m itte d t o E h ig h tsw o o d H o s p it a l w ere t r e a t e d b y t h i s m ea n s.
T h is f o m
o f tr e a tm e n t was c o n t in u e d d a i l y f o r
a p e r i o d o f s e v e n d a y s , t h e d o sa g e b e in g i n j e c t e d i n t o t h e v a s t u s l a t e r a l i s m u scle o f th e t h i g h . becam e a p p a r e n t c l i n i c a l l y little
A f t e r s e v e r a l w eek s o f t r i a l i t ,
t h a t t h i s mode o f tr e a tm e n t w as o f
v a lu e i n th e c a s e o f p e r s o n s a d m itte d w it h o r who s u b s e
q u e n t ly d e v e lo p e d a p y o g e n ic c o m p lic a t io n , s u c h a s c a t a r r h a l o r s u p p u r a t iv e o t i t i s m e d ia .
As o t h e r w o rk ers have shown t h a t
i n t e m i t t e n t in tr a m u s c u la r P e n i c i l l i n
in d o sa g e o f 2 0 ,0 0 0 t o
3 0 ,0 0 0 u n i t s q u ic k ly h e a l s up t h e s e l e s i o n s in m o st c a s e s , th e p a t i e n t s w it h s e p t i c c o m p lic a t io n s had t h e i r t r e a t m e n t s d u ly qm ended to t h i s o t h e r m eth o d .
The i n t e r m i t t e n t P e n i c i l l i n
c o u r s e was c o n tin u e d u n t i l t h e c o m p lic a t io n had c l e a r e d u p .
— ü1 — D e s c r i p t i o n o f t h e Tfard. At K h igh tsw ood F e v e r H o s p i t a l , G lasgow , t h e r e i s one ward d e v o te d e x c l u s i v e l y t o t h e tr e a tm e n t o f s o a r l e t f e v e r . T h is ward h a s f i v e com partm ents and th e t o t a l bed c a p a c it y i s f o r 21 p a t i e n t s .
Two o f t h e s e a r e u se d f o r new a d m is s io n s and
tw o f o r c o n v a le s c e n t p a t i e n t s .
The f i f t h
com partm ent i s o f
th e n a tu r e o f a s i d e room and i s u se d as an o b s e r v a t io n c u b i c l e . I t was t h e cu stom t o t r a n s f e r th e p a t i e n t s from th e a c u t e t o t h e c o n v a le s c e n t ward on th e 8 th day i f t h e y w ere fo u n d t o be c lin ic a lly w e ll.
That i s ,
th e y w ere t r a n s f e r r e d in many
i n s t a n c e s b e f o r e th e r e s u l t s from th e r o u t in e n o se and t h r o a t sw abs w ere known and ev en in th e f a c e o f a p o s i t i v e r e s u l t . I t w as h op ed t h a t by t h e u s e o f a c u t e and c o n v a l e s c e n t w ard s th e in c id e n c e o f r e - i n f e c t i o n be r e d u c e d .
and t h e c o m p l i c a t i o n r a t e w o u ld
From t h e w ork o f A l l i s o n
and Brown ( 1 9 3 7 )
it
is
known t h a t many c a s e s o f r e - i n f e c t io n o r o f c o m p l i c a t i o n s a f t e r a d m is s io n t o
a f e v e r h o s p i t a l a r e d u e t o c r o s s i n f e c t i o n w it h a
d i f f e r e n t G r i f f i t h s e r o l o g i c a l t y p e o f h a e m o ly t ic s t r e p t o c o c c u s .
The Q u e stio n o f a C l i n i c a l C o n tr o l E x p e r im e n t. In v ie w o f th e l i m i t e d number o f p a t i e n t s who c o u ld be a d m itte d a t one t im e , i t was d e c id e d t o t r e a t by th e p e n i c i l l i n m ethod as p r e v i o u s l y d e s c r ib e d a l l c a s e s a d m itte d .
By t h i s
means th e m ethod c o u ld be t r i e d ou t in a la r g e r s e r i e s o f c a s e s . V ery f u l l n o t e s o f o a s e s h a v e b een k e p t a t jKnightswood H o s p it a l and i t was c o n s id e r e d t h a t a r e v ie w o f t h e c a s e s t r e a t e d in th e
— b2 — h o s p i t a l d u r in g t h e tw o p r e v io u s y e a r s c o n tr o l.
c o u ld b e u s e d a s a
'
T h e se tw o y e a r s a r e c o n s i d e r e d s e p a r a t e l y and a r e
\
e a c h com pared b y s t a t i s t i c a l m eth o d s w i t h t h e e x p e r i m e n t a l D u r in g 1946 and 1 9 ^ 7 , c a s e s o f t h e d i s e a s e w e r e
p e r io d .
t r e a t e d by s c a r l e t f e v e r c o n c e n tr a te d g lo b u lin (B u r r o u g h s W e llc o m e ),
a n tito x in
a d o s a g e o f 3 ,0 0 0 u n i t s b e in g u s e d i n
m ild c a s e s and 1 0 ,0 0 0 u n i t s
i n t h e s e v e r e fo r m .
B ra d fo rd H i l l (1 9 4 8 ) s t a t e s - «In t r y i n g t o c o n t r o l an e x p e r im e n t one s h o u ld t r y as much a s p o s s i b l e t o h ave th e v a r io u s grou p s th e same i n a l l r e l e v a n t r e s p e c t s as a com p lex c h a in o f c a u s a t io n i s
o f t e n in v o l v e d .
By u s in g a l t e r n a t e
c a s e s f o r tr e a tm e n t and f o r c o n t r o l we can o f t e n have a s a t i s f a c t o r y b a s i s f o r a c l i n i c a l e x p e r im e n t.
T h is i s so b e c a u s e
in th e lo n g ru n we can f a i r l y r e l y upon random a llo t m e n t o f p a t i e n t s to e q u a l i s e in th e tw o g ro u p s t h e d i s t r i b u t i o n o f im p o r ta n t c h a r a c t e r i s i t i c s .
B etw een i n d i v i d u a l s o f e a c h
grou p t h e r e may be l a r g e d i f f e r e n c e s b u t i n th e lo n g run ea ch t y p e w i l l be e q u a lly r e p r e s e n t e d in e a c h g r o u p .
The age and
t h e s e x o f th e p a t i e n t s may be e q u a lis e d by e x t e n d in g th e m ethod to t h is .« The c o n t r o l m eth od a d o p te d i n t h i s t h e s i s ,
w h ils t
a d m it t e d ly n o t s o s a t i s f a c t o r y a s t h e c o n c u r r e n t m e th o d , s id e r e d o f v a lu e i f th e
ca ses
d is c u s s io n
it
is
con
can be p r o v e d by s t a t i s t i c a l m eth o d s t h a t
o f s c a r le t fe v e r tr e a te d
i n t h e t h r e e p e r i o d s u n d er
a r e s i m i l a r i n i n t e n s i t y on a d m is s io n .
I f th is
is
so
_
63
-
t h e n t h e y can be com pared i n e v a lu a t in g t h e e f f i c a c y o f th e s e p a r a t e tr e a tm e n t m ethods a d o p te d d u r in g t h e s e p e r i o d s . T h is t y p e o f c o n t r o l i s a d o p te d i n t h i s t h e s i s . The i d e a l m ethod o f c o n t r o l e x p e r im e n t w ou ld r e q u ir e f o u r or f i v e s i m i l a r w a r d s.
The r o u t in e tr e a tm e n t in e a c h
o f t h e s e w ards w ould be d i f f e r e n t .
For ex a m p le , i t
is
su g
g e s t e d t h a t w ards c o u ld be s e t a s id e as f o l l o w s 1 s t Ward - C ases h a v in g no t r e a t m e n t . 2nd , , - S c a r l e t f e v e r a n t i t o x i n 3 ,0 0 0 or 1 0 ,0 0 0 u n i t s . 3rd ,, - S c a r l e t f e v e r a n t i t o x i n and a su lp h on am id e d r u g . 4 th ,, - p e n i c i l l i n e x p e r im e n t. G ases c o u ld be a l l o c a t e d t o th e wards by a r o t a s y s t e m . Under t h i s r e g im e we w ould have c a s e s t r e a t e d i n a s i m i l a r ty p e o f w ard , b y n u r s e s o f s i m i l a r t r a i n i n g and u n d er th e s u p e r v is io n o f t h e same m e d ic a l s t a f f . as t h i s
U n f o r t u n a t e ly ,
an arran gem en t s u c h
c o u ld n o t be c a r r ie d o u t a t K hightsw ood F ev er H o s p i t a l .
The C l i n i c a l D e s c r i p t i o n o f t h e D i s e a s e w i t h R e f e r e n c e t o t h e p r e v a i l i n g M ild n e s s a t t h e P r e s e n t T im e .
I t i s cu sto m a ry i n a f e v e r h o s p i t a l f o r c a s e s t o be v ie w e d by th e R e s id e n t p h y s ic ia n p r io r t o t h e i r a d m is s io n t o th e a p p r o p r ia te w ard .
E very e f f o r t i s made t o e n s u r e t h a t no
c r o s s i n f e c t i o n o c c u r s in a ward due t o th e in t r o d u c t i o n o f a w r o n g ly d ia g n o sfe d i n f e c t i o u s c a s e * The c l i n i c a l c r i t e r i a u s u a l l y a d o p te d f o r t h e d i a g n o s i s o f s c a r l e t f e v e r w i l l now be c o n s i d e r e d . p e r io d o f th e d is e a s e
is
a s e x tr e m e l i m i t s
to seven d ays.
oib
The in c u b a t io n
c o n s id e r e d t o be tw o t o f o u r d a y s w i t h A h i s t o r y o f c o n ta c t w ith
- û4 a known c a s e i s h e l p f u l in d i a g n o s i s . fe v e r is
The o n s e t o f s c a r l e t
a b r u p t, w ith h e a d a c h e , u s u a l l y f r o n t a l , m a la is e ,
n a u s e a , v o m it in g , f e v e r and a s o r e t h r o a t .
T w en ty -fo u r t o
48 h o u rs a f t e r th e o n s e t t h e r a s h a p p e a r s . The s i g n s o f s c a r l e t f e v e r c o n s i s t o f f e v e r , th e in je c tio n
o f th e t h r o a t , th e a p p ea ra n ce o f th e to n g u e and th e
ty p ic a l s c a r le t fev er ra sh . fe v e r is
At th e p r e s e n t d a y , s c a r l e t
a m ild i l l n e s s and i n many c a s e s t h e te m p e r a tu r e i s
o n ly s l i g h t l y e l e v a t e d .
H ow ever, te m p e r a tu r e s o f b etw een
lOO^F. and 1 0 ) 0 ? . s t i l l o c c u r .
The p u ls e r a t e i s e l e v a t e d
ou t o f a l l p r o p o r t io n t o th e te m p e r a tu r e and t h i s
i s due t o t h e
a c t i o n o f th e t o x i n on th e h e a r t m u s c le . M ost c a s e s nowadays show o n ly s l i g h t e n la r g e m e n t and in fla m m a tio n o f t h e t o n s i l s , b u t t h e s e v e r e r ty p e o f c a s e h as f o l l i c u l a r e x u d a te .
T h is f o l l i c u l a r e x u d a te i s
e a s i l y rem oved .
The t o n s i l l a r lymph g la n d s a re in m ost c a s e s s l i g h t l y e n la r g e d . The a p p ea ra n ce o f th e to n g u e i s i n many c a s e s c h a r a c t e r is tic .
To b e g in w ith th e t i p
body i s w h it e f u r r e d .
o f th e to n g u e i s r e d , w h ereas th e
L a ter th e w h ite s tr a w b e r r y to n g u e o f
s c a r l e t f e v e r becom es a p p a r e n t. th e fu r .
The r e d p a p i l l a e appear th ro u g h
On th e 2nd or )r d day th e fu r p e e l s o f f l e a v i n g th e
t y p i c a l s tr a w b e r r y to n g u e o f s c a r l e t f e v e r . The r a s h o f s c a r l e t f e v e r a p p ea rs on e i t h e r t h e 2nd or )r d d ay.
I t c o n s i s t s o f a p u n c ta te e ry th em a , b u t t h i s d o es n o t
o ccu r on th e f a c e .
The f a c e i s ,
h ow ever, u s u a l l y f lu s h e d and
ü)
-
-
h as a c h a r a c t e r i s t i c c ir c u m o r a l p a l l o r . d is e a s e i s
The r a s h i n th e
o f t e n c o a r s e and m a cu la r on th e e x t r e m i t i e s .
The o r d e r o f a p p ea ra n ce o f th e r a s h i s f i r s t th e f l u s h o f th e f a c e , th e n a p u n c ta t e ery th em a o f th e n e c k p a s s in g on t o t h e t r u n k , th e u p p er lim b s and th e l e g s . t h e d u r a t io n o f th e r a s h i s some c a s e s i t
At t h e p r e s e n t tim e
o f v e r y s h o r t d u r a t io n b u t in
can l a s t from t h r e e t o s i x d a y s .
The r a s h i s
e a s i l y fa d e d on p r e s s u r e . The i l l n e s s s t a r t s t o s u b s id e a b o u t th e t h i r d day when t h e te m p e r a tu r e f a l l s ,
th e t h r o a t s u b s id e s and th e r a s h f a d e s .
D esq u am ation commences a t a b o u t t h e end o f th e f i r s t w eek and i s m ost m arked on th e hands and f e e t .
The o rd er o f p r o g r e s s
o f d esq u a m a tio n i s s i m i l a r t o th e o rd er o f t h e o n s e t o f th e rash .
I n t h e m ild form o f s c a r l e t f e v e r now p r e v a l e n t ,
d esq u a m a tio n i s
i n many c a s e s a lm o s t n o n - e x i s t e n t .
At K n ig h tsw o o d , as w i l l be shown l a t e r ,
over th e
t h r e e p e r io d s r e v ie w e d many c a s e s w ere a d m itte d t o t h e s c a r l e t f e v e r ward who had a m in im al r a s h or no r a s h a t a l l #
In a l l
o f t h e s e c a s e s a d e f i n i t e h i s t o r y o f a p u n c ta te e r y th e m a to u s r a s h was fo r th c o m in g .
I n many o f th e c a s e s r e v ie w e d th e
p u n c ta te e r y th e m a to u s r a s h o n ly l a s t e d up t o f o u r h o u r s a f t e r a d m is sio n t o h o s p i t a l .
T hese f a c t o r s a g a in em p h a sise t h e
p r e v a i l i n g m ild ty p e o f th e i l l n e s s .
A l l c a s e s a d m itte d t o
th e ward had in fla m m a tio n o f th e t h r o a t , h o w ev er.
- 66 The T aking o f R o u tin e N ose and T h ro a t S w ab s. On a d m is s io n t o th e w ard, d u r in g th e 1948 p e r i o d , t h r o a t and n o s e sw abs w ere ta k e n and were a g a in r e p e a t e d on th e f o l l o w i n g d a y . and 9 th d a y s .
Swabs w ere a g a in done on th e y t h , 8 th
T h is m a t e r i a l was in o c u la t e d on g e n t ia n b lo o d
agar p l a t e s and in c u b a te d f o r 24 h ou rs a t ) 7 ^ 0 . s e le c tiv e
T h is i s a
c u l t u r e m ed ia and a llo w s f o r e a s y i s o l a t i o n
str e p to c o c c a l c o lo n ie s .
The r e s u l t s
of
o f i n d i v i d u a l sw abs
were d e te r m in e d b y c u l t u r a l c h a r a c t e r i s t i c s and in d o u b t f u l c a s e s by th e e x a m in a tio n o f a sm ear from a c o lo n y s t a i n e d by Gram’ s m eth od .
The t y p i c a l c o l o n i e s o f h a e m o ly t ic s t r e p t o
c o c c i a re r e c o g n i s e d by b e in g s m a l l , d i s c r e t e , s e m i- t r a n s p a r e n t d i s c s a b ou t 1 mm. in diameter and w it h c l e a r zo n es d e v e lo p in g around them due t o th e d i f f u s i b l e h a e m o ly s in p rod u ced by th e o r g a n ism .
I t i s p o in t e d o u t a t t h i s s t a g e t h a t i n a l l c u lt u r e s
p o s i t i v e f o r h a e m o ly t ic s t r e p t o c o c c u s th e organ ism grown was
|
s e n s itiv e
j
to p e n i c i l l i n .
D u rin g 1946 and I 947 t h r o a t swabs
o n ly w ere ta k e n and d u r in g t h i s p e r io d th e t e s t s f o r s e n s i t i v i t y t o p e n i c i l l i n w ere n o t d o n e . A D e s c r ip t io n o f th e C u ltu r e M ed ia. A s h o r t d e s c r i p t i o n o f t h e m ethod o f m a n u fa ctu re o f th e c u lt u r e m ed ia u se d in th e 1948 p e r io d w i l l now be g i v e n . A w a te ry e x t r a c t o f b e e f was f i r s t o f a l l made u s in g f r e s h le a n m eat f r e e d a s f a r as p o s s i b l e from f a t .
The m eat i n a m in ced
s t a t e was added t o th e w a ter in a p r o p o r tio n o f ) 0 0 gm s. t o
— 67 — 1 litr e .
The e x t r a c t i o n p r o c e s s l a s t e d 24 h o u rs and to o k
p la c e in a
r e fr ig e r a to r .
The f l u i d was th e n f i l t e r e d
th r o u g h m u slin end t h e r e a f t e r b o i l e d f o r 1 ) m in u te s .
As a
r e s u l t o f t h i s h e a t in g th e m eat p r o t e in i n th e e x t r a c t was p r e c ip it a t e d by c o a g u la tio n .
To r e n d e r th e e x t r a c t f r e e o f
coagu lu m t h e m a t e r ia l was f i l t e r e d th ro u g h p a p e r .
Com m ercial
p e p to n e in a p r o p o r t io n o f one p er c e n t , and sodium c h l o r i d e in a p r o p o r t io n o f 0 . ) p e r c e n t , w ere ad d ed . The p r o p o r t io n o f agar added t o s o l i d i f y th e b r o th c u l t u r e m ed ia was 2 p e r c e n t .
A f t e r th e agar was added t h e
b r o t h Was p la c e d in th e stea m s t e r i l i s e r f o r one hour t o e f f e c t s o lu t io n .
As l a r g e q u a n t i t i e s w ere made a t one tim e t h e agar
was f i l t e r e d th r o u g h c o a r s e sa n d and paper p u lp . N u t r ie n t a g a r i s s o l i d a t 3 7 0 0 . , th e optimum te m p e r a tu r e f o r m ost o r g a n is m s .
A te m p e r a tu r e o f ^0 ^0 » i s r e q u ir e d t o m e lt
i t and when m e lte d i t m ust be c o o le d t o 4 2 ^ 0 . t o s o l i d i f y . The n u t r i e n t agar medium may th u s be c o o le d b e lo w th e c o a g u la t io n p o in t o f serum p r o t e i n and y e t rem ain f l u i d . The optimum P g . f o r c u lt u r e m ed ia i s b etw een 7 . 2 and 7 . 6 and th e n u t r i e n t a g a r m ed ia p rep a red i s u s i n g a com parator m eth o d . agar a t
a d ju ste d to t h i s
B lo o d was added t o t h e n u t r i e n t
in th e p r o p o r t io n o f 10 p e r c e n t .
The b lo o d
u s e d was s t e r i l e o x a la t e d h o r s e b lo o d as s u p p lie d by M e s sr s . B urrou gh s W ellcom e & Co.
To e v e r y 100 c . c .
o f b lo o d agar was
added 1 c . c . o f O .O l p e r c e n t , g e n t ia n v i o l e t s o l u t i o n .
T h is
-
68
g i v e s a c o n c e n t r a t io n o f one in a m i l l i o n g e n t ia n v i o l e t in th e b l o o d .a g a r .
The g e n t ia n v i o l e t i n h i b i t s th e g ro w th o f
c e r t a i n p a th o g e n s b u t a llo w s th e c u lt u r e o f h a e m o ly t ic s t r e p t o c o c c i t o go on u n a b a te d . a t th e ed g e o f t h e m e d ia .
A s m a ll d i t c h was c u t ou t
I n to t h i s d i t c h was p ou red an
a g a r s o l u t i o n c o n t a in in g p e n i c i l l i n . a d d in g 1 c . o . per c . c .
T h is was made up by
o f a P e n i c i l l i n s o l u t i o n c o n t a in in g 100 u n i t s
to 100 c . c .
o f m e lte d a g a r .
T h is g i v e s a p e n i c i l l i n
c o n c e n t r a t io n o f one u n i t P e n i c i l l i n p e r c u b ic c e n t im e t r e .
It
i s u n n e c e s s a r y t o l e a v e th e p l a t e s o v e r - n ig h t i n th e r e f r i g e r a t o r b e f o r e i n o c u l a t i o n as t h e p e n i c i l l i n r e a d i l y d i f f u s e s
in t o
th e m ed ia . I n o c u l a t i o n o f th e c u l t u r e m edia i s c a r r ie d o u t a t r i g h t a n g le s t o th e g u t t e r a c r o s s th e p e t r i d i s h . P e n ic illin s e n s itiv e
W ith
org a n ism s g ro w th d o es n o t o c c u r r i g h t up
t o th e e d g e s o f th e g u t t e r b u t i s
i n h i b i t e d to a d i s t a n c e v a r y
in g w it h t h e i r s e n s i t i v i t y to p e n i c i l l i n .
R e s i s t a n t organ ism s
a re n o t i n h i b i t e d . The M ethod U sed t o Code I n f o r m a t io n . F or e a c h i n d i v i d u a l c a s e a punch card was p r e p a r e d . The in fo r m a t io n c o l l e c t e d was e x t r a c t e d from t h i s ca rd u s in g a s u i t a b l e cod e s y s t e m .
A sp ecim en card i s show n.
nvoiNilo nviD ^^Aaisiw3H00ia Aoqioiaaiàya ASonoxvwavH O 'Ava-)t Noixvonawoo NOiJLoajNi ssoaa s is o N ô v ra 0 3 « a n v
NOixoajNi anduinw N 0 J1 0 3 JN I 3 1 9 N I S
r -
3
gê
I 5 C iÇ
n o n
Chapter 9
XS
igTPTAWfPTQlir
or
IHE
STATISTICAL
MEggODS
ÜSBD
-
69
-
I n tr o d u c tio n .
T h is t h e s i s depends t o a la r g e e x t e n t on t h e s t a t i s t i c a l a n a l y s i s o f in fo r m a t io n r e g a r d in g c a s e s o f s c a r l e t f e v e r t r e a t e d in K n igh tsw ood H o s p i t a l d u rin g th e p e r io d J a n u a ry , 1 9 4 6 , t o J u ly , 1 9 4 8 .
The v a r io u s
s t a t i s t i c a l m ethods u se d w i l l now he d is c u s s e d s o t h a t th e m ethods o f a n a l y s i s in th e t h e s i s w i l l n o t l a t e r n eed e x p la n a tio n .
The d e f i n i t i o n s and m ethods shown a re l a r g e l y
ta k e n from th e p r i n c i p l e s o f M e d ica l S t a t i s t i c s
by
B ra d fo rd H i l l . The a v er a g e i s th e a r i t h m e t i c mean o f a l l o b s e r v a t io n s ; th a t i s ,
th e sum
o f a l l th e o b s e r v a t io n s d iv id e d by th e
number o f o b s e r v a t i o n s . The mode i s
d e f i n e d a s b e in g t h e m o st f r e q u e n t v a lu e
o b se r v e d in th e s e r i e s . v a tio n s i s
th e v a lu e
The m ed ia n o f a s e r i e s
o f ob ser
o f t h e c e n t r a l o b s e r v a t i o n when a l l t h e
o b s e r v a tio n s are l i s t e d
in o r d e r fr o m t h e h i g h e s t t o
th e lo w e s t
The I m p o r ta n c e o f t h e F r e q u e n c y D i s t r i b u t i o n . In s t a t i s t i c a l w ork t h e f r e q u e n c y d i s t r i b u t i o n s e r ie s
o f v a lu e s i s
o f t h e u tm o s t im p o r t a n c e .
V a lu e o f a s e r i e s a lo n e i s n o t s u f f i c i e n t .
of a
The mean The c a l c u l a t i o n
o f th e s ta n d a r d d e v ia t io n g iv e s a p ic t u r e o f th e d i s t r i b u t i o n a ro u n d t h e a v e r a g e v a lu e a t a g l a n c e . is
a m e a su r e o f th e s c a t t e r
The s t a n d a r d d e v i a t i o n
o f o b s e r v a t i o n s r o u n d t h e i r m ean.
A l a r g e sta n d a r d d e v i a t i o n show s t h a t th e fr e q u e n c y
-
70 -
d i s t r i b u t i o n i s w id e ly s p r e a d o u t from th e mean. s ta n d a r d d e v i a t i o n show s t h a t th e d i s t r i b u t i o n i s c o n c e n t r a t e d ab ou t t h e m ean.
A s m a ll c lo s e ly
In th e work t o f o l l o w , u s e i s
made o f gro u p ed s e r i e s o f o b s e r v a t io n s and th e m ethod o f a r r i v i n g a t th e sta n d a r d d e v i a t i o n in t h e i r c a s e i s now show n. M ethod o f C a lc u la t in g t h e S ta n d a rd D e v ia t io n - Grouped S e r i e s Exam ple 1 . 1946. I r r e s p e c tiv e o f S e x . D u r a tio n o f R ash a f t e r A d m issio n t o H o s p i t a l . 1 D u r a tio n i*n -Hours 061218Mo = 2 4 303642 48 54 60 66 72 78 84 90 96 102
2 HO. 34 25 30 47 85 23 10 12 8 2 2 2 4 1
2 x 5 -136 - 73 -1 0 0 - 47 0 + 25 20 36 32 10 12
-1
0 +1 2 3 4 5 6 7 8.
9 lo ll
1
12 13
—
1 307
Mean i n # r k i n g U n it s *. Mean i n H ea l U n its
4
3 W orking U n it s -4 -3 -2
= =
'
52 9 -
11 -
3 5 x 4 544 225 200 47 0 25 40 108 128 30 72 98 236 81 121 -
13
169
-1 4 6
2,162
= -1 4 6 = - 0.4756 307 27 - 2 .8 5 0 2 4 .1 5
- 71 27 h ou rs i s th e c e n t r e o f th e group a g a i n s t w h ich t h e Mo was p la c e d . H ote t h a t th e c o r r e c t i o n h a s now t o be s u b s t r a c t e d f o r th e s i g n o f th e mean in W orking U n it s i s n e g a t i v e . Mean S q u ared D e v ia t io n
=
2162 307
=
7 .0 4 4
S ta n d a r d D e v ia t io n in W orking U n it s y 7 .0 4 - ( 0 .4 7 5 )
= 2.6103 R e a l S ta n d a rd D e v ia t io n
=
2 .6 1 x 6
= 15.66 Form u lae u se d i n S am p lin g i n t h i s T h e s i s . L et one sam ple c o n t a in n x members and th e o th e r n^ m em bers.
A ls o l e t m^, m^, s ^ , 82 be th e means and s ta n d a r d
d e v i a t i o n s o f t h e two s a m p le s .
mx - m2 i s
c a lc u la te d .
The a p p r o p r ia te sta n d a r d e r r o r i s g iv e n b y th e fo r m u la D = th e S ta n d a rd E r r o r
I
( s i ) ^ + ( 8 2 )^ I— — —
T h is fo r m u la g i v e s t h e s ta n d a r d e r r o r o f d i f f e r e n c e o f m eans.
In com paring th e d i f f e r e n c e b etw een th e means o f
t h e two sa m p le s ( i n a l l c a s e s i n t h i s t h e s i s f a i r l y l a r g e s a m p le s ) th e fo r m u la i s u se d t h a t i f mx - m2 i s e q u a l t o or g r e a t e r th a n 2D n u m e r ic a lly , m^ i s s i g n i f i c a n t l y d i f f e r e n t from mg.
I f mx - # 2 i s l e s s th a n 2D, th e two means m igh t
w e l l h ave b een d e r iv e d from th e same u n i v e r s e .
2
72
-
U se i s te st.
_
a l s o made in t h i s t h e s i s o f th e
(c h i)
An exam p le o f t h e f o u r - f o l d t a b le w i l l f i r s t o f a l l
be show n. Humber o f I n d iv id u a le Sam ple 1 I n o c u la t e d
Sam ple 2 Hot I n o c u la t e d
A tta c k e d
a
b
a
+b
Hot a t t a c k e d
o
d
c
+d
T o ta l
a + c
C o n sid e r th e p r o p o r t io n -
b + d
T o t a ls
a+b+o+d
a and b a+c b+d
Are t h e y s i g n i f i c a n t l y d i f f e r e n t from one a n o th e r? X^ f o r th e « f o u r - f o l d t a b l e * i s c a l c u l a t e d as f o l l o w s ; 9 r âdtk±2±ÊV 'Sr = K ad - bo) 2 i (a+b +c+d) (a+ b ) (c+ d ) (a + c ) (b+d) where ad i s t h e b ig g e r o f th e two c r o s s p r o d u c t s . I f X^ i s g r e a t e r th a n 5 .8 4 1 , one p r o p o r t io n i s s id e r e d s i g n i f i c a n t l y d i f f e r e n t from th e o t h e r .
con
The appro
p r i a t e number o f d e g r e e s o f fre ed o m i s fo u n d as th e number o f c l a s s e s t o w h ich v a lu e s can be a s s ig n e d a r b i t r a r i l y . th e « f o u r - f o l d t a b l e * we ca n o n ly f i l l
U sin g
one c l a s s a r b i t r a r i l y
b e c a u s e when t h a t i s done t h e se c o n d c l a s s i s a u t o m a t ic a lly d e te r m in e d .
T h e r e fo r e in t h i s c a s e e n t e r in g th e t a b le o f
X^ ( F i s h e r ’ s T a b le s) w ith one d e g r e e o f freed o m t o r e a c h th e 2 5 p e r c e n t , l e v e l o f s i g n i f i c a n c e X w ould have t o be e q u a l t o or g r e a t e r th a n 5 * 8 4 1 .
- 73 An exam p le o f a n o th e r ty p e o f
ta b le u sed in t h is
t h e s i s t o com pare t h r e e g ro u p s f o r tw o f a c t o r s i s now shown (a 2
X
n ta b le ) .
Exam ple 2 . ^ . S e v e r i t y o f I l l n e s s on A d m issio n C a ses o f S c a r l e t F e v e r . I r r e s p e c tiv e o f S e x . p e r io d s
T o t a ls 1948
1946
'■ 1947
Ho. w it h sh a rp i l l n e s s Ho. w it h m ild and m oder a t e i l l n e s s ....................... T o t a l number o b se r v e d . . p e r c e n t a g e in ea ch group w it h sh a rp i l l n e s s . . . p e r c e n t a g e w it h m ild or m od erate i l l n e s s ..........
125
1
71
33
229
254 379
1 168 1 239
188 221
610 839
33
! 29.7
1 4 .9
27.29
77
! 70.3
85.3
72.71
1 . Ho. w it h s h a r p i l l n e s s 2 . E x p e c te d H o. w ith sh arp i l l n e s s on h y p o t h e s is t h a t sh a r p i l l n e s s and y e a r a re u n r e la t e d . . . 5 , D i f f e r e n c e o b se r v e d m in u s e x p e c t e d ................ 4 . ( D i f f e r e n c e ) ^ ....................... 5 . (D iffe r e n c e )^ E x p e c te d Ho.
125
33
229
229
1 . Ho. w it h m ild and m o d erate i l l n e s s . . 2 . E x p e c te d Ho. w it h m ild and m o d era te i l l n e s s 5 . D i f f e r e n c e o b se r v e d m inus e x p e c t e d .......... 4 . ( D i f f e r e n c e ) ^ .................. 5 . f D i f f e r e n c e )^ E x p e c te d Ho. T o t a ls x^ = 2 3 . 8 8
103.4
65.21
60.32
+21.6 4 6 6 .56
+3 . 7 9 33.32 0 .5 1 4 0
- 27.32 745.2
-
12.36
-
4.512
254 273.3 - 21.5 462.2 1.678 379
n = 2.
71
168 173.8 - 5.8 33.64 0.1933 239
P = l e s s th an O .O l.
-
188
610
160.7
610
27.3 743.2 4 .6 3 8 221
839
S ig n ific a n t.
-
In e n t e r i n g t h e X o f freed o m ) i s
2
74
-
t a b l e in t h i s c a s e n ( t h e d e g r e e
2.
The v a lu e n in F i s h e r ’ s t a b l e s a p p lic a b le t o a p a r tic u la r X n = (c -1 )
c a l c u l a t i o n can be fo u n d by means o f th e r u l e ( r - 1 ) where c i s th e number o f colum ns e x c lu d in g
th e t o t a l column end r th e number o f row s in th e t a b l e . In th e exam ple shown (E xam ple 2) n = ( 3 - 1 )
(2 -1 ) = 2.
In. t h i s exam ple i t
i s w ith n = 2 t h a t F i s h e r ' s t a b l e s a re 2 u sed . In t h i s c a s e e n t e r i n g th e X t a b l e w ith 2 d e g r e s s o f 2 freed o m t o r e a c h th e 5 p e r c e n t , l e v e l o f s i g n i f i c a n c e , X w o u ld h ave t o be e q u a l t o or g r e a t e r th a n 5 - 9 9 ‘ In s t a t i s t i c a l work o f t h i s n a tu r e i t m ust be r e c o g n is e d a t a l l t im e s t h a t we a r e w e ig h in g p r o b a b i l i t i e s b u t n e v e r r e a c h in g m a th e m a tic a l p r o o f .
Ctianter 10
THB
CCagABISOM
OF
THB
THBBB PBBIODS
ADMISSION
g iM P iiras.
OTBBB
KË.TIMf.
- 73 A d m issio n F i n d i n g s . The t h r e e p e r io d s w i l l now he compared*
To b e g in
w it h c o n s id e r a t i o n w i l l be g iv e n t o th e age and s e x in c id e n c e o f c a s e s o f s c a r l e t f e v e r a d m itte d t o K n igh tsw ood H o s p it a l d u r in g th e t h r e e p e r i o d s . The c a s e s o f s c a r l e t f e v e r a d m itte d t o h o s p i t a l d u r in g t h e t h r e e p e r io d s are shown t o h ave a s i m i l a r age d i s t r i b u t i o n . The s e x r a t i o
o f c a s e s t r e a t e d in K n igh tsw ood changed d u r in g
t h e 1948 p e r io d , th e m ale a d m is sio n r a t e b e in g p r o p o r t io n a t e ly in c r e a s e d .
T h is d id n o t o ccu r by i n t e n t i o n and was due t o
f a c t o r s in h o s p i t a l a d m in i s t r a t i o n .
In t h i s i n v e s t i g a t i o n ,
h o w ev er, a l l m a tte r s c o n s id e r e d s t a t i s t i c a l l y a re g iv e n s e p a r a t e l y as f a r a s i s p o s s i b l e u n d er t h e h e a d in g s , m a le s , fe m a le s ,
and i r r e s p e c t i v e o f s e x .
T h e r e fo r e ,
it
is
c o n s id e r e d t h a t t h i s a p p a ren t d is c r e p a n c y can be ig n o r e d .
—y6 — p ig . 1 . K Jiightsw ood C a ses - Age and S e x D i s t r i b u t i o n
Age Group in
Tears
1947 u n t i l O ctob er
1946
N o v ., 1947 J u ly , 1 9 4 8 .
Male ! FansJe !T o ta l Male ! F e m a le |T o t a l Male j F e m a le T o t a l 28
0-
40 10-
18
11
20-
10
25 3035-
40-
196
189
379
112
127
221
- 77 Fi& L_2' K n igh tsw ood C a ses - A ver age Age on A d m issio n and S ta n d a rd D e v ia t io n from t h i s f o r th e T hree P e r io d s u n d er R e v ie w . 1946
1947 u n t i l O ctob er
N o v .. 1947 ■ J u ly . 1948
9*85 7 * 912
1 1 .4 2 8 .9
1 0 .4 8.769
1 1 .2 1 6 8 .9 7
1 0 .8 8 8 .4 1
9*36 7*03
1 0 .5 8 . I 65
1 1 .0 9 8 8 .6 4 0
9*98 8 .1 4 8
M a les : A verage Age ...................... S ta n d a rd D e v ia t io n ... F em a les ; .................. A verage Age S ta n d a rd D e v ia t io n ... I r r e s p e c tiv e o f S e x : A verage Age ....................... S ta n d a rd D e v ia t io n ...
K n igh tsw ood O ases - Agas on A d m issio n Q èm parison T ab le 1947 w it h 1948 m^—m^
2D
1946 w it h 1947 m^“ m^
2D
1946 w it h 1948 m£
2D
M a les .............
1 .0 2
2.259
1.57
2.025
0.55
1 .8 8 4
F em ales . . . .
1.52
2.126
0.93
0 .6
1.856
1.959
I r r e s p e c tiv e o f Sex . . .
1 .1 1
1 .5 6 4
0.598
1.397
0.52
1.37
- 78 The q u e s tio n n e x t to be t a c k le d i s w hether or n o t th e age i n c i d e n c e o f c a s e s o f s c a r l e t f e v e r a d m itte d t o
K nightsw ood H o s p it a l i s s im ila r t o th e age in c id e n c e o f th e d is e a s e as o c c u r r in g in th e C ity o f G lasgow .
The f i g u r e s
f o r th e C ity o f Glasgow were o b ta in ed from th e H ea lth and W elfare D epartm ent. From th e s t a t i s t i c a l a n a ly s is made i t i s found th a t on th e w hole th e K nightsw ood c a s e s are o f an o ld e r average age than th e c a se s o f th e C ity in g e n e r a l.
The m a jo r ity
o f c a s e s a d m itted to K nightswood H o s p ita l come from th e w e st-e n d o f th e C ity and th e K nightswood H ousing Scheme. T his le a d s one t o p u t forw ard th e view th a t w ith b e t t e r h o u sin g c o n d it io n s and l e s s overcrow ding s c a r l e t f e v e r i s c o n tr a c te d a t a l a t e r average a ge.
This l i n e o f argument
w i l l n o t be d e a l t w ith fu r th e r as th e re i s no in fo r m a tio n r e a d i l y a v a ila b le whereby th e age o f o n s e t o f s c a r l e t fe v e r c o u ld be c o r r e la t e d w ith th e h o u sin g c o n d it io n s . in p a s s in g i t s h o u ld be n o te d t h a t s c a r l e t f e v e r r a r e l y a f f e c t s c h ild r e n under one y e a r o f a g e .
N abarro and
S ig n y (1 9 3 1 ) s t a t e t h a t c h ild r e n up t o s i x m onths e i t h e r i n h e r i t an im m unity from t h e i r m oth er o r t h e i r s k in s a re n on r e a c tiv e to s tr e p to c o c c i.
B a b ies» b lo o d d o e s n o t a lw a y s
c a u s e b la n c h in g o f a s c a r l e t f e v e r r a s h .
B a b ie s l o s e t h i s
p a s s i v e im m unity or n o n - r e a c t i v i t y a t a b o u t s i x m onths o f
age
and t h e r e a f t e r th e m a j o r it y are D ick p o s i t i v e s lo w ly b ecom ing
- 79 n e g a t i v e as t h e y p r o g r e s s t o a d u lt l i f e .
T h is a l t e r a t i o n
in th e r e a c t i o n i s p r o b a b ly due t o r e p e a t e d s u b - i n f e c t i o n w it h t h e h a e m o ly t ic s t r e p t o c o c c u s .
From th e age o f one y e a r
onwards th e in c id e n c e o f s c a r l e t f e v e r s t e a d i l y i n c r e a s e s .
The d is e a s e i s most fr e q u e n t about th e s c h o o l j o in in g a g e. I t i s u s u a l l y s t a t e d t h a t 80 p e r c e n t , o f c a s e s o c c u r b etw een one y e a r and t e n y e a r s o f a g e .
A f t e r p u b e r ty th e in c id e n c e
s t e a d i l y d e c l i n e s b u t t h e d i s e a s e n o t uncommonly o c c u r s in a d u lt l i f e .
- 80 F ig .
4.
C it y o f G la sg o w ; Age and S ex D i s t r i b u t i o n o f a l l C a ses o f S c a r le t F e v er.
1946
Age G roups
M.
1947
F.
T.
H.
1948
F.
T.
M.
F.
T.
0-
4to
454
914
425
4o6
831
5 93
526 1 ,1 1 9
5-
709
818 1 , 5 2 7
591
776 1 , 3 6 7
677
846 1 ,5 2 3
10-
290
422
712
356
539
895
349
505
854
15-
69
77
146
89
156
245,
82
147
229
20-
8
26
34
25
61
86
17
39
56
2 5 -j
7
20
27
1#
17
36
13
21
34
30 -)
7
20
27
19
18
36
12
20
32
3 5 -)
7
8
15
11
11
22
10
10
20
4 0 -)
7
8
15
11
12
23
11
10
21
4 5 -1
2
6
3
7
10
2
5
7
5 0 -)
1
4
5
4
7
11
2
6
8
5 5 -)
0
1
1
1
1
2
1
1
2
60- )
1
1
2
-
1
1
1
1
2
65-
-
-
1
1
2
-
1
1
T o ta ls
4
1 ,5 6 8 1 ,8 6 3 5 ,4 3 1 1 ,5 5 4 2 ,0 1 3 3 ,5 6 7 1 ,7 7 0 2 ,1 3 8 3 ,9 0 8
— 81 —
n & - ....5,.
C ity o f G lasgow ; Average Age ( i n T e a rs) o f O a s e s . 19 4 6
1947
1948
9*355 7*6
8 .2 8 6 .8
1 0 .2 7*57
9*44 7*255
9*84 7*6
8 .8 9 7*017
M a le s; A verage ^ge ...................... 8 . 1 ) 5 Stan dard D e v ia tio n . . . 6 .0 7 F e m a le s; A verage Age ....................... Standard D e v ia tio n . . .
8 .9 9 6 .7 9
I r r e s p e c t iv e o f S e x ; Average Age ...................... 8 . 6 Stan dard D e v ia tio n . . . 6 .8 5
Fig"
6.
Average Age o f K nightsw ood O ases compared w ith A verage Age o f S im ila r Y ear Glasgow C a s e s . Comparison Table iiii
3 ^
m i— m2
2D
M a le s .................... 1*7 1 5 1 .1 7
2 .0 7
1 .7 2 5
2 .1 2
1.542
F e m a le s ............. 2 .2 2
1 .2 7 6
0 .6 8
1.529
0 .0 8
1*549
I r r e s p e c tiv e o f Sex . . . .
0 .8 7 0
1 .2
1 .1 4 6
1.09
1.117
1*9
m i-m2
2D
2S
m i-m2
I
MiW : CM
i6r^RT»v|T^VSi
fiS f0 >or
6m
ÿÿ
^r-
ii
-Üt3
Ï3 I
i
Tl'Oh"
IÏ-
i
ïæ i ?
i+c-
'w t
m
— 82 —
The n e x t f a c t o r t o he c o n s id e r e d i s t h e a v e r a g e day o f a d m is s io n to h o s p i t a l o f c a s e s o f s c a r l e t f e v e r i n th e t h r e e p e r i o d s .
The a v e r a g e day o f a d m is sio n to
h o s p i t a l i s fo u n d t o h e s i m i l a r o v e r th e t h r e e o b s e r v e d p e r io d s .
There a p p e a r s t o he a d is c r e p a n c y i n th e
’ I r r e s p e c t i v e o f S e x ’ f i g u r e s on com p aring th e p e r io d 1 9 4 7 w it h 1 9 4 6 .
I t w o u ld a p p ea r h e r e t h a t th e day o f
i l l n e s s on a d m is s io n i s t h a n i n th e I 9 4 6 p e r i o d . how ever, i t
is
s i g n i f i c a n t l y more ad v a n ced in 1947 T aking t h e t o t a l p i c t u r e t o g e t h e r ,
c o n s id e r e d t h a t t h e a v e r a g e day o f a d m is s io n
d u r in g 1948 ca n he s a i d t o he s i m i l a r t o t h a t o f 1 9 4 6 and 1947.
— 83 ” Ig r e g g e h o y D i a t r i b u t i o n t o show t h e D ays o f I l i n e i on w h ic h C a se s o f S c a r l e t j ^ v e r w ere a d m itte d d u r in g th e T hree P e r io d s u n d e r R e v ie w .
P e r io d
S ex M ales
1946
194 7
1948
1
2
10
75 38 21 15
3
4
6
5
8
7 8 10
9 10 11 12 — 4
196
2
1
1
183
7
1
5
379
5 5
5
5 1
I r r e s p e c 18 140 81 53 26 20 12 10 6 tiv e
F em a les
8
65 43 32 11 12
2
T o ta l
•
M ales
5
26 30 14 16
4
6
3 1
2
-
5
112
Fem ale s
6
37 32 19
9
6
3 -
2
-
4
127
I r r e s p e c 11 tiv e
63 62 33 25 13 12
6 1
4
-
9
239
M ales
7
29 35 24 22 12
1
4 -
-
-
1
135
F em ales
-
21 2: 17 1 2
6
5
1 -
1
-
-
86
Irresp ec t iv e
7
50 5É 41 34 18
6
5 -
1
-
1
221
9
- 84 F ig '
8.
A verage Day o f I l l n e s s on A d m issio n to H o s p it a l f o r th e T hree P e r io d s u n d e r R ev iew . 1947
124 8
4.62 2.549
4.197 1.74
3 .9 3 1 .9 3
4.32 2.35
4.268 1 .6 8 2
4 .0 7 2.169
4.47 2.453
4 .2 4 1.79
1946 M a le s: Ave rage • • • • • • • • • • • • . 4 .2 5 S ta n d a r d D e v ia t io n . . . 2 .4 6 7 F e m a le s: A verage .............................. S ta n d a rd D e v ia t io n . . I r r e s p e c t i v e o f S ex : Ave ra g e .............................. S ta n d a r d D e v ia t io n . .
n & j— i -
Average Day o f I l l n e s s on A d m issio n to H o s p i t a l . C om parison b etw een t h e Y e a r s . 1948 w i t h 1947 m i-m2
2D
1947 w it h 1 9 4 6 m i-m2
2D
1948 w it h 1 9 4 6 m i-m2
M a le s ............. 0 .4 2 3
0.564
0 .3 7
0.5946
0.053
0.462
0.052
0.547
0 .3 9
0.5046
0 .3 3 8
0 .4 6
0 .3 9 8
0 .4
0 .3 8 7 8
0.17
0 .3 2 8
F e m a le s . . . .
I r r e s p e c tiv e o f s e x . . . 0 .2
.LL: uj-We-^lS^ oM~ yf
yk«: iAirb^z:-HtWk
^p
- 85 On a d m is s io n t o t h e w ard an a s s e s s m e n t o f th e c l i n i c a l s e v e r i t y o f th e d i s e a s e i s made and r e c o r d e d b y th e r e s id e n t p h y s ic ia n .
The a s s e s s m e n t made by t h e d o c t o r i s
an e s t im a t e o f th e d e g r e e o f i l l n e s s o f th e p a t i e n t t a k in g i n t o a c c o u n t s o r e t h r o a t , p y r e x i a , t o x i g e n i c i t y and t h e p r e s e n c e ( f c o m p li c a t i o n s .
The te r m s u s e d in t h e d e s c r i p t i o n
o f t h e d i s e a s e a re m i l d , m o d erate and s e v e r e o r s h a ip . As th e a s s e s s m e n t s made b y v a r io u s d o c t o r s w i l l v a r y t o some e x t e n t , m ild and m o d era te c a s e s a re c o n s id e r e d t o g e t h e r and a r e com pared o v e r t h e t h r e e y e a r s w it h th e num bers c a l l e d severe.
The in fo r m a t io n fo u n d in t h e s e t a b l e s i s l a r g e l y
a m a t t e r o f o p in io n a s t h e e s t i m a t e s o f s e v e r a l r e s i d e n t d o c t o r s a r e c o n s id e r e d .
H ow ever, i n s p i t e o f t h i s i t
does
a p p ea r t h a t t h e r e i s a s i g n i f i c a n t c l i n i c a l d i f f e r e n c e b e tw e e n th e 1948 c a s e s and th e c a s e s in c lu d e d in th e e a r l i e r s e r ie s *
The c a s e s i n th e 1948 s e r i e s a r e fo u n d t o be
c l i n i c a l l y l e s s s e v e r e th a n t h o s e o f th e p r e v io u s y e a r s . Prom a c o n s id e r a t i o n o f th e t a b l e s i t w i l l be s e e n t h a t a su d d en ch an ge h a s o c c u r r e d in 1948 in t h a t d u rin g t h i s p e r io d t h e c a s e s a p p ea red m il d e r .
— 8b — P ig . 1 0 . The S e v e r i t y o f I l l n e s s a s ju d g e d C l i n i c a l l y . C lin ic a l S e v e r ity
J a n u a ry t o O c to b e r 1^)47
1946
M a le s ; M ild and
i
l î î l l i r . .. ^ iS e s B
Novem ber 1947 t o J u ly i 9 4 j
..
T o ta l .,..
1)6 69.4
78 69 . 6
120
60 ) 0 . 6
)4 )0 .4
_ il
196
112
88.8
122.
F em ales : M ild and 118
6 4 .))
90
7 0 .8
® iiS b 8 3 . . _ 6 2
)).6
_2i
29.2
T o ta l • ••
18)
^27
68
JA
79.1
2 1 .0
-Ê É
I r r e s p e c tiv e of SW M ild and
T o ta l . . .
a j.
6 7 .1
iS i
) ) .»
)7 9
16»
-Ü 2 )9
7 0 .4
1 9 -7
18»
» ? .i
-Ü
1‘ - ’
i!i
— 87 “ g ig .
11.
U s in g th e " P o u rfo ld " M ethod th e R e s u l t s g iv e n i n P i g . IQ a re now a n a l y s e d .
M a les
P e m a les I r r e s p e c tiv e o f S ex
1 9 4 8 w it h 1947 19 47 w it h 19 46 1948 w it h 1946 X2 P P P1 3 .0 8 L ess 0 .0 0 6 6 16.27 0.9 L ess th a n th a n 0 .0 1 0 .0 1 1 .4 0 6 15.18
0 .3
0.0454
0.9
5.17
0 .0 2
L ess th a n 0 .0 1
0.5411
0 .5
22.54
L ess th a n 0 .0 1
12 W ith t h e Same M a t e r ia l ( P i g . 1 0 ) b u t u s in g a 2 x n t o th e T hree P e r io d s u n d e r R eview th e f o l l o w i n g R e s u l t s a r e o b t a in e d .
M a les Pem ale s I r r e s p e c tiv e o f Sex
19.07 6.019 23.88
n s 2
P
2
L e s s th a n 0 .0 1
2 2
0.5 L e s s th a n 0 .0 1
T a b le
S ig n ific a n c e S ig n ific a n t S ig n ific a n t S ig n ific a n t 1
tt
WO
* 88 — O ver th e y e a r s i t h as b e e n th e cu stom t o r e c o r d a d e s c r i p t i o n o f th e t h r o a t o f t h e n e w ly a d m itte d c a s e . T hree term s a r e commonly u s e d i n K n igh tsw ood H o s p it a l and e a c h w i l l now be d e f in e d . The term minimum in fla m m a tio n i s ta k e n to mean a m i l d l y in fla m e d t h r o a t .
By an in fla m e d t h r o a t i s m eant a
d e f i n i t e in fla m m a tio n o f th e t h r o a t w it h oed em atou s s w e l l i n g o f th e f a u c e s .
The
s e v e r e s t ty p e i s th e c a s e w it h
s e v e r e in fla m m a tio n and a p u r u le n t e x u d a te o v e r th e t o n s illa r areas.
The o a s e s w ith a m ild and m od erate
in fla m m a tio n o f th e t h r o a t a re c o n s id e r e d t o g e t h e r i n th e s t a t i s t i c a l a n a ly s is .
I t i s h e ld t h a t t h e d i f f e r e n c e
b e tw e e n m ild and m od erate in fla m m a tio n c o u ld be a m a t t e r o f p e r so n a l o p in io n .
The p r e s e n c e , h o w ev er, o f a t o n s i l l a r
e x u d a te can be c o n s id e r e d to be f a c t u a l in f o r m a t io n . The f i n d i n g s f o r th e f e m a le s and a ls o t h o s e f o r i r r e s p e c t i v e o f s e x s u g g e s t ÿ h a t o v e r th e t h r e e p e r io d s t h e r e h a s b een a p r o g r e s s i v e l e s s e n i n g in th e s e v e r i t y o f t h e t h r o a t in fe c tio n .
T here i s no su ch s u g g e s t i o n , h o w ev er, w it h t h e
m a le f i n d i n g s .
When t h e f i n d i n g s a r e a n a ly s e d s t a t i s t i c a l l y
u s in g a 2^ ( 2 x n ) t a b l e , i t a p p e a r s t h a t t h e c h a n g e s o v e r t h e t h r e e p e r io d * a r e n o t s i g n i f i c a n t .
T h u s, o y e r t h e t h r e e
p e r i o d s u n d er a n a l y s i s , th e s t a t e o f t h e t h r o a t on a d m is s io n oan be c o n s id e r e d s i m i l a r .
- 89 -
gi&jL. I n s t a t e o f T h roat on A d m is s io n . .................
1946
1947
1948
8 3 .2
f 92 8 2 .1
jÉ 115 8 3 .2
370
33 1 6 .8
20 1 7 .9
20 1 4 .8
73
M eiles; N o . w it h I n fla m e d T h ro a t 163 N o . w ith E x u d a te . T o t a l N o. O b serv ed
f e r j o * ________________
19 6
112
135
T o ta l
443
F e m a le s ; N o . w i t h I n fla m e d T h ro a t 135 N o . w it h E xudate T o ta l N o. O b serv ed
7 3 .8
100 7 8 .8
74 8 6 .1
309
_ 4 8 2 6 .2
_2% 2 1 .2
12 1 3 .9
87
183
127
86
396
I r r e s p e c tiv e of sex; N o. w it h In fla m e d T h ro a t 298 N o. w it h E xu d ate T o t a l N o. O b served . . . . .
7 8 . b 192 8 0 .3 81 2 1 .4
379
47 1 9 . 7 239
189 8 5 -5
679
32 1 4 .5
160
221
839
- 90 g ig . U s in g 2 X n
14.
t a b l e s th e in f o r m a t io n in F i g . 13 i s
now a n a ly s e d :
n s 2
P
M a les
0 .5 8 7
2
G r e a te r th a n 0 .8
F em a les
5 .2 4 4
2
G r e a te r th a n 0 .0 5
2
G r e a te r th a n 0 .1
I r r e s p e c tiv e o f S ex
4 .3 7 7
S ig n ific a n c e N ot s ig n ific a n t N ot S ig n ific a n t
N ot s ig n ific a n t
STflTf;
of
RoAT 0 *l\-
HRftW-T
g]
I#
- 91 T h ro a t sw abs w ere ta k e n on a d m is s io n i n a l l c a s e s , sw ab b in g w as done on th e degr o f a d m is s io n and th e f o l l o w i n g d ay and i f e i t h e r on c u l t u r e show ed th e h a e m o ly tic s t r e p t o c o c c u s t h e t h r o a t was c o n s id e r e d p o s i t i v e .
By th e t a k in g o f
two sw abs i t w as h op ea t o a v o id th e ch an ce o f r e c o r d in g n e g a t i v e r e s u l t s due t o any e r r o r in th e t e c h n iq u e w h ic h may have a r is e n . On e x a m in a tio n o f th e f i g u r e s and b e f o r e c o n s id e r a t io n th e X
t e s t i t a p p e a r s t h a t in 1 9 4 8 many more c a s e s we re
a d m it t e d th a n b e f o r e w it h a n e g a t iv e t h r o a t sw ab . i r r e s p e c t i v e o f s e x r e s u l t s a re shown b y th e s ig n ific a n t.
That i s ,
The
t e s t to be
f o r t h e i r r e s p e c t i v e o f s e x f i g u r e s th e
lo w e r p o s i t i v e r a t e r e c o r d e d i n 1948 i s
s i g n i f i c a n t and d id
n o t l i k e l y o ccu r by ch an ce. E n te r in g t h e X^ t a b l e w it h 2 d e g r e e s o f fr eed o m , we f i n d , h o w ev er, t h a t th e m ale and fe m a le r e s u l t s when ta k e n s e p a r a t e l y b a r e ly r e a c h th e 5 p e r c e n t , l e v e l o f s i g n i f i c a n c e (X^ e q u a l t o o r g r e a t e r th a n 2 . 9 9 ) .
One i s f o r c e d t o th e
c o n c l u s i o n h er e t h a t e i t h e r th e r e i s no s i g n i f i c a n t d i f f e r e n c e o r t h a t t h e number o f c a s e s in c lu d e d in th e m ale and fe m a le g r o u p s i s n o t g r e a t enough to g i v e s i g n i f i c a n t r e s u l t s . The l a t t e r v ie w i s p r o b a b ly th e c o r r e c t o n e . O ver th e t h r e e y e a r s i t i s fou n d t h a t a c o n s id e r a b le num ber o f c a s e s have a n e g a t iv e t h r o a t c u lt u r e on a d m is s io n . T h is m ig h t be a t t r i b u t e d by some t o f a u l t y d ia g n o s i s and t h u s
— 92 — t h e n e g a t iv e a d m is s io n sw abs w ou ld be due to th e i n c l u s i o n i n th e s e r i e s o f d i s e a s e s n o t c a u s e d b y t h é h a e m o ly tic s t r e p t o c o c c u s , su c h a s German m e a s l e s .
H ow ever, a l l o f t h e
c a s e s u n d er c o n s id e r a t i o n w ere c a r e f u l l y exam ined and w ere c o n s id e r e d t o be g e n u in e s c a r l e t f e v e r .
I t s h o u ld be
r e a l i s e d , h o w ev er, t h a t t h e d i s e a s e a t t h e p r e s e n t tim e i s o f a v e r y m ild t y p e .
The v iew i s
t h e r e f o r e p u t fo rw a rd
t h a t i n a c o n s id e r a b le p e r c e n t a g e o f c a s e s th e t h r o a t i n f e c t i o n h a s in e f f e c t c l e a r e d up p r i o r t o a d m is s io n to h o s p ita l. B u rto n and B a lm a in ( I 9 2 9 ) r e p o r t e d t h a t o u t o f 262 c a s e s o f s c a r l e t f e v e r , I 91 o r 79 p e r c e n t , on a d m is s io n show ed h a e m o ly tic s t r e p t o c o c c i in t h e i r f a u c e s .
A llo w in g
f o r th e a d m itte d s u b s t a n t i a l r e d u c t io n in th e s e v e r i t y o f t h e d i s e a s e sLnoe t h e n , t h e f i g u r e s fou n d i n th e i n v e s t i g a t i o n p e r i o d s ca n be ta k e n to be a tr u e in d e x o f th e p r o p o r t io n o f p o s i t i v e s on a d m is s io n . AS w i l l be shown l a t e r t h e d u r a tio n o f th e r a s h i n s c a r l d t f e v e r a t th e p r e s e n t tim e i s v e r y s h o r t .
As th e t o x i n
i s p ro d u c ed a t th e s i t e o f i n f e c t i o n by th e o rg a n ism i t
is
c o n s id e r e d t h a t t h e s e two f a c t o r s can p r o b a b ly be c o r r e l a t e d . W ith th e d isa p p e a r a n c e o f th e o rg a n ism from th e t h r o a t th e t o x i n p r o d u c t io n c e a s e s and t h i s m igh t p a r t i a l l y a c c o u n t f o r th e
s h o r t d u r a tio n o f t h e r a s ^ .
On th e o t h e r h an d , th e
s c a r l e t f e v e r r a s h i s o f v e r y s h o r t d u r a tio n in c a s e s w here
- 93 t h e t h r o a t sw abs rem ain p o s i t i v e
f o r many d a y s .
I t m ig h t b e
a r g u e d , t h e r e f o r e , t h a t th e s h o r t d u r a t io n o f th e r a s h and in d e e d o f t h e o t h e r t o x i c fe v e r is
p r o p e r tie s o f p r e se n t-d a y s c a r le t
due to a p o o r p r o d u c t io n o f t o x i n b y t h e o rg a n ism
o r t h e p r o d u c t io n o f a t o x i n w it h l i t t l e
p o ten cy .
H ow ever, b e f o r e l e a v i n g t h i s s u b j e c t t h e v iew w i l l a g a in b e s t a t e d t h a t i f a l a r g e r s e r i e s o f c a s e s had b een c o n s id e r e d th e n i n a l l p r o b a b i l i t y th e m ale and fe m a le p o s i t i v e r e s u l t s f o r t h e 19 4 8 p e r i o d w o u ld have shown a s i g n i f i c a n t d e c lin e .
^ / »
- 94 • 21& :
il-
T h ro a t Swabs on A d m is s io n . R e s u l t s o f T e s t f o r H a e m o ly tio S t r e p t o c o o o u s . P e r io d 1946 M ale s ; N o . w it h a P o s i t i v e € T h r o a t R e s u lt . . . . 1 ) 9 71%29 N o . w it h a N e g a tiv e T h ro a t R e s u lt . . . . 2 6 .7 1 T o t a l ......................... 195 F e m a le s ; N o . w it h a P o s i t i v e T h ro a t R e s u lt . . . . 118 6 6 . 6 7 N o . w it h a N e g a tiv e T h r o a t R e s u lt . . . . 33.33 T o t a l ......................... ^ I r r e s p e c t i v e cf Sex; N o . w it h a P o s i t i v e T h ro a t R e s u lt . . . . 227 6 9 .0 8 N o . w i t h a N e g a t iv e T h ro a t R e s u lt . . . . ^ 3 0 .9 2 T o t a l .......................... 372
F ig . U sin g 2 X n
19 4 7
Ï9 4 8
4, 72 64%28
# 80 2 9 .2 7
_40 3 5 .7 2 112
55 4 0 .7 3 ^
92 7 3 .0 2 34 ^
2 6 .9 8
l6 4 68 .9 _J± 3 1 .1 238
21 4 3 .0 2 ^
221
281
i5i 442
49 3 6 . 9 8
129
T o ta l
229
m 389
2 8 .3 7
220
4 1 .6 3
281 831
16
t a b l e s th e in fo r m a t io n r e g a r d in g th e
a d m is s io n t h r o a t swabs i s now a n a ly s e d .
n B 2
P
S ig n ific a n c e
M a les
2.34
2
G r e a te r than 0.02
N ot s ig n if ic a n t enough
F em a les
2.91
2
I r r e s p e c tiv e o f S ex
8 .2 4 2
Ju st g r e a te r th a n 0 . 0 2 L e s s than 0.02
B a r e ly s i g n i f i c a n t enough S ig n ific a n t
2
m
m y.
- 95 Tile r e c o r d in g s o f a d m is sio n te m p e r a tu r e s can be c o n s id e r e d f a c t u a l .
The fr e q u e n c y d i s t r i b u t i o n o f a d m is s io n
t e m p e r a t u r e s w i l l now b e show n. On e x a m in a tio n o f F i g . 17 i t
i s a p p a r e n t how m ild
an i l l n e s s s c a r l e t f e v e r i s a t th e p r e s e n t t im e .
The
a v e r a g e te m p er a tu r e f o r a l l c a s e s i s 9 9 . 4 ° f . i n I 946 Eind 9 8 .9 4 ® F . i n 1 9 4 8 .
ffhen t h e s e r e s u l t s a re c o n s id e r e d from
a s t a t i s t i c a l s ta n d p o in t i t
i s fo u n d t h a t th e a v e r a g e
te m p e r a tu r e on a d m is s io n i n I 948 i s s i g h i f i d a h t l y lo w e r th a n t h e a v e r a g e te m p e r a tu r e on a d m is s io n i n 1 9 4 6 , c o n s id e r i n g th e I 947 ana 19 4 6 p e r io d s i t
In
i s o b serv ed th a t
t h e m a le and i r r e s p e c t i v e o f s e x f i g u r e s a re s i g n i f i c a n t l y lo w e r i n 1947 when com pared w it h I 9 4 6 .
T h is d o e s n o t ,
h o w e v e r , a p p ly t o th e fe m a le f i n d i n g s .
C o n s id e r in g th e
w h o le p i c t u r e , h o w e v e r , i t can be s a i d t h a t t h e r e h a s b een a p r o g r e s s i v e d im in u t io n in th e a v e r a g e a d m is sio n te m p e r a tu r e s.
- 96 -
m NO ON p ON 00 H H *r\ Eo4
I
•H
•H
•H
vO
•H
CM
- 105 F ig .
24.
A verage P u l s e R ate on A d m issio n to H o s p it a l and tJie S ta n d a rd D e v ia t io n from " th ia t o r t h e T h ree P e r io d s u n d er R ev iew .
Sex M ales
1946 A verage
1 0 8 .9 2 8
A verage
107.815
1 1 4 .1 2 4
1 1 ) .5 8
111 .0 4
1 7 .4 ) 8
19.02
21.47
109.426
109.071
19.41
19.902
2 0 .0 5 9 9
S tan d ard D e v ia t io n A verage
I r r e s p e c tiv e
1 1 1 .4 ) 9
S ta n d a rd D e v ia t io n
I lK z
1948
1 0 4 . )7 5 1 8 .6 7 )
S ta n d a rd D e v ia t io n Fem ale s
1947
1 8 .0 1 5
18.729
2%.
A v era g e P u ls e R ate on A d m ission to H o s p i t a l . Q om parisen b etw een th e Y e a r s .
1948 w it h 1947 S ex
1947 w it h 1946 2D
1948 w it h 1946
2D
m i-m2
M a les
) .4 4 4.764
4.55
4.544
1 .1 1
4 .2 8 8
Fem ale s
2.54
5.72
0.54
4 .1 8
) .0 8
5 .2 4
o.)5
).67
1 .4
) .1 1 8
2 .)6
3.253
I r r e s p e c tiv e o f S ex
m2
I
m i-m2
2D
!
m
Ho S to b r g
I i
I i3. 0
i
— 106 — The number o f c a s e s a d m itted to h o s p i t a l as s c a r l e t f e v e r b u t who had no ra sh on a d m issio n w i l l now be c o n s id e r e d . I t i s th u s found th a t th e r e has been a ste a d y in c r e a s e i n th e number o f c a s e s ad m itted to h o s p i t a l s s s c a r l e t f e v e r who were found to have no r a sh on a r r i v a l a t th e h o s p i t a l . T h is m ig h t be a t t r ib u t e d by some to f a u l t y d i a g n o s i s . H ow ever, i t i s c o n sid e r e d th a t t h e s e c a s e s were in f a c t c a s e s o f m ild s c a r l e t f e v e r .
In a l l o f th e s e p a t i e n t s a h i s t o r y
o f h a v in g had a p u n c ta te eryth em atou s ra sh o u t s id e was fo r th c o m in g .
- 107 P ig . 26. C a se s a d m itte d t o H o s p it a l a s S c a r l e t P e v e r b u t who had no B ash on A d m is s io n . P e r io d 1946 M a le s ; C a s e s w it h a Hash on A d m issio n .......... C a s e s w it h no Hash on A d m i s s i o n T o t a l ......................... F e m a le s ; C a se s w it h a Hash on A d m i s s i o n C a s e s w it h no Hash on A d m i s s io n
1947
^ 1 ) 7 8 0 .1 0
^ 67 5 9 .8 0
39 19*90 126
4 ) 4 0 .2 0 112
1 ) 0 8 2 .0 0
86 67*80
33 1 8 .0 0
T o t a l .........................
3 2 .2 0
183
127
I r r e s p e c tiv e o f S e x : C a s e s w it h a Hash on A d m i s s i o n 307 8 1 .0 0 C a s e s w it h no Hash on A d m i s s i o n 72 19*00 T o t a l .......................... 379
P ig .
1948 $ 80 5 9 .4 0
T o ta l
304
) ) 4 0 .6 0
139 443
52 6 0 .2 0
288
^
2 1 39*80 86
108, 396
153 6 4 .0 0
132 6 0 .0 0
592
86 3 6 .0 0
89 4 0 .0 0 221
247 839
239
27
2 A gain u s in g a 2 x n c a l c u l a t i o n th e in fo r m a t io n c o n t a in e d in P i g . 26 i s c o n s id e r e d . X2 M a les F e m a les I r r e s p e c tiv e o f S ex
n = 2
r
S ig n ! 11 canoe
22.52 16.002
2 2
L e s s th a n 0 .0 1 L e s s th a n 0 .0 1
S ig n ific a n t S ig n ific a n t
3 7 -1 0
2
L e s s th a n 0 .0 1
S ig n ific a n t
III ill
Î
— lO 8 —
An a tte m p t w i l l now be made to p r o v e th e c a s e s w it h o u t a r a s h on a d m is sio n h a d , i n f a c t , a s g r e a t an in c id e n c e o f p o s i t i v e t h r o a t swabs f o r th e h a e m o ly tic s t r e p t o c o c c u s a s t h e c a s e s a d m itte d w it h a r a s h . Prom a c o n s id e r a t io n o f P i g . 28 i t
can be s e e n t h a t th e
num ber o f p o s i t i v e t h r o a t swabs on a d m is s io n i s th e same i r r e s p e c t i v e o f w h e th e r th e c a s e s i n v o lv e d had a ra sh o r n o t on a d m is s io n .
T h is i s h e ld to be f a i r l y s tr o n g e v id e n c e f o r
t h e argum ent t h a t a l l c a s e s c o n s id e r e d w ere in d e e d c a s e s o f s c a r le t fe v e r .
- 109 P ig .
28.
T h roat Swab B e s u l t s on Id m iaain n H r r e s p e o t lT e o f S e x ) . Comparing O a ses w it h no fiaah on A d m issio n w it h O a ses w it h a R aeh . T h roat P o s itiv e 1948
W ith o u t Hash . . 4? W ith B ash . . . . _82_ T o ta l
1947
W ith o u t Bash . . + W ith B a s h ...I l l T o ta l
T h roat N e g a t iv e
5 2 .7 9 6 2 .1 2
129 53
6 4 .6 5 7 1 .1 5
164
1 9 4 6 i W ith ou t B ash . . 54 7 4 .3 2 * W ith B a s h ^ 6 7 .5 0 T o ta l Grand T o t a l W ith o u t Bash . . W ith B a s h ...2 i l T o ta l
258
154 531
T o t a ls
42 JO
89 122
92
221
29 42
82 156
74
238
17
71 302
^
242 520
281
832
+ One c a s e w it h ra sh - no sw ahs a v a i l a b l e . P W ith o u t r a s h - on e c a s e , no sw a b s. * W ith r a s h - 5 c a s e s , no sw ab s.
1 .4 )2
0 .7 8 3 9
1 .5 7 1
373
88 122
63.63 6 7 .2 8
X
0 .8 6 1 2
àf
u_ is r
X ii
- 110 -
R e fe r e n c e w i l l now be made t o th e d a y s o f i l l n e s s on w h ic h c a s e s w ere a d m itte d in c o n s id e r i n g th e p r e s e n c e o r a b s e n c e o f a r a s h on a d m is s io n . There h a s b een o v e r th e t h r e e p e r io d s a s t e a d y r i s e i n th e number o f c a s e s a d m itte d w it h o u t
a r a s h . When t h i s
f a c t o r i s c o n s id e r e d in r e l a t i o n t o th e day o f a d m is s io n t h e f i n d i n g s a re s t i l l
s ig n ific a n t.
On c o n s id e r in g th e
o a s e s a d m itte d on th e f i r s t and s e c o n d day o f th e i l l n e s s it
i s fo u n d t h a t
r a s h o c c u r r e d in
t h e g r e a t e s t in c id e n c e
o f cases
w it h o u t a
th e 1948 p e r io d .
When, h o w ev er, th e c a s e s a d m itte d on th e t h i r d day o f i l l n e s s are c o n s id e r e d i t i s fo u n d t h a t th e g r e a t e s t i n c i d e n c e o f c a s e s w ith o u t a r a sh o c c u r in th e 1947 p e r io d . F o r c a s e s a d m itte d on th e f o u r t h and sub se quent d a y s , t h e 1 9 4 7 and 1948 f i n d i n g s are s i m i l a r and g iv e a s i g n i f i c a n t l y g r e a t e r number w it h o u t a ra sh when oompared w it h 1 9 4 6 .
- I ll 29 C a ses w it h no Hash on A d m issio n w i t h r e f e r e n c e to th e D ays o f I l l n e s s ô î P ^ o h A d m itted Gashes a d m itte d on th e 1 s t and 2nd Day o f I l l n e s s 1946
1947
W ith o u t Hash . . 14 8 .8 6 W ith H a s h 144 9 1 .1 4 T o ta l
158
» 9*556
..........
X^ * 2 2 .4 8
12 2 1 .0 0 4 ^ 7 8 .9 0
3o 259
57
289
P = l e s s th a n 0 . 0 1 .
5 6 .1 8 Jb 95*82 81 n K 2
C a se s
S ig n ific a n t.
24 J8
3 8 .8 0 6 1 .2 0
62
15 2 5 .8 0 4 J 7 4 .2 0
44 157
58
201
P = l e s s th an 0 . 0 1 .
S ig n ific a n t.
a d m itte d on th e 4 t h and S u b seq u en t D ays o f I l l n e s s
W ith o u t Bash . . W ith Hash . . . . . T o ta l . . . . . . . X^ = 1 2 . 9
T o ta l
a d m itte d on th e 3rd Day o f I l l n e s s
W ith o u t Hash . . W ith Hash . . . . . T o ta l
5 ,4 0 9 4 .6 0
74
n * 2
C a ses
4 JO
194 8
53 37*90 _ 8i 6 2 .1 0 140
n # 2
58 _42 103
5 6 .3 0 4 3 .7 0
62 5 8 .5 0 _ 4 4 4 1 .5 0 106
P - l e s s than 0 . 0 1 .
173 2J6 349
S ig n ific a n t.
- 112 The n e x t m a tt e r t o he c o n s id e r e d i s
th e ty p e o f
c o m p lic a t io n p r e s e n t on a d m is s io n . A lb u m in u ria was a n e g l i g i b l e f a c t o r d u r in g t h e t h r e e p e r i o d s r e v ie w e d a s w a s, o f c o u r s e , to be e x p e c te d w it h th e te m p e r a tu r e a v e r a g e s so lo w .
I n th e e a r l y s t a g e s o f s c a r l e t
f e v e r a lb u m in u r ia i s r e l a t e d to th e f e v e r and i s n o t s i m i l a r to
th e s e v e r e n e p h r i t i s w h ich can d e v e lo p a t a l a t e r s t a g e o f
s c a r le t fe v e r .
The i n t e r e s t i n g f a c t o r em ergin g from an
a n a l y s i s o f th e a d m issio n c o m p lic a t io n s i s t h a t w i t h th e l a t e r g roup Si t h e r e i s a g r e a t e r p e r c e n ta g e o f c a s e s o f s e v e r e c e r v i c a l a d e n i t i s , w h erea s t h e p e r c e n t a g e o f p e r s o n s w it h o t i t i s m ed ia d im in is h e s in th e 1948 p e r i o d .
These f in d i n g s
have s t a t i s t i c a l s ig n ific a n c e . I n a good p e r c e n ta g e o f th e c a s e s o f c e r v i c a l a d e n i t i s i t w a s fo u n d n e c e s s a r y to have s u r g ic a l i n t e r f e r e n c e . C e r v i c a l a d e n i t i s can be a t t r i b u t e d to th e a c t io n o f th e p y o g e n ic f a c t o r o f th e haemo l y t i c
str e p to c o c c u s.
j
I t w ould
t h u s a p p ea r t h a t o v e r th e th r e e y e a r s in v o lv e d t h i s f a c t o r h a s in c r e a s e d in in p o r t a n c e .
O t i t i s m ed ia , i t i s t h o u g h t ,
o c c u r s due t o t h e I n v a s iv e Component.
The o rg a n ism h a s
overcom e t h e l o c a l t h r o a t d e f e n c e s , n a m ely , th e t o n s i l s and t h e t o n s i l l a r ly m p h a tic g la n d , and h as in v a d ed th e m id d le ear.
i t w i l l be n o t ic e d t h a t in th e 1948 p e r io d th e o a s e s
o f o t i t i s m ed ia a re s i g n i f i c a n t l y lo w e r th a n b e f o r e .
T h is
j
— 113 *“ may have o c c u rre d due to a d im in u tio n in th e in v a siv e power o f th e organism .
are have p re v io u s ly shown t h a t th e to x ic
f a c t o r o f th e h aem olytic s tre p to c o c c u s a s e x h ib ite d in th e d is e a s e c a lle d s c a r l e t f e v e r has d im in ish ed m arkedly o v er re c e n t y e a rs.
In th e th re e p e rio d s review ed th e re has been
a p ro g re s s iv e d im in u tio n o f th e to x io e f f e c t s as tim e ad v an ced .
- 114 P ig .
30
G o m p lic a tio n s p r e s e n t on A d m ission { ir r e s p e c tiv e o f S ex 3 "
1216 S e v e r e C e r v ic a l A d e n i t is . . . B 29.02
n B 2
C a ta rrh a l O t i t i s
0 .7 9
14
P s= l e s s th an 0 . 0 1 .
.................... . .
S u p p u r a tiv e O t i t i s
J
1J41
55
1 4 .5 0
...............
2 .1 0
T o t a l C ases o f O t i t i s M edia ........................... ..
1 6 .6 3
518?
1248 2?
1 0 .4 0
S ig n ific a n t. 11
4.95
4 .2 0
6
2.72
46 1 9 . 2 5
17
36 1 5 .1 0 10
7.691
F o r t o t a l o a s e s o f O t i t i s M edia V 13*28
n s 2
P s l e s s th a n 0 . 0 1 .
A l b u m i n u r i a .....................................
3
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