K ooij, R .: D rrm utologica 117: 336-354 (1958)
From the W estfort In stitu tio n , Pretoria, and the U niversity of Pretoria
On th e N a tu re o f th e K v eim R eactio n an d th e P a th o g e ­
nesis o f Sarcoidosis (M orbus B esn ie r-B o e ck -S c h au m a n n )
In 1889 B esnier from F ra n c e d escribed a sk in disease c h aracterized
b y larg e violaceous sw ellings on th e nose, th e ears an d above th e in te rp h a la n g e a l jo in ts of th e fingers. T h is disease he called lu p u s pernio.
A sim ilar case w as re p o rte d b y Tenneson in 1892 in w hich for th e first
tim e a histological e x a m in a tio n w as m ad e, show ing p rep o n d eran ce of
e p ith elio id cells an d g ia n t cells. A t a m eeting in Oslo in 1897 Caesar
Boeck d e m o n stra te d a p a tie n t w ho show ed m ultiple in filtratio n s in th e
sk in la stin g several y ears a n d sw elling o f th e superficial ly m p h a tic
g lan d s, w hich w ere p a rtic u la rly larg e. H isto p ath o lo g ical e x am in atio n
o f a sk in lesion show ed foci o f e p ith e lio id connective tissu e cells w ith
larg e p ale n uclei an d som e g ia n t cells. Boeck considered th is h isto ­
logical p ic tu re to resem ble t h a t o f sarcom a an d called th e disease
“ m u ltip le ben ig n sarcoid o f th e s k in ” . Schaum ann in 1914, found t h a t
th e a b o v e disease m ig h t affect th e sk in , ly m p h nodes, tonsils, lungs,
spleen, liv e r an d bone m arro w . H e p a rtic u la rly stressed th e system ic
n a tu re o f th e disease. I n 1909 Iieerfordt described a febris u v eoparotid e a su b ch ro n ica, w hich w as fo u n d m a n y years la te r to be a fe a tu re
o f sarcoidosis. Jiin g lin g (1919) d escribed changes in th e bones as
“ o ste itis tu b e rc u lo sa m u ltip lex c y stic a ” .
T h e disease on th e c o n tin e n t is u su a lly called M orbus B esnier-B oeckS c h a u m a n n , w hile in th e A nglo-saxon lite ra tu re it is called sarcoidosis.
T h e etiology is still o b scu re; p a rtic u la rly th e relation w hich it bears
to tu b e rc u lo sis h as not been s e ttle d y e t. The diagnosis is m ad e on
clinical signs, a h isto p ath o lo g ical ex am in atio n being o f g re a t im p o r­
ta n c e , if n o t essentiel, to show th e sarcoid s tru c tu re o f th e process.
T h e sarcoid s tru c tu re is c h a ra c terise d by well-defined follicles o f
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B y R . K O O IJ
K o o ij
337
ep ith elo id cells a n d inco n sp icu o u s o r no necrosis. H o w ev er th e h isto ­
logical c rite ria for sarcoid v a ry as w as clearly show n b y Ronchese
(1942). Rojichese se n t a h istological section, clinical p h o to g ra p h s and
a b rie f su m m a rv of a case o f sarcoidosis to som e w ell-know n s tu d e n ts
o f d e rm a to p a th o lo g y . T h e ir opin io n v aried from “ L u p u s V ulgaris, no
evidence o f S arco id ” to “ T y p ic a l S arcoid of B oeck” . S im ilar h isto ­
logical p ic tu re s can b e p ro d u ced b y a n u m b er o f d ifferen t ag en ts, such
as th e lep ro sy b acillu s, tu b e rc le bacillus, trep o n em a p a llid u m , b r u ­
cella, schistosom a M ansoni, silicates, b eryllium , zirconium a n d o th ers.
T h erefo re no d efinite conclusions reg arding th e cause o f sarcoidosis
can be d raw n from th e h istological p ictu re alone.
T h e so-called K v eim re a c tio n is used as a d iag n o stic te s t. A b o u t
th e v alu e of th is te s t o pinions a re d iv id ed , th o u g h g en erally one finds
th e te s t useful. T h e K v eim re a c tio n is an u n u su a l ty p e o f reactio n .
K v eim a n tig e n is p re p a re d b y e x tra c tio n w ith saline fro m sarcoid
tissu e, in jected in tra d e rm a lly (0.1 -0 .2 cc.) and th e in jectio n is called
p o sitiv e w hen a p ap u le o f a b o u t 5 m m . has developed a m o n th la te r
an d p ersists fo r one or sev eral m o n th s. Some people req u ire h isto ­
logical in v e stig a tio n o f th e p a p u le , w hich m ust show a sarcoid (like)
s tru c tu re . As fa r as I know th e re is only one sim ilar re a c tio n in clinical
use. T h is is th e M itsu d a re a c tio n in leprosy, also ch a ra c terise d b y th e
d ev elo p m en t of a d e la y e d re a c tio n w hich is read 28 d a y s a fte r th e
in tra d e rm a l in jectio n o f lep ro m in . T h e M itsuda rea c tio n has no d ia ­
gnostic valu e because m a n y h e a lth y people show a p o sitiv e reactio n
to lep ro m in . T h e M itsu d a re a c tio n is o f use for th e classification of
lep ro sy an d its prognosis. I t is u su a lly positive in th e tu b ercu lo id
ty p e o f leprosy w hich h as a good prognosis and n eg ativ e in th e leprom a to u s ty p e w hich h as a b a d prognosis. B ecause skin reactio n s o f th e
tu b e rc u lin ty p e w hich a re usu ally re a d a fte r 48 hours are called delayed
reactio n s th e ab o v e reactio n s w hich are read a fte r 28 d a y s w ill be
called “ v e ry la te re a c tio n s” . T h e re is also a stro n g resem b lan ce to th e
v e ry la te sk in reactio n s o b ta in e d b y in tra d e rm a l in je c tio n o f sus­
p ensions o f skin an d liv e r fro m h e a lth y people, as re c e n tly h as been
described b y K o o ij a n d Gerritsen (1956-1958). D u rin g th e ir in v e sti­
g a tio n s on th e n a tu re o f th e lep ro m in reactio n th e y also stu d ied
sk in te sts w ith suspensions o f n o rm al tissue. B ecause th e leprosy
bacillus c a n n o t be c u ltiv a te d , th e lep rom in h as to be p re p a re d from
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K v e im Reaction
338
K o o ij, On the Nature of the Kvcim Reaction and the Pathogenesis
b acilli-co n tain in g lep ro m a to u s tissu e b y e x tra c tio n w ith saline. L ep ro ­
m in co n seq u en tly c o n tain s bacilli an d tissue. To assess th e p a rt played
b y th e tissu e in th e lep ro m in re a c tio n K ooij and Gerritsen (1956)
carried o u t skin te s ts w ith p re p a ra tio n s from n o rm al skin a n d liver,
m ad e in th e sam e w ay as lep ro m in is p rep ared from lep ro m ato u s
tissue. T h ese p re p a ra tio n s evoked in leprosy p a tie n ts th e sam e
reactio n s as lep ro m in e.g. p o sitiv e reactio n s in th e tu b ercu lo id ty p e
an d n e g a tiv e ones in th e le p ro m a to u s ty p e . T h e ty p ic a l fe a tu re o f th e
M itsu d a re a c tio n is n o t its p o sitiv ity in the tu b ercu lo id ty p e , b u t
its n e g a tiv ity in th e lep ro m a to u s ty p e . A t first only w eak positive
reactio n s w ere o b ta in e d b u t la te r w ith c o n cen trated suspensions of
n o rm al liv er, p re p a re d b y e x tra c tio n w ith chloroform and tre a tm e n t
w ith e th e r, e q u a lly stro n g reactio n s could be evoked as w ith leprom in
(see fig. 1).
T h ese c o n c e n tra te d suspensions of n o rm al tissu e evoked in leprosy
p a tie n ts th e sam e reactio n s as lep ro m in , th e p a tie n ts m ainly show ing
p o sitiv e re a c tio n s in tu b ercu lo id lep ro sy and n eg ativ e ones in lep ro ­
m a to u s lep ro sy (see ta b le I).
TABLE I
P atients w ith Tuberculoid Leprosy (natives)
Readings in mm after
Preparation
P (20) *
S (20)
W (15)
48 hours
1 week
2 weeks
3 weeks
4 weeks
4.1
3.4
8.0
7.9
7.9
7.0
10.2
9.3
6.9
8.9
8.9
8.5
6.8
6.7
8.0
P atients w ith Leprom atous Leprosy (natives)
P (15) *
S (15)
W (16)
P re p .P
=
Prep. S
Prep. W
=
48 hours
1 week
2 weeks
3 weeks
4 weeks
2.5
2.1
3.9
5.1
2.4
3.5
0.9
2.1
2.1
0.7
1.1
2.2
0.4
0.5
1.2
Lepromin prepared from leprom atous earlobes (M itsuda-W ademethod).
Lepromin prepared from leprom atous liver (M itsuda-W adc-mcthod).
C oncentrated suspension of norm al liver obtained by extraction w ith
chloroform and treatm en t w ith ether (100 X cone.),
numbers between ( ) show th e num ber of p atients tested w ith th a t
particular preparation.
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Readings in mm -,a fter
Preparation
of Sarcoidosis (M orbus B esnier-B oeck-S chaum ann)
339
W ith suspensions o f n o rm al tissu e also positive v e ry la te reactio n s
w ere o b tain e d in h e a lth y p eople (ta b le I I) ju s t as lep ro m in does.
TA B LE II
H ealthy Garbage Collectors (natives)
S k in tests w ith 0.1 c.c. norm al liver suspension ( D harm endra 25 X cone.)
p rep . V
N um ber
48 hours
1 week
2 weeks
3 weeks
2624
4010
8819
5110
498
2924
1210
348
1525
988
568
7450
4012
3230
3430
6
3
3
11
0
2
11
6
1
14
2
9
0
4
7
7
0
5
8
6
0
11
10
4
2
4
15
0
5
14
8
1
6
10
8
2
12
8
5
2
0
15
0
5
10
7
6
6
3
7
2
0
0
2
7
2
3
4
1
0
4 weeks
7
4
7
0
0
16 Ulc
0
4
11
5
7
6
7
11
4
6 weeks
7
3
2
0
0
14
0
0
4
2
6
5
1
6
2
H istological e x a m in a tio n of th e re a ctio n p ap ules o f th e se h e a lth y
people could n o t be ca rrie d o u t. H ow ever, in a n o th e r unfinished
in v e stig a tio n in h e a lth y p eo p le th e reaction p ap u les w ere exam in ed
h istologically, an d a few , b u t n o t all reaction p ap u les, show ed a
tu b e rc u lo id (sarcoid) s tru c tu re . In tu b ercu lo id leprosy th e p ap ules
ev oked b y a suspension o f n o rm a l tissu e show ed a tu b e rc u lo id (sarcoid)
s tru c tu re , in th e sam e w ay as th o se ev oked by lep ro m in . W ith a clini­
cally a c tiv e K v eim a n tig e n p re p a re d from an enlarged ly m p h gland o f a
p a tie n t w ith sarcoidosis (o b ta in e d fro m D r. Jam es, L ondon) v e ry la te
p o sitiv e reactio n s w ere evoked in a few p a tie n ts w ith tu b ercu lo id
lep ro sy . B y c o n c e n tra tin g a clinically n o t v ery a c tiv e K v e im an tig en
K fro m a “ sarco id ” spleen (o b ta in e d from D r. K u p er, L ondon) v ery
la te p o sitiv e reactio n s w ere also o b ta in ed in p a tie n ts w ith tu b e rc u ­
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Ulc = U lceration
K o o ij, On the Nature of the Kveim Reaction and the Pathogenesis
loid lep ro sy (fig. 1) an d th e reactio n s w ere n eg ativ e in p a tie n ts w ith
le p ro m a to u s leprosy. H isto lo g ically th e se papules also show ed a tu b e r­
culoid (sarcoid) stru c tu re . As can be seen in fig. 1 th e p ap u le evoked
w ith K v eim a n tig e n p re p a re d b y e x tra c tio n w ith chloroform an d
tr e a tm e n t w ith e th e r is la rg e r th a n th e one p re p a re d b y e x tra c tio n
w ith saline. T h is was u su ally th e case; how ever th e n u m b er o f cases
a re to o few fo r a definite conclusion. In c id e n ta lly Rogers a n d H aserick
(1954) re p o rte d th a t, w ith K veim a n tig e n w ashed w ith e th e r, stro n g e r
re a c tio n s w ere o b ta in e d . T h is w'ould be a fu rth e r resem blance betw een
K v eim a n tig e n a n d a n o rm al tissu e suspension because th e n orm al
tissu e suspensions p re p a re d b y e x tra c tio n w ith chloroform an d tr e a t­
m e n t w ith e th e r wrere also m ore a c tiv e th a n th o se o b tain ed b y e x ­
tra c tio n w ith saline. I t is obvious t h a t th ere is a g reat c o n fo rm ity
b etw een th e p re p a ra tio n o f K v eim a n tig e n , leprom in and th e n o rm al
tissu e su spension as well as in th e reactions to these com pounds.
H isto p a th o lo g ic a llv th e reactio n p a p u les u su ally show a tu b ercu lo id
(sarcoid) s tru c tu re . T h e a c tiv e p rin cip le o f th e above co m pounds is
p ro b a b ly b o u n d to co rp u scu lar elem en ts and boiling did n o t d e stro y
th e a c tiv ity of th e p re p a ra tio n s. F o r fu rth e r in fo rm atio n refer to th e
a rtic le o f K o o ij an d Gerritsen (1958).
O n th e g ro u n d o f th e abo v e re su lts it is assum ed th a t th e K veim
a n tig e n does n o t co n tain a specific su b stan ce an d th a t in th e K veim
re a c tio n we a re dealing w ith a sarcoid m ode o f reactio n o r isom orphic
p h en o m en o n in c e rta in people (in d iv id u al disposition). In su p p o rt of
th is h y p o th e sis are th e c o m m u n icatio n s of Nelson (1948, 1949). H e
re p o rte d th a t all o f 11 p a tie n ts w ith sarcoidosis wrho show ed a p o sitive
c u ta n e o u s re a c tio n to th e K v eim a n tig e n also show ed a ty p ic a l s a r­
coidlike response to th e in je c tio n o f suspensions o f n o rm al spleen,
p re p a re d in th e sam e wra y as th e K v eim an tig en . A t a la te r d a te ,
N elson succeeded only p a rtia lly in c o rro b o ra tin g his first resu lts w ith
n o rm a l spleen suspensions, as s ta te d in a personal co m m u n icatio n to
Danbolt (1954). P utkonen (1943, 1945), too, o b tain ed in p a tie n ts w ith
sarcoidosis v e ry la te w eak re a c tio n s, sim ilar to those described b y
K v eim a fte r th e in tra c u ta n e o u s in jectio n of saline suspensions of
leu k aem ic h u m a n ly m p h nodes a n d tu b ercu lo u s ly m p h g lands. M any
m ore e x p e rim e n ts h av e been c arried o u t w'ith th e p u rp o se o f pro v o k in g
p o sitiv e re a c tio n s in p a tie n ts w ith sarcoidosis b y injectin g p a rtic u la te
a n d o th e r elem en ts in th e skin. D anbolt (1954) did it w ith c a tg u t,
R efvem (1948) w ith silicates, lla x th a u sen (1948) w ith ta lc a n d aleuron a te , Schaum an a n d Seeberg (1948) w ith In d ia n in k an d paraffin oil.
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340
o f Sarcoidosis (M orbus B esnier-B oeck-S chaum ann)
341
All th e se ex p e rim e n ts h a v e given n eg ativ e resu lts. T he reason th a t
w e o b ta in e d p o sitiv e re su lts is p ro b ab ly th e use o f c o n c e n tra ted
ch lo ro fo rm -eth er e x tra c ts o f n o rm a l tissue. T he m eth o d o f p re p a ra ­
tio n of th e K v eim a n tig e n is v e ry in accu rate. T h erefore it is very
d ifficu lt to o b ta in a K v eim a n tig e n su itab le for clinical use as it
a p p e a rs in th e follow ing e x tr a c t from a recent a rticle b y N elson an d
Schw im m er (1957). “ In view o f th e cru d e n a tu re o f th e suspension
used in th e K v eim te s ts , s ta n d a rd is a tio n o f th e specificity is n o t easy.
E a c h lo t o f K v eim suspen sio n , th e re fo re m u st b e te ste d fo r re a c tiv ity
a n d specificity in n o rm al in d iv id u als, in p a tie n ts w ith a c tiv e sarcoi­
dosis an d in p a tie n ts w ith diseases o th e r th a n sarcoidosis before th e
m a te ria l can be u sed fo r d iag n o stic purposes. Som e su sp ensions p re ­
p a re d fro m histologically ty p ic a l sarcoid tissue m ay be to ta lly in e rt
w hen te ste d , o th e r a n tig e n s p re p a re d from com parable tissu e sources
b y th e sam e tech n ic h a v e b e e n fo u n d to b e q u ite non-specific in th a t
th e y y ield p a p u la r re a c tio n s in v irtu a lly all v o lu n te e rs.” F ro m th e
ab o v e it w ill be clear how d ifficu lt it is to co m p are th e resu lts of
d ifferen t K veim a n tig e n s o f th e v a rio u s inv estig atio n s. P ro b a b ly it is
th e n u m b e r, th e chem ical co m p o sitio n an d th e size o f th e p articles
w hich is of im p o rta n c e fo r th e a c tiv ity o f th e p re p a ra tio n .
A ssum ing we can d e te c t a sarcoid m ode o f re a c tio n in c ertain
in d iv id u a ls w ith th e K v eim an tig e n th e n it w ould be possible th a t
p a tie n ts w ith sarcoidosis sh o u ld re a c t m ore stro n g ly to th e K veim
a n tig e n . I n a g reem en t w ith th is is th e fact th a t P utkonen (1943, 1945)
decided on th e m in im u m e x te n t of a positive reactio n b y co m paring
it w ith th e re su lts o b ta in e d in c o n tro l p a tie n ts. F o r th e p re se n t th e
K v eim reactio n is m ore o f scientific th a n p ractical im p o rta n c e . I n ­
v e stig a tio n s on a g re a t n u m b e r o f p a tie n ts w ith sarcoidosis an d con­
tro ls a re n ecessary usin g one a c tiv e b a tc h o f K v eim an tig e n .
O n th e se g ro u n d s th e disease sarcoidosis is considered to be a
sy n d ro m e th a t can be cau sed b y m a n y different a g e n ts in c e rta in
in d iv id u als w ho h av e th e c a p a c ity to respond w ith a sarcoid reactio n .
I n su p p o rt o f th is h y p o th e sis co n d itio n s are d escribed resem bling
sarcoidosis w hich w ere caused b y silicates, b ery lliu m , zirconium ,
sp iro ch aetes, tu b e rc le bacilli a n d lep rosy bacilli.
R efvem (1948) fo u n d c ry sta llin e m a te ria l (silicates) in th e h isto ­
logical sections o f 4 o u t o f 100 cases diagnosed as sarcoidosis. Degos
an d Carteaud (1953) describ ed a p a tie n t, diagnosed as suffering from
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( 1 ) Silicates
342
K o o ij, On the Nature of the Kveim Reaction and the Pathogenesis
clinically a n d histologically ty p ic a l sarcoidosis. L a te r, in th e lesions
fro m th is p a tie n t, silica c ry sta ls w ere found. T h ey m en tio n th e o ccu r­
ren ce o f a second sim ilar case. A rzt (1955) described a n o th e r p a tie n t
a n d m en tio n s sim ilar cases from th e lite ra tu re . Tw o fu rth e r p a tie n ts
a re re p o rte d b y van Steenbergen a n d Jansen (1953) w hile M acdonald
(1956) d escribed a p a tie n t w ith ren al sarcoidosis in w hich m an y in u ltin u c le a te g ia n t cells co n ta in e d clear cry stallin e frag m en ts o f an
a p p e a ra n c e a p tly d escribed as “ g lasslike” . V arious sarcoid-like silica
g ra n u lo m a s o f th e skin a re re p o rte d usually due to tra u m a . C on­
sp icu o u s is th e long la te n t perio d o f m a n y years betw een tra u m a and
th e d ev elo p m en t of th e lesions.
G entry e t al. (1955) stu d ie d th e d is trib u tio n in th e U n ited S ta te s o f
A m erica o f 350 cases of sarcoidosis in m ilita ry personnel d u rin g W orld
W a r I I . T h e ir u n ju stifia b le conclusion w as th a t residence in th e ru ra l
a re a s o f th e S o u th -E a st, w here th e soil is of fine san d y ty p e , a p p ears
to fa v o u r th e d ev elo p m en t o f sarcoidosis.
( 2 ) B erylliu m
B ery lliu m can cause a disease in d istin g u ish ab le from sarcoidosis.
A ccording to H ardy (1956), a t th e m o m en t it is n o t possible to m ake
a c o rre c t differential diagnosis b etw een sarcoidosis a n d b ery lliu m
poiso n in g w ith c h e st-ro en tg en o g rap h ic changes or th e h isto p a th o logical reactio n as th e criterio n . O nly th e discovery th ro u g h spectro g ra p h ic o r chem ical m eans of b e ry lliu m in tissu e show ing a g ra n u lo ­
m a to u s sarcoid-like p ic tu re is decisive. In te re stin g is th e o b serv atio n
o f Sneddon (1955), who fo u n d histologically a delayed sarcoid reactio n
in a p a tie n t w ith a sy stem ic b e ry lliu m disease, in th e p o sitive p a tc h
te s t-s ite , evoked b y a 1 % a n d 2 % so lu tio n o f b ery lliu m su lp h a te a n d
b e ry lliu m n itra te . T h e b iopsy w as ta k e n th ree weeks a fte r th e p a tc h
te s t. As fare as is know n o cu lar, to n silla r, p a ro tid lesions an d cystic
b o n e ch an g es h a v e n o t been seen in beryllium poisoning. Nelson an d
Schtvim m er (1957) re p o rte d a p o sitiv e K veim reaction in a p a tie n t
w ith b e ry lliu m poisoning.
R u b in e t al. (1956) d escribed th e occurrence o f sarcoid-like g ra n u lo ­
m as in th e ax illae a fte r th e use o f c e rta in d eodorants. H istologically
th e s tru c tu re w as tu b e rc u lo id , w ith o u t necrosis. Shelley (1957) an d
Shelley an d H u xley (1958) h a v e show n th a t th ese kind of g ran u lo m as
a re cau sed b y th e zirconium o f th e d eo d o ran ts.
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( 3 ) Z irconium
of Sarcoidosis (Morbus licsnior-Hoeck-Schaumaim)
343
( 4 ) Spirochaetes
P autrier (1936), Blocli an d T zanck, each have described a case of
clinically and histologically ty p ic a l sarcoidosis, w hich healed very
q u ick ly w ith arsp h en am in es.
( 5 ) Tubercle bacilli
T h ere are m an y s u p p o rte rs of th e view th a t sarcoidosis is caused by
th e tu b ercle bacillus. I will only m e n tio n a few p u b licatio n s on th is
su b je c t. E pidem iological stu d ies b y m eans of chest X -ra y s by Burger
a n d K iithe (1940), by A p p e lm a n (1947) an d by Baas an d van Voorst
Voder (1957) show ed th a t a t le a st in th e N eth erlan d s th e re is in the
m a jo rity o f p u lm o n a ry cases of sarcoidosis a causal relatio n sh ip w ith
tu b ercu lo sis. Van R yssel (1947) (th e N etherlands) carried o u t e x te n ­
sive p o st m o rtem e x a m in a tio n s of 3 cases of sarcoidosis an d cam e to
th e conclusion th a t sarcoidosis p ro b ab ly is a form o f tub ercu lo sis.
Vosbein and Bonnevie (1940) in D en m ark found th a t 9 of 34 p a tie n ts
w ith sarcoidosis of th e sk in had been exposed to a tu b e rc u lo u s in ­
fectio n . T he sam e freq u en cy o f expo sure to tu b ercu lo u s infection was
fo u n d in th e ir p a tie n ts w ith tu b ercu lo sis o f th e skin.
Citron (1957) an d Scudding (1956, 1957) ( I n s titu te o f th e C hest,
B ro m p to n , L ondon) ca rrie d o u t im m unological stu d ies in p a tie n ts
w ith sarcoidosis. Besides th e u su al tub ercu lin skin te st th ey p e r­
form ed a skin test w ith tu b e rc u lin m ixed w ith cortisone a c e ta te su s­
pension, which te s t is m uch m ore sensitive. A m ong th e 28 p a tie n ts
w ith sarcoidosis w ho failed to re a c t to tu b ercu lin , 14 re a c te d to tu b e r­
culin plus cortisone. O f th e 14 p a tie n ts w ith sarcoidosis w ho failed to
react e ith e r to tu b ercu lin or to tu b ercu lin plus cortiso n e, seven had
clear evidence o f p rev io u s tu b e rc u lo u s infection. Citron and Scudding
conclude th a t a t le a st in E n g la n d th e m ajo rity of cases o f sarcoidosis
are caused b y a tu b e rc u lo u s infectio n. T hey assum e th a t generally
sarcoidosis is an u n u su al tissu e reactio n to a tu b ercu lo u s in fectio n .
In iny opinion an e x p la n a tio n for th is is th a t som e in d iv id u als have
th e c a p a c ity to react u n d e r c e rta in circum stances to an infection w ith
th e tu b ercle bacillus w ith a sarcoid reaction.
M any w orkers ( D arier, K lingm iiller [1930], U nna, I-.ever) re p o rt
th a t d ifferen tiatio n of sarcoidosis from tuberculoid leprosy in som e
cases m ay be im possible on h isto p ath o lo g ical g ro unds. W e have the
26
Dermatologien, Vol. 117, No. 5 ( l ‘Lr>U)
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(()) Leprosy B acilli
344
K ooij
Fig. 1. P atien t No. 12 954. Tuberculoid leprosy. Skin reactions sixty days after the
intraderm al injection in a patient with tuberculoid leprosy. The upperm ost papule
is evoked w ith K veim antigen k . 1 times concentrated. The middle papule is evoked
by extraction of Kveim antigen K with chloroform and treatm ent with ether. The
two lowest papules are evoked with a concentrated suspension id’ normal liver pre­
pared by extraction with chloroform and treatm en t with ether (75 times concent­
rated). The Mitsuda reaction with lepromin, prepared according the W ade-Mitsuda-m ethod. had a diam eter of 8 m m . (no photograph taken).
Fig. 2. No. 12 967. Lupus pernio type of leprosy.
Fig. 5. No. 690. Leprosy resembling sarcoidosis.
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Fig. 3. No. 18 061. Tuberculoid leprosy, reactive stage.
Lesion on nose resembles angio-lupoid of Brocq and Pautrier.
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Fig. 4. P atient No. 13 061. Epitheloid cell tubercle.
Fig. ft. Patient No. 690. Rpitheloid cell tubercles with slight reaction in the coriuni.
346
K o o ij. On the Nature of the Kveim Reaction and the Pathogenesis
sam e experience. M any o f o u r histological sections o f tu b ercu lo id
lep ro sy resem bled m ore or less th o se o f sarcoidosis. In a b o u t 8 0 % o f
o u r p a tie n ts w ith tu b ercu lo id lepro sy, no leprosy bacilli could he
found in th e lesions. C linically also th e re is a stro n g resem blance to
leprosy. In th e 4 V2 years th a t I h av e w orked in th e W estfort L eper
In s titu tio n w ith an an n u a l av erag e o f 1000 p a tie n ts an d a tu rn o v e r
o f 500 a y e a r I h av e seen ev ery v a rie ty of skin lesion described as
ty p ic a l fo r sarcoidosis n am ely, th e m acu lar, n odular, plaque an d tu m o r
ty p e . P ic tu re s resem bling lu p u s p e rn io and angiolupoid have been
o b serv ed . Swollen earlobes, w hich sh o u ld be ty p ic a l for lu p u s pernio
are q u ite c h a ra c te ristic for th e le p ro m a to u s, borderline and th e tu b e r­
culoid in reactio n form o f leprosy. I presum e th a t several cases d e ­
scrib ed as lu p u s pernio have been caused by th e leprosy bacillus.
T h e p ap u le o f th e M itsuda reactio n , too, resem bles a lesion o f s a r­
coidosis. K issm eyer (1932) p o in ts to th e resem blance in colour o f th e
lesions o f sarcoidosis and leprosy.
Illustrative Cases
No. 12 967: N ative male, aged 28.
Admission: 28th August, 1956.
Unset: 1956. Diagnosis: Tuberculoid leprosy in reactive stage.
Clinical Data.
Skin: Raised spongy violaceous swellings on the face. Lesions with infiltrated
erythem atous margins and healing centres on the trunk and limbs (sec fig. 2).
Neurological. Some lesions on trunk and limbs showed anaesthesia to light touch
(cotton, wool).
Septem ber. 1956. Biopsy from a plaque on the left breast.
Histological report. Periadnexal infiltration of spindle cells and group of epithe­
lioid cells in the cutis giving a tuberculoid picture. Occasional acid-fast bacilli are
seen. December 1956. Biopsy from a hypopigm ented healing centre of a lesion of the
left shoulder area. Histological report. Non-specific. Acid-fast bacilli not seen.
Lepromin reaction (D harm endra antigen). 18 hours: 1 m m . 28 days: 3 mm.
Tuberculin reaction (P l’D, 10 TU)
IT mm . Ide reaction: negative.
Treatment: Diaminodiphenyl-sulphone (1)I)S). Stibophcn. cortisone, atabrin.
Course: 7. 9. 1956. Lesions very red and spongy. 23. 11. 1956: Lesions subsiding.
22. 7. 1957: Lesions flat. Novembre 1957: Declared arrested.
At intervals of I or 2 m onths smears were taken from the right and left earlobes
(E R . EL), the lesions on forehead (ER. EL) and cheek (CR. CL) and of the nasal
mucosa (NS). Smears were stained by routine. Ziehl-Neelsen-method. The smears
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Skin Smears.
347
of Sarcoidosis (M orbus B esnier-B oeck-S chaum anii)
were assessed by tin* num ber of acid-fast bacilli present, being recorded as negative,
very scanty (VSC), 1 -f-, 2 -f-t 3 -f- and 4 4*»
Results Skin Smears.
II. 56
It). 56
ER
FU R 2
Cr
1
NS
FU R
5. 57
7. 57
ER
FUR
CR
NS
EL
FH I,
CL
NS
-
l +
1. 57
2. 57
4. 57
ER
FH R
CR
NS
EL
FH I.
CL
NS
ER
FH R
CR
NS
II. 57
9. 57
10. 57
ER
FH R
CR
NS
EL
FH R
CR
NS
ER
FH R
CR
NS
Comment
Vo. 13 061: N ative male, aged 25.
Admission: 28th November. 1956.
Onset: 1953. Diagnosis: Tuberculoid leprosy in a reactive stage.
Clinical data.
Skin: Spongy plaques on face, trunk and limbs. Plaque on nose resembles angio1li]mid of Brocq and P au trier (see fig. 3).
\eurological: Some lesions on the limbs show anaesthesia to touch.
Dec. 1956. Biopsy from a plaque on the right hip.
Histological report. Leprom atous. Acid-fast bacilli -t - . May. 1957.
Second biopsy from a plaque on the right hip (May. 1957).
Histological report: Epithcloid cell tubercles. Acid fast bacilli: negative (sec fig. 1).
Lepromin reaction (D harm endra antigen). 48 hours: 0 mm. 28 days: 2 mm.
Tuberculin Reaction: P P D (10 TU) = 10 mm. Chest X -ray: no abnorm alities.
Kolmer Reaction: negative.
Treatment: DDS and Stibophen.
Course: March. 1957. New spongy plaques on face. May. 1957. Lesions paler and
some with healing centres. Ja n u a ry , 1958. Lesions flatter.
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Case resem bles lu p u s p e rn io ty p e of sarcoidosis. T h ere w ere in this
p a tie n t no sw ellings of th e ears or o f th e fingers. H ow ever, we have
seen lep ro sy cases sim ilar to th e ab ove w ith swelling o f the ears an d
the lingers. T h e h isto p a th o lo g y o f p a tie n t 12 967 was co n siste n t in
th e first biopsy specim en w ith sarcoidosis. In the histological sections
th e acid -fast bacilli w ere scarce an d could easily be m issed. T he skin
sm ears w ere p o sitiv e, for a few m o n th s only. T he histological p ictu re
o f th e second biopsy w as non-specific, showing the changes in h isto ­
logical s tru c tu re of v a rio u s lesions a t different tim es in th e sam e
p a tie n t.
348
K o o i j . On the Nature of the Kvcim R eaction a n d the Pathogenesis
Skin smears.
Also a few sm ears were ta k e n from lesions on the b u ttoc ks, tru n k a n d limbs.
11. 56
ER
-
2. 57
4. 57
1. 57
FH R
A rm s L vse
KI-
B utt. R. vse
B utt. L. vse
CI.
FH R 3 +
3 +
CR
Ns
I 'll I,
NS
I p till F ebruary, 1958. monthly smears were always bacillary negative.
Comment
L esion on th e nose resem bles angio-lupoid of B rocq and P a u trie r.
H isto p a th o lo g y o f th e second b io p sy specim en is co n sisten t w ith
th a t o f sarcoidosis. T he skin sm ears w ere only positive fo r a few
m o n th s.
.Vo. 690: W hite woman, aged 30.
Onset: 1954.
Admission: 14th March. 1954. Tuberculoid leprosy in a slight reactive stage.
Clinical data.
Skin: Bluish-red nodules on face and limbs.
Neurological. Anaesthesia to light touch in a lesion on the right thigh and a lesion
on the dorsolateral side of the right foot.
April. 1954. Biopsy from a slight reactive nodule of the left calf.
Histological report. Kpitheloid cell tubercles in the corium with slight reaction.
Acid-fast bacilli: negative (fig. 6).
Lepromin reaction: D harm cndra antigen. 48 hours: 10 mm. 28 days: no record.
Tuberculin reaction: (PPD . 10 'IT )
0 mm.
Kolmer reaction: negative.
Treatment: DDS; IN H ; Stibophcn.
Course: Ju n e, 1954. Lesions subsiding. Septem ber. 1954. Lesions still ery th em at­
ous. Jan u ary . 1954. Baby born. 1st March. 1955. Declared arrested and discharged.
Skin smears.
Monthly skin smears always negative.
C linically an d histologically th is case is in d istin g u ish ab le from
sarcoidosis, n o d u la r form . O ne could argue th a t the disease in this
p a tie n t is n o t caused b y th e lep ro sy bacillus, because bacilli were
n e v e r fo u n d . T h e p o in ts in fav o u r o f leprosy being:
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Comment
o f Sarcoidosis (M orbus B csnicr-B oeck-S chaum ann)
349
(1) A naesth esia o f som e lesions.
(2) Cousin o f p a tie n t suffered from tuberculoid lep ro sy , w ith
a n aesth esia of th e lesions an d c o n tra c tu res o f b o th h an d s. No bacilli
w ere found.
O sseous involv em en t such as cy sts and d eform ation o f h an d s and
feet can also he fo u n d in p a tie n ts w ith leprosy. Fig. 7 show s cy st
fo rm a tio n in tlie p ro x im al p h a la n x of th e fo u rth finger in a p a tie n t
w ith lep ro m a to u s lep ro sy sim ilar to th a t described in sarcoidosis.
7. Patient No. 12 662. Cyst formation proximal phalanx of the fourth finger in
a p atien t with leprom atous leprosy.
In v o lv em en t o f th e lungs in leprosy had n o t been in ten siv ely
in v e stig a te d h u t it is th o u g h t th a t th e y are rarely affected. A ccording
to Rabello (1930) who su p p lies m a n y arg u m en ts in fav o u r o f his
th e o ry th a t leprosy is th e cause o f sarcoidosis, th e re occur in leprosy
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W e o bserved a sim ilar c y st fo rm a tio n in a p a tie n t w ith tuberculoid
leprosy. In b o th p a tie n ts th e serological syphilis reactio n s were
negativ e.
K o o ij. On the Nature of the Kveim Reaction and the Pathogenesis
lung p ic tu re s in d istin g u ish ab le from sarcoidosis. G eneralised lym pha d e n o p a th y an d increase in serum p ro te in occur b o th in leprosy and
sarcoidosis.
N eurological changes often occur in leprosy an d are rep o rted a few
tim es in sarcoidosis. Ernstirig a n d Sillevis Sm itt (1944, 1048) described
live p a tie n ts w ith sarcoidosis who show ed p araly sis of the cerebral
nerves. It is n o ticeab le th a t in fo u r o f these p a tie n ts the nervi faciales
w ere p a ra ly se d an d it is p a rtic u la rly facialis p araly sis w hich so often
trait be seen in leprosy. A n aesthesia o f th e lesions, which is essential
for th e diagnosis o f tu b ercu lo id lep ro sy, is seldom if never m entioned
in sarcoidosis. H ow ever, I believe th e lesions o f sarcoidosis are
a p p a re n tly rarely exam ined for sen satio n of touch, h eat a n d cold.
L iver a n d spleen are fre q u e n tly affected in b o th diseases.
I t is th e re fo re e v id e n t t h a t th e clinical and histological p ictu re o f
sarcoidosis can be evoked b y m an y a g en ts. P ro b ab ly th ere are m inor
v a rie tie s in th e clinical sy m p to m s according to the ag en t, e.g. rare
lung ch an g es in leprosy, no bone lesions in beryllium in to x icatio n
an d so on. It fre q u e n tly h a p p e n s th a t because o f th e finding o f the
c a u sa tiv e a g e n t in a p a tie n t w ith a clinical and histopathological
p ic tu re o f sarcoidosis, th e diagnosis of sarcoidosis is d ro p p ed . In
m y o p in io n , th is policy is w rong for th e elucidation of th e sarcoidosis
problem . I w ould propose t h a t w hen clinically a n d h isto pathologieally
th e diagnosis sarcoidosis is m ade, one m u st retain this diagnosis and
w hen th e c a u sa tiv e agent is fo u n d th is m ust be m entioned e.g. s a r­
coidosis cau sed b y tu b ercu lo sis, sy p h ilis, leprosy, silicates, b eryllium .
O th erw ise sarcoidosis rem ain s a diagnosis by exclusion.
P ro b a b lv it will be difficult to ch ange the nam e o f th e original
disease. In th a t case I w ould pro p o se th a t w hen th ere is a resem blance
th is be m en tio n e d in th e n am e e.g. sarcoidosis-like silicosis - tu b e rc u ­
losis —lep ro sy etc. F o r th e sam e reaso n I w ould propose to bring u n d e r
th e h ead in g sarcoidosis th e M elkerso n-R osenthal syndrom e, Cheilitis
g ra n u lo m a to sa (M iesch er), sarcoids of D arier-R oussy an d o th e r
diseases in w hich lesions show a sarcoid stru c tu re histo p ath o lo g ieally .
K ooij (1950) proposed to m a in ta in th e original c riteria o f D arier and
R oussy for th e condition called sarcoids of D arier-R oussy and to
reserve th e n am e for a su b c u ta n e o u s localisation o f sarcoidosis, all
o th e r cases being non-specific p a n n ic u litis.
F u rth e rm o re ev ery p a tie n t w ith sarcoidosis should be th o ro u g h ly
ex am in ed to ex clu d e th e a b o v em en tio n ed causes, a tte n tio n being paid
especially to th e te stin g for an a e sth e sia of th e lesions and to histo-
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350
of Sarcoidosis (Morbus Mcsiiicr-liocck-Schaiiimiiin)
35 i
logical nerve changes. In a d d itio n consideration m u st be paid to
causes o f th e co n d itio n w hich are at present unknow n.
Acknowledgement. This paper is published with the permission of the Secretary for
H ealth, Pretoria. South-Airiea. W e are indebted to Dr. W. ./■ Pepler. In stitu te of
Pathology. P retoria, and D r . i f Hinwright. D epartm ent of Pathology, D urban, for
tile histological investigations.
S u m m itry
A rg u m en ts are b ro u g h t fo rw a rd in su p p o rt o f th e view th a t the
k v e im reactio n is th e ex p ressio n o f a sarcoid m ode o f reactio n in
c e rta in in d iv id u als (.............
'
), and th a t th e K veim a n ti­
10889
gen does n o t co n tain specific su b stan ces. Sim ilar reactio n s were also
o b ta in e d w ith suspensions o f no rm al tissue. Sarcoidosis is considered
to be a sy n d ro m e w hich can be evoked by m an y ag en ts in c ertain
in d iv id u als. E x am p les are given o f sarcoidosis-like co n d itio n s caused
b y silicates, b ery lliu m , zirco n iu m , sp iro ch aetes, tu b ercle bacilli and
lep ro sy bacilli. It is d esirab le th a t in these cases th e diagnosis of
sarcoidosis be re ta in e d , w hile th e cause is m en tio n ed . T his will
p rev en t sarcoidosis becom ing a diagnosis by exclusion.
Z it sa m m n i fuss it ng
Es w erden G rü n d e d a fü r angegeben, d aß die K v eim -R e a k tio n d er
A u sd ru ck einer sark o id en R e a k tio n bei gew issen In d iv id u e n sei
(individuelle D isposition) u n d d a ß das K veim -R eagens keine spezi­
fischen S u b stan zen e n th a lte . Ä hnliche R eaktionen ergeben auch
S uspensionen aus n o rm alem G ew ebe. Die Sarkoidosis w ird als S y n ­
drom b e tra c h te t, das bei gew issen In d iv id u en d u rch verschiedene
A gentien h erv o rg eru fen w erden k a n n . Es w erden B eispiele z itiert fü r
sark o id o sisäh n lieh e R e a k tio n e n , die durch S ilik ate, B eryllium ,
Z irco n iu m , S p iro c h ä te n , T u b erk elb azillen und L ep rabazillen h e rv o r­
gerufen w erden. Es ist w ü n sch en sw ert, in solchen Fällen die D iagnose
S arkoidose d urch d eren U rsach e zu ergänzen. D ad u rch kan n v e rh in ­
d ert w erden, d a ß S arkoidose eine D iagnose per exclusionem w ird.
L’a u te u r av an ce c e rta in s a rg u m e n ts m o n tra n t que la réactio n de
K veim est l’expression d ’une te n d a n ce de certain s in d iv id u s à faire
des sarcoïdes (disp o sitio n in d iv id u elle), et que le ré a c tif de K veim ne
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Résum é
352
K o o i j . O n the. ¡Nature of the K vcim R eaction and the P athogenesis
c o n tien t a u cu n e su b stan ce spécifique. Des reactions sem blables
p e u v e n t ê tre p ro voquées p a r des e x tra its de tissus n o rm au x . La
sarcoidose d o it ê tre considérée com m e un syndrom e, qui peu t ê tre
déclenchée p a r p lusieurs ag en ts chez des in d ividus prédisposés.
L ’a u te u r d o n n e des exem ples de réactio n s sarcoides déclenchées p a r
des silicates, p a r le b éry lliu m , p a r le zirconium , les sp iro ch ètes, les
bacilles tu b e rc u le u x et de la lèpre. D ans de tels cas, il serait in d iq u é
de c o m p lé te r le d iagnostic en n o m m a n t la cause de la réactio n . On
é v ite ra it de faire ainsi de la sarcoidose un diagnostic par exclusion.
Appelm an, A . C.: Over holtcvorm ing bij de ziektc van Besnicr-Bocck. Ncd. Gencesk.
01: 2985 2992 (1947).
Arzt, L.: Foreign body granulomas and Bocck's sarcoid. J . invest. Derm. 24: 155
166 (1955).
Haas. M . A . cn Van Voorsl Vader. P. .1. A .: Epidcmiologisch onderzoek bij het.
syndroom van Besnier-Boeck (sarcoidosis). Ned. Gencesk. 101: 1111-1116 (1957).
Hesnier. E.: L upus pernio de la face: Synovites fongeuses (Scrofulo-tuberculcuses)
sym étriques des extrém ités supérieures. A nn. Derm. Syph. 3: 417 (1892): eit.
by Longcope and Freiman. p. 1.
Much. II.: eit. by Pautrier, p. 731.
Hoeck, C.: Norsk Mag. Lægevid. 60: 1321 (1899): eit. by Danboll. p. 122.
Hour. D. .1. IE: Over de ziekte van Bcsnier-Boeck-Schaum ann: med. Diss. (A m ster­
dam 1942).
Burger, G. C. E. en Kiitlie, C. II. ./..’ Bijdrage to t de kennis over intrathoraeale
localisaties van het lym phogranulom a benignum (Ziekte van Schaum annBesnier-Boeck). Gencesk. Bladen, pp. 1 37 (De Erven. F. Bohn N. V., Haarlem
1940).
Citron, K . M. and Scadding, J . G.: The effect of cortisone upon the reaction of the
skin to tuberculin in tuberculosis and in sarcoidosis. Q uart. Med. 26: 277-289
(1957) .
Citron. K . M .: The immunological aspect of sarcoidosis. Brit. J . Derm. 70: 48 57
(1958) .
Panbolt, M .: Sarcoidosis; Chapter 8. R. M. B. MacKenna. Modern Trends in Derma­
tology. Second Series (B utterw orth & Co. London 1954).
Parier, J .: eit. by Klingmiiller, p. 562.
Pegos, R. ct Carteaud. IE: Granulosc silicotique à type de sarcoidose. Discussion
d'une maladie de Schaumann authentique. Bull. Soc. Franc;. Derm. 60: 258-260
(1953).
Enisling, IV. en Sillevis Smitt. W. G.: Neurologische verschijnselen bij de ziektc van
Besnier-Boeck-Schaumann. Gencesk. Bladen, pp. 1-40 (De Erven F. Bohn N. V.,
H aarlem 1944). A bstract: E xccrpta med.. Sect. XV. Tuberculosis 1: 71 (1948).
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Les corticostéroïdes pour le tra ite m e n t de cas rebelles
de tu b erculides p apulonécro tiq u es et nodulaires *
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A cô té des problèm es que pose encore l’étio -pathogénie des tu b e r­
culides, leu r tra ite m e n t aussi s’av è re d é cev an t, so u v en t bien d ’a v a n ­
tage q u e celui des tubercu lo ses cu tan ées ty p iq u e s. Pilles do n n en t
l’im pression q u e leur évolution g én éralem en t bénigne m ais récidi­
v a n te est p lu s so u v en t sp o n ta n é e que le résultat des m oyens th é ra ­
p e u tiq u e s m is en œ u v re.
D epuis mes je u n e s années de d erm ato lo g iste, ces derniers ont b e a u ­
coup v a rié : huile de foie de m orue, sels de ch au x , injections de sels
de m é ta u x ra re s: injections arsén icales, de B ism u th et de sels d ’o r: