Intensive Care Med (2000) 26: S 146-S 147

9 Springer-Verlag 2000
C. Bohuon A b r i e f hi st or y o f pr ocal ci t oni n
C. Bohuon
Institut Gustave-Roussy, 39, rue Camille Desmoulins,
F-94805 Villejuif cedex, France
During the last decade our group at the Institute G.
Roussy was studying tumor markers. We were particu-
larly interested in calcitonin (CT), an excellent marker
for medullary thyroid cancer (MTC). In order to obtain
a highly specific and sensitive assay for CT, we decided
to produce monoclonal antibodies (Mabs) against its
moieties. We then successfully developed a highly sensi-
tive and specific assay for CT. During this time, howev-
er, we also produced a library of Mabs which not only
recognized CT but also procalcitonin (PCT) and the N
or C terminal of calcitonin precursor molecules, calcito-
nin glycine (CTG) and katacalcin (KC). A major prob-
lem was the lack of pure PCT, essential for standardiza-
tion of assays. At that time, procalcitonin could be pro-
duced in small amounts by a very difficult synthesis pro-
cess. Fortunately, we found that PTN 47, a peptide of 47
amino acids could be successfully used as a standard in-
stead of procalcitonin. This peptide contains two epi-
topes which react with Mabs against KC and CT in the
same manner as PCT does. Equipped with this new and
standardized radioimmunometric assay, we not only
studied patients with MTC but also patients suffering
from other malignant and non-malignant diseases. We
noted that PCT levels were specially increased in pa-
tients with small cell carcinoma of the lung. This sug-
gested that the neuroendocrine cells of the lungs were
a probable site of PCT production.
Clinical exploitation of PCT at this point seemed re-
mote so that clinical studies with PCT were abandoned
for some years. A few months before the Gulf War in
1991, a group of French army physicians (Dr Carsin
and co-workers were interested in markers of severe
lung injury brought about by the inhalation of toxic gas-
es. I suggested including PCT as a potentially useful
marker for this condition. After some months of studies
with burn patients with or without inhalational trauma
we found that some had high levels of PCT, much higher
than those which had been observed in the initial study
of various cancer patients. Going back to the burn pa-
tient files, we found that these patients suffered from se-
vere sepsis and septic shock. This made us aware of the
relationship between PCT and sepsis.
Due to the highly intricate clinical problems in these
burn patients, it was difficult to substantiate this hypoth-
esis unequivocally. We therefore decided to study young
patients with meningitis and other severe infections. Dr.
Gendrel, a pediatrician in Paris [1], collaborated with us
to make this possible. In pediatric patients we found a
marked increase of PCT in bacterial, but not in viral, in-
fections and not in patients without infections. This con-
firmed our hypothesis and we published these data in
the Lancet in 1993 [1]. In the following months, other
groups established contact with me in order to design
studies on PCT. Three of these were particularly fruitful.
The first study was initiated with Professor Dandon-
na (Rochester, USA). We administered a safe bolus of
endotoxin (4,ng/kg) to volunteers and measured PCT
and cytokines fat defined intervals. In this study, PCT ap-
peared in the blood after 3 h, reached a plateau after 6 h
and remained at these levels for up to 24 h [2]. These
data suggested that in vivo release of endotoxin might
be detected by PCT up to 24 h after an infectious stimu-
lus.
A second study was initiated with Professor Smith in
Bangkok in patients with meliodosis. This disease, fre-
quent in that part of the world, was highly interesting
to study because of its severity and its death rate of
about 50 %. In this study we demonstrated that all pa-
tients with PCT levels higher than 100 ng/ml died. Pa-
tients with less severe disease had PCT levels substan-
tially lower than 100 ng/ml and, ultimately, a decrease
of PCT was associated with a favorable outcome [3].
S 147
The t hi rd st udy was i ni t i at ed fol l owi ng a call f r om
Pr of essor Davi s f r om Pert h, Aust ral i a. He suggest ed
t hat PCT i ncreases mi ght be r el at ed t o t he l ow val ues
of Ca ++ observed i n pat i ent s wi t h severe mal ar i a [4].
However, we did not fi nd any correl at i on of Ca ++ wi t h
PCT levels in t hese pat i ent s.
Fi ve years aft er our initial report in t he Lancet many
papers, communi cat i ons, abst ract s and post ers have
conf i r med our findings. PCT is a very i nt er est i ng and
ori gi nal mar ker whi ch is not onl y hel pful in t he di agno-
sis of severe bact eri al i nfect i on, but also i ndi cat i ve of
its severity. A new i mmuno- l umi nomet r i c assay
( I LMA) has been ma r ke t e d by BRAHMS (Berl i n)
since 1996. Its sensi t i vi t y is about 0.1 ng/ ml , whi ch is
hi gher t han t he level f ound in bl ood donors. At present ,
much remai ns t o be done. Due t o t he initial findings,
most l y connect ed wi t h clinical trials, t he f undament al
aspects of PCT are still at an ear l y stage of bei ng under-
stood. We know t hat monkeys, and per haps hamst ers,
have a si mi l ar pat t er n of rel ease of PCT. Mice, rat s and
rabbits seem unabl e t o pr oduce PCT.
It has been difficult t o fi nd PCT in in vitro studies, in-
di cat i ng t hat not onl y endot oxi n (or TNF- a) but also as
yet uni dent i f i ed co-st i mul at i ve fact ors may be necessary
for its i nduct i on. Whi ch cells pr oduce PCT duri ng infec-
tions is also not known. However , t he results of a r ecent
st udy not yet publ i shed ( Ber gmann et al.) i ndi cat e t hat
t he liver is l i kel y t o be t he pri nci pal origin of PCT pro-
duct i on. Finally, r ecombi nant PCT usi ng Escherichia
coli has been pr oduced by scientists f r om BRAHMS.
To concl ude, I wish t o emphasi ze t hat , as is of t en t he
case, t he combi nat i on of an excel l ent and specific assay
and a ver y careful clinical st udy made t he di scovery pos-
sible.
References
1. Assicot M, Gendrel D, Carsin H, Ray-
mond J, Guilbaud J, Bohuon C (1993)
High serum procalcitonin concentra-
tions in patients with sepsis and infec-
tion. Lancet 341:515-518
2. Dandonna E Nix D, Wilson ME Aljada
A, Love J, Assicot M, Bohuon C (1994)
Procalcitonin increases after endotoxin
injection in normal subjects. J Clin En-
docrinol Metab 79:1605-1608
3. Smith MD, Suputtamongkol Y, Chao-
wagul W, Assicot M, Bohuon C, Petit-
jean S, White NJ (1995) Elevated serum
procalcitonin levels in patients with
meloidosis. Clin Infect Dis 20:641-645
4. Davis TME, Assicot M, Bohuon C, St
John A, Li GQ, Anh TK (1994) Serum
procalcitonin concentrations in acute
malaria. Trans R Soc Trop Med Hyg
88:670--671