AbstractToxigenic Corynebacterium ulcerans is an emerging cause of diphtheria. In contrast to the classical diphtheria pathogen C. diphtheriae, human-to-human transmission of this primarily zoonotic pathogen has not been clearly documented. Here we report on a two-person cluster suggesting an initial zoonotic and a subsequent human-to-human transmission event

Hörmansdorfer, S.

Konrad, R.

Sing, A.

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ORIGINAL ARTICLE EPIDEMIOLOGYPossible human-to-human transmission of toxigenic Corynebacterium
ulceransR. Konrad1,2, S. Hörmansdorfer1 and A. Sing1,2
1) Bavarian Health and Food Safety Authority and 2) Consiliary Laboratory on Diphtheria, Oberschleißheim, GermanyAbstractToxigenic Corynebacterium ulcerans is an emerging cause of diphtheria. In contrast to the classical diphtheria pathogen C. diphtheriae, human-to-
human transmission of this primarily zoonotic pathogen has not been clearly documented. Here we report on a two-person cluster suggesting
an initial zoonotic and a subsequent human-to-human transmission event.
Clinical Microbiology and Infection © 2015 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All
rights reserved.
Keywords: Corynebacterium ulcerans, diphtheria, person-to-person transmission, zoonotic transmission, zoonosis
Original Submission: 8 April 2015; Revised Submission: 15 May 2015; Accepted: 18 May 2015
Editor: S.J. Cutler
Article published online: 28 May 2015Clin
Cli
httCorresponding author: A. Sing, Bavarian Health and Food Safety
Authority, Veterinärstraße 2, 85764 Oberschleißheim, Germany
E-mail: andreas.sing@lgl.bayern.deIntroductionDiphtheria and diphtheria-like illness are caused by Corynebac-
terium species harbouring the diphtheria toxin–encoding tox
gene. C. diphtheriae was responsible for the high morbidity and
mortality of this classical infectious disease until the introduc-
tion of the respective vaccine—and still is in several parts of the
world, especially in less developed countries or after disruption
of public health systems by natural or human-made disasters.
Local outbreaks or large-scale epidemics are supported by the
fact that the human pathogen C. diphtheriae is primarily trans-
mitted directly from human to human.
In recent years, diphtheria-like infections with toxigenic C.
ulcerans have outnumbered those caused by toxigenic C. diph-
theriae in many industrialized countries [1–3]. Most of the re-
ported human infections with this zoonotic pathogen are
related to animal contact and are supposed to be transmitted
from animal to human. In contrast to C. diphtheriae, so far
human-to-human transmission of C. ulcerans has not beenMicrobiol Infect 2015; 21: 768–771
nical Microbiology and Infection © 2015 European Society of Clinical Microbiology and Infect
p://dx.doi.org/10.1016/j.cmi.2015.05.021documented [2,4,5]. Here we report a possible case of human-
to-human transmitted toxigenic C. ulcerans.Case reportIn October 2014 an ambulatory healthcare center sent a
Corynebacterium ulcerans strain isolated from a pharyngeal swab
of a 13-year-old girl with tonsillitis to the Consiliary Laboratory
of Diphtheria (CLoD) for toxigenicity testing by tox PCR and, if
positive, Elek testing according to the diagnostic algorithm
established at the CLoD [6,7]. At the onset of symptoms, the
girl had a sore throat which increasingly worsened in the
following 2 days. Low fever (temperature <38°C), headache
and severe sickness were accompanied by a sweetly foul-
smelling whitish mucous in the throat. During the afternoon,
swallowing became increasingly harder. On day 3 a pharyngeal
swab was taken that grew C. ulcerans in pure culture on day 4.
On day 5 penicillin was started, leading to immediate
improvement of the symptoms after two doses. Penicillin
therapy was continued for 14 days. Two control pharyngeal
swabs taken on days 10 and 11 did not grow Corynebacteria.
Species identiﬁcation of C. ulcerans was conﬁrmed at the
CLoD by MALDI-TOFMS (matrix-assisted laser desorption-
ionization time-of-ﬂight mass spectrometry) analysis (score:ious Diseases. Published by Elsevier Ltd. All rights reserved
CMI Konrad et al. Transmission of C. ulcerans 7692.4) and API Coryne (API code 0111326). Toxigenicity of the
isolate was conﬁrmed both by a positive real-time PCR [8] and
a positive modiﬁed Elek test [9]. The local health authority was
immediately informed, all ﬁve household family members were
tested for Corynebacteria. Additionally, all of them received a
booster vaccination. Similar to the German management
recommendations for contacts to a C. diphtheriae patient
(http://www.rki.de/DE/Content/Infekt/EpidBull/Merkblaetter/
Ratgeber_Diphtherie.html), prophylactic antibiotic therapy
was offered but ﬁnally was not administered. While both
parents and two sisters were free of C. ulcerans, the 81-year-
old asymptomatic grandmother was found to carry toxigenic
C. ulcerans in her throat. For multilocus sequence typing
(MLST), a modiﬁed scheme of C. diphtheriae was used [10].
The isolates from the girl and her grandmother had identical
alleles, and both belonged to sequence type (ST) 332 (http://
pubmlst.org/cdiphtheriae/). After a completed eradication
therapy with penicillin, the grandmother tested negative for C.
ulcerans.
The family lived on a farm in northeastern Bavaria, Germany,
with cattle and pigs as well as with a dog, a pet cat and three
farm cats. All animals were asymptomatic. The girl was re-
ported to have only contact with the pet cat and to a lesser
extent with the dog, but not with the three free-roaming farm
cats or the stable animals. Her grandmother basically had no
close animal contact but worked sometimes in the stable,
however without having close cattle contact or milking the
cows. She was the only person in the household to occasionally
drink fresh cow’s milk after boiling. Although recommended by
the local health authority and the CLoD, testing the animals was
unfortunately not possible. Neither the girl nor her grand-
mother had an underlying disease or was immunosuppressed.DiscussionIn the last few years, reports on human infections by toxigenic
C. ulcerans outnumber those caused by toxigenic C. diphtheriae
in Europe [1–3]. In the past 5 years (2010 to November 2014),
80% of the 46 C. ulcerans from humans sent to the German
CLoD were toxigenic, whereas only 8% out of 182 C. diph-
theriae were so. The majority of them were isolated from
extrapharyngeal sites, but a few reported cases were associated
with respiratory diphtheria or diphtheria-like disease. Trans-
mission between farm animals like pigs and cattle or pet ani-
mals, such as dogs or cats, and humans can occur [11–14]. In
the case reported here, we found two members of the same
household harbouring toxigenic C. ulcerans in the throat,
causing diphtheria-like disease in one of them. Unfortunately, it
was not possible to sample the farm and pet animals.Clinical Microbiology and Infection © 2015 European Society of Clinical MicrobiologyIn contrast to the human pathogen C. diphtheriae, which is
predominantly transmitted via droplets from person to person,
resulting in outbreaks or epidemics, human-to-human trans-
mission of the zoonotic pathogen C. ulcerans has so far not been
documented [2,4,5]. Moreover, secondary diphtheria cases
linked to an index case of C. ulcerans infection or symptomatic
C. ulcerans outbreaks have not been published until now.
Only three instances of human toxigenic C. ulcerans infections
involving more than one person have been reported previously.
The ﬁrst two-patient cluster comprised a young woman with a
sore throat and an asymptomatic person identiﬁed during an
outbreak investigation in a religious community in a remote area
of North Devon, England, in 1981 [15]. The most likely mode of
transmission was drinking raw milk obtained from an infected
cow herd, since the organism could be isolated from bulk milk
samples of the respective farm. No evidence for
human-to-human transmission is provided [15]. Two additional
toxigenic C. ulcerans clusters of two were reported from
England in 1996 and 1998, respectively [2]: a 20-year-old man
with a sore throat and his asymptomatic 18-year-old sibling,
both living in a rural area, but without cattle contact (also
mentioned as personal communication without additional data
in [4] and [16]), as well as a 35-year-old man with classical
respiratory diphtheria and his asymptomatic 11-year-old son
who owned ﬁve household dogs, and who tested negative for C.
ulcerans (also mentioned in [16]). For the two most recent
cases, the authors speculate that the absence of any apparent
source of infection might indicate the possibility of person-to-
person transmission [2]. However, for both clusters, no addi-
tional data on domestic pet contact (in the ﬁrst instance), on the
intensity of pet animal contact or on the presence or absence of
symptoms in the animals or on the types of clinical material
tested (in the second instance) were reported.
In the case reported here, three potential reasons for the
two human infections by a molecularly identical toxigenic C.
ulcerans strain can be discussed.
Firstly, two independent zoonotic transmission events might
be possible, one most likely by contact with an asymptomati-
cally infected pet animal (cat or dog) in the case of the girl and
the other probably by ingestion of possibly improperly boiled
raw cow’s milk. However, no reports on cattle as C. ulcerans
carriers or as a source for human infections are known so far
from Germany; the most recent reports from other European
countries date back more than 15 years and are mainly from
England and France. Therefore, and for probabilistic reasons,
this scenario is the least likely.
Secondly, both persons might have been infected by the
same asymptomatic carrier animal. The anamnestic and epide-
miologic evidence does not support this hypothesis, since
closer animal contact was basically denied for the grandmother.and Infectious Diseases. Published by Elsevier Ltd. All rights reserved, CMI, 21, 768–771
770 Clinical Microbiology and Infection, Volume 21 Number 8, August 2015 CMIThirdly, person-to-person transmission might have occurred
after an initial zoonotic transmission to one of the persons. On
the basis of the contact investigation and previous reports on
the epidemiology of C. ulcerans, the most probable scenario is
that the girl was infected by one of the two domestic animals,
most likely the single cat with access to the house. This two-
step scenario of an initial zoonotic and a subsequent person-
to-person transmission seems to be the most likely hypothesis.
Interestingly, in all four two-person clusters, including the
present one, there was only a single symptomatic patient; sec-
ondary diphtheria cases did not develop from the index case,
suggesting a very low risk of person-to-person transmission of
symptomatic C. ulcerans diphtheria compared to C. diphtheriae.
Among others, this observationmight be linked to the observation
that the cytotoxic activity of diphtheria toxin from C. ulcerans is
probably signiﬁcantly lower than that from C. diphtheriae [17].
Moreover, the girl’s tonsillitis had developed despite a
completed ﬁrst vaccination round with diphtheria toxoid at the
ﬁrst year of life and a booster dose in 2013, provided according
to German vaccination recommendations. This is in concordance
with a previous analysis of patient data from a report by Tiwari
et al. [18], where 11 out of 15 patients with diphtheria-like ill-
nesses due to toxigenic C. ulcerans were fully or partly vaccinated
[19]. Similarly, half of 48 patients with symptomatic infections
caused by toxigenic C. ulcerans detected in the United Kingdom
between 1986 and 2008 were fully (21/48) or partially (3/48)
immunized [2]. However, because a proven vaccine against
diphtheria caused by toxigenic C. ulcerans is not available, the
diphtheria toxoid vaccine directed against C. diphtheriae–caused
diphtheria has to be used in the hope of preventing at least partly
serious diphtheria-like symptoms by toxigenic C. ulcerans as well.
Investigations of the population structure of circulating
C. ulcerans in humans and animals based on modern sequence-
based methods have just started. The MLST scheme previously
developed for C. diphtheriae [20] has now been adopted for C.
ulcerans, and the ﬁrst STs have been deﬁned and included into
the Pubmlst database (http://pubmlst.org/cdiphtheriae/)
[10,13,21]. ST 332 has been found so far twice in Germany; one
isolate was derived from an asymptomatic cat and one from the
wound of a woman [10]. Interestingly, two distinct C. ulcerans
ST clusters comprising four and three isolates (ST 288 and ST
287), respectively, have recently been described in strains iso-
lated between 2007 and 2012 in England, but no epidemiologic
links could be established in either cluster [21].ConclusionOur case report raises the possibility of person-to-person
transmission of toxigenic C. ulcerans. Although this obviouslyClinical Microbiology and Infection © 2015 European Society of Clinical Microbiology and Infectoccurs much less frequently than with toxigenic C. diphtheriae, it
is prudent to advise public health authorities to manage
diphtheria-like infections caused by toxigenic C. ulcerans similarly
to those caused by C. diphtheriae with respect to contact tracing,
subsequent eradication antibiosis and booster vaccination, as
suggested previously [4]. Moreover, because zoonotic trans-
mission might usually be the initial event, source tracing should
include investigation of both livestock and pet animals as well as a
food intake interrogation, especially with regard to raw milk.Transparency declarationThe study was partly supported by the Bavarian State Ministry
of Health and Care as well as by the German Federal Ministry of
Health via the Robert Koch-Institute and its National Reference
Laboratories Network (09-47, FKZ 1369-359 and FKZ 415).
All authors report no conﬂicts of interest relevant to this
article.AcknowledgementsThe authors thank W. Schmidt, A. Mahl, J. Fräßdorf and S. Wolf
for technical assistance. We also thank the local health au-
thorities in Ansbach, Germany, for their support during the
source investigation, especially when trying to get animal swabs.References[1] Bonmarin I, Guiso N, Le Flèche-Matéos A, Patey O, Patrick AD, Levy-
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Possible human-to-human transmission of toxigenic Corynebacterium ulcerans 

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Possible human-to-human transmission of toxigenic Corynebacterium ulcerans

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