Contacts The National Centre for Zoonosis Research

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					Contacts

      Dr Phil Jones
      Dr Eleni Michalopoulou
      Nicola Henley
      Dr. Will Sopwith
      Dr. Androulla Efstratiou


Exploration of the prevalence of toxigenic
Cornyebacterium ulcerans, an emerging human
pathogen, in companion animals in NW England

Diphtheria caused by toxigenic Corynebacterium ulcerans is recognised as an emerging
infectious disease in humans in many countries, including the UK. There is increasing
evidence that, as yet, uncharacterised animal reservoirs of C. ulcerans are significant for
human disease and that the role of unpasteurised milk consumption is decreasingly
important. There have been several recent incidents where human cases of C. ulcerans
have been associated with carriage or infection in pets. There is evidence that immunity
to diphtheria afforded through the childhood vaccination programme is waning in adult
populations and although a booster dose to address this has been introduced, population
coverage with the booster is relatively low. There is, therefore, an increasingly vulnerable
population in the UK and a potentially large reservoir of infection with little knowledge
about the risks of zoonotic transmission. There is a danger that C. ulcerans will fall
between the responsibilities of animal and human health agencies, not being recognised
as a significant health threat by either.

Background

Human diphtheria is a severe, acute disease of the upper respiratory tract, classically
caused by toxigenic strains of Corynebacterium diphtheriæ. Clinical presentation is
associated with the formation of an oropharyngeal diphtheritic membrane (which can
physically obstruct respiration) and the absorption of toxins leading to neurological and
cardiac disease and frequently resulting in death. Vaccination programmes developed in
the first half of the twentieth century have dramatically reduced clinical disease around
the world, but the potential still exists for large-scale epidemics, as demonstrated in
Russia and the newly independent states of the former Soviet Union during the 1990s.
Small numbers of cases of diphtheria caused by C. diphtheriæ are still diagnosed in the
UK but are often associated with travel to countries where the disease is endemic.

C. ulcerans is a closely related organism that can also produce the diphtheria toxin.
Human infection with toxigenic strains of C. ulcerans can present as classical diphtheria,
but other clinical presentations also occur.
C. ulcerans does not cause large epidemics and, although human-to-human transmission
is thought to be unlikely, the organism has been isolated from a pair of siblings and from
a father and son. Over recent years, C. ulcerans has been isolated from clinical samples in
many countries including the USA, Canada, Japan, Germany, Italy, the Netherlands,
Switzerland and France. In the UK, 50 clinical isolates of toxigenic C. ulcerans were
submitted to the Streptococcus and Diphtheria Reference Unit between 1986 and 2003.
Since that time, there have been two additional cases of diphtheria caused by C. ulcerans,
one of which was fatal. Infection with C. ulcerans is increasingly recognised as an
emerging infectious disease in many countries, including the UK, and there is evidence
that the number of cases and the severity of clinical signs may be increasing. However,
the source of the majority of human cases remains unknown. C. ulcerans has been
associated with clinical mastitis in cattle and people drinking unpasteurised milk from
affected herds have become infected. Nevertheless, an increasing number of cases of
C. ulcerans infection in humans do not appear to be associated with the consumption of
unpasteurised dairy products, raising the possibility that other animal reservoirs may
exist. Evidence to support this hypothesis is starting to accumulate. Seven isolates of
C. ulcerans were identified in cats with bilateral nasal discharge in the UK in 2002 -
2003. All isolates were found to be toxigenic and were of the same ribotypes as 50
human isolates from the UK, suggesting that cats may act as a reservoir for human
infection. In addition, C. ulcerans has been isolated from pet dogs that were in contact
with three human cases of the disease in the UK and France. The organism has been
isolated from a range of other species, but isolation from pet cats and dogs is potentially
very important from a public health perspective.

C. ulcerans is not recognised as a major pathogen of animals and is certainly not of
economic importance. As a result, animal health organisations (including DEFRA) do not
consider it a funding priority. In addition, studies investigating animal populations for the
presence of potential human pathogens do not attract human health funding. However,
the implications for human patients and their families can be devastating and the health
protection resource required to investigate, including the assessment and communication
of risk, is significant. If pets are able to act as symptomless carriers, it is essential to
estimate the prevalence in animal populations and to identify risk factors for carriage.
This work has not been done anywhere in the world and would provide invaluable
information about potential animal reservoirs for this emerging infectious disease.

Preliminary Study

The use of 16s gene sequencing to characterise the range of
Corynebacterium spp. isolated from the mouths of healthy dogs and cats in
northwest England

Swabs from the oropharynx have been taken from around 500 cats and dogs at local
rescue centres. These were cultured and presumptive Corynebacterium colonies selected
and transferred to fresh blood agar plates. Molecular identification of the isolates was
carried out.
                Preliminary Results

                                 Healthy cats and dogs carry a range of Corynebacterium spp.
                                 Sequencing of 16s gene identifies Corynebacterium spp. reliably ...

                         BUT

                                 ... may not differentiate between some closely-related species, e.g. C. ulcerans
                                  and C. pseudotuberculosis.
                                 Additional sequencing of other genes (e.g. rpoB) may be required on a small
                                  proportion of isolates to differentiate closely related Corynebacterium spp.
                                  Colonies sub-cultured from individual animals

                    80
                                                                                      cat
                    70
                                                                                      dog
Number of animals




                    60

                    50

                    40

                    30

                    20

                    10

                     0
                              0      1       2       3        4       5     6     7
                                                 Number of colonies




                References

                                 De Zoysa A, Hawkey PM, Engler K, George R, Mann G, Reilly W, Taylor D and
                                  Efstratiou A. (2005). Characterization of toxigenic Corynebacterium ulcerans
                                  strains isolated from humans and domestic cats in the United Kingdom. J Clin
                                  Microbiol 43(9) 4377-81.
                                 (1997). Respiratory diphtheria caused by Corynebacterium ulcerans--Terre
                                  Haute, Indiana, 1996. MMWR Morb Mortal Wkly Rep 46(15) 330-2.
                                 Dewinter LM, Bernard KA and Romney MG. (2005). Human clinical isolates of
                                  Corynebacterium diphtheriae and Corynebacterium ulcerans collected in Canada
                                  from 1999 to 2003 but not fitting reporting criteria for cases of diphtheria. J Clin
                                  Microbiol 43(7) 3447-9.
   Hatanaka A, Tsunoda A, Okamoto M, Ooe K, Nakamura A, Miyakoshi M, et al.
    (2003). Corynebacterium ulcerans diphtheria in Japan. Emerg Infect Dis 9(6)
    752-3.
   (2002). Nasopharyngeal Corynebacterium ulcerans diphtheria in the Netherlands.
    Euro Surveill 6(7).
   Lartigue MF, Monnet X, Le Fleche A, Grimont PA, Benet JJ, Durrbach A, et al.
    (2005). Corynebacterium ulcerans in an immunocompromised patient with
    diphtheria and her dog. J Clin Microbiol 43(2) 999-1001.
   (2007). Laboratory confirmed case of toxigenic Corynebacterium ulcerans.
    Health Protect Rep 1(10).
   (2006). A case of diphtheria caused by toxigenic Corynebacterium ulcerans.
    Commun Dis Rep CDR Wkly 16(4).
   Hart RJ. (1984). Corynebacterium ulcerans in humans and cattle in North Devon.
    J Hyg (Lond) 92(2) 161-4.
   Bostock AD, Gilbert FR, Lewis D, Smith DC. (1984). Corynebacterium ulcerans
    infection associated with untreated milk. J Infect 9(3) 286-8.

				
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