MAJOR ARTICLE

Investigations of 2 Cases of Diphtheria-Like Illness

Due to Toxigenic Corynebacterium ulcerans
Tejpratap S. P. Tiwari,1 Anne Golaz,1 Diana T. Yu,3 Kristen R. Ehresmann,4 Timothy F. Jones,5 Hal E. Hill,6
Pamela K. Cassiday,1 Lucia C. Pawloski,1 John S. Moran,1 Tanja Popovic,2 and Melinda Wharton1
1
Division of Bacterial Diseases, National Center for Immunization and Respiratory Diseases, and 2Office of the Director, Centers for Disease
Control and Prevention, Atlanta, Georgia; 3Thurston County Public Health and Social Services, Olympia, Washington; 4Infectious Disease
Epidemiology Prevention and Control, Minnesota Department of Health, St. Paul; and 5Communicable and Environmental Disease Services,
Tennessee Department of Health, Nashville, and 6Memorial Hospital, Chattanooga, Tennessee

Background. We present 2 case reports in the United States and investigations of diphtheria-like illness caused
by toxigenic Corynebacterium ulcerans. A fatal case occurred in a 75-year-old male Washington resident who was
treated with clindamycin but did not receive equine diphtheria antitoxin. A second, nonfatal case occurred in a
66-year-old female Tennessee resident who received erythromycin and diphtheria antitoxin.
Methods. Both case patients and close human and animal contacts were investigated by their respective state
health departments.
Results. C. ulcerans isolated from the patient who died was resistant to erythromycin and clindamycin. For
both isolates, conventional polymerase chain reaction results were positive for A and B subunits of diphtheria
toxin gene tox, and modified Elek tests confirmed toxin production. The source of infection remained undetermined
for both cases. Neither patient was up-to-date with diphtheria toxoid vaccination.
Conclusion. These case reports highlight the importance of early treatment with diphtheria antitoxin, the
selection of effective antimicrobial agents, and prevention through up-to-date vaccination.

Toxigenic Corynebacterium ulcerans was first isolated
from the throat of a patient with respiratory diphtheria
like illness in 1926 [1]. Toxigenic strains of C. ulcerans
produce a diphtheria toxin that is similar to that pro-
duced by toxigenic strains of Corynebacterium diphth-
eriae [2, 3]. Diphtheria toxin contributes to the for-
mation of a pseudomembrane that characterizes
respiratory diphtheria and may cause cardiac and neu-
rologic sequelae. C. ulcerans also produces a dermo-
necrotic toxin that is similar to that produced by Cor-
eynbacterium pseudotuberculosis [2].
C. ulcerans is a commensal in animals and has been
isolated from a wide host of domestic and wild animals
(table 1) [418]. These animals may serve as reservoirs
for human infection. C. ulcerans causes mastitis in cattle
Received 19 June 2007; accepted 24 September 2007; electronically published
20 December 2007.
Reprints or correspondence: Dr. Tejpratap Tiwari, Centers for Disease Control
and Prevention, NCIRD/DBD/MVPD Branch, Mailstop C-25, 1600 Clifton Rd. NE,
Atlanta, GA 30333 (tit2@cdc.gov).
Clinical Infectious Diseases 2008; 46:395401
 2007 by the Infectious Diseases Society of America. All rights reserved.
1058-4838/2008/4603-0007$15.00
DOI: 10.1086/525262
and goats. Handling of infected dairy animals and con-
sumption of contaminated milk have been associated
with respiratory diphtherialike disease caused by C.
ulcerans [19]. C. ulcerans is also reported to cause cu-
taneous lesions in humans [20, 21].
The epidemiology of human infections caused by C.
ulcerans is not well known. As shown in table 2, re-
spiratory diphtherialike illnesses caused by toxigenic
strains of C. ulcerans are increasingly reported from
developed countries [35, 2241]. C. ulcerans ac-
counted for 21 (58%) of 36 human toxin-producing
isolates of Corynebacterium species in the United King-
dom from 1997 through 2002 [42], 3 (33%) of 9 isolates
in Canada from 1999 through 2003 [43], and 1 (33%)
of 3 isolates in Italy from 1990 through 2001 [44].
In the United States, 5 confirmed or probable cases
of respiratory diphtheria caused by C. diphtheriae (in-
cluding 1 imported fatal case) were reported during the
period 19992005. During the same period, the Centers
for Disease Control and Prevention (CDC) received
reports of 2 cases (1 fatal) of diphtheria-like illness
caused by C. ulcerans; prior to 1999, the last reported
case of diphtheria-like illness caused by C. ulcerans in
the United States occurred in 1996 [31]. We report the

Diphtheria-Like Illnesses Due to C. ulcerans CID 2008:46 (1 February) 395

 Table 1. Reported animal sources of toxigenic Corynebacterium ulcerans.

Reference Year Country Animal source Clinical presentation

[4] 2006 France Dog Nose (asymptomatic)
[5] 2005 France Dog Labial lesion, rhinorrhea
[6] 2005 United States Goat Meningoencephalitis
[7] 2002 United Kingdom Free-ranging otters Lung tissue, intestines (postmortem)
[8] 2002 United Kingdom Cats Chronic nasal discharge
[9] 2000 Spain Dromedary camel Caseous lymphadenitis
[10] 2000 United States Macaque Cephalic implants
[11] 1999 France Cows Mastitis
[12] 1988 Canada Richardson ground squirrels Gangrenous dermatitis
[13] 1984 United Kingdom Cows Mastitis
[14] 1984 Romania Horses Unknown
[15] 1977 Romania Nonhuman primates Respiratory tract
[16] 1974 United States Bonnet macaque Mastitis
[17] 1972 United States Monkeys Pneumonia, lung abscess, cervical
abscess, bite wounds
[18] 1967 United Kingdom Dairy herds Mastitis

epidemiologic investigations of these 2 cases of respiratory
diphtherialike illnesses caused by C. ulcerans in Washington
and Tennessee.
METHODS
The Washington State Department of Health and the Tennessee
Department of Health conducted epidemiologic investigations
of patients A and B. The investigations included reviewing both
patients medical records, identifying close household contacts,
obtaining nasopharyngeal swab specimens from contacts, of-
fering postexposure prophylaxis with penicillin or erythro-
mycin, and administering an age-appropriate diphtheria toxoid
vaccine to those who were not current with vaccination. Per-
sonnel from the Minnesota Department of Health interviewed
family members and investigated cattle at the Minnesota dairy
farm visited by patient A. Oral and rectal swab specimens were
obtained from animal contacts of both patients.
RESULTS
Patient A (Washington). In 1999, a 75-year-old white non-
Hispanic man presented to an emergency department with a
3-day history of sore throat with difficulty in swallowing and
fever. The result of a rapid streptococcal test of a throat swab
specimen was negative. The patient was prescribed erythro-
mycin and sent home; the patient reported allergies to ceph-
alosporins and penicillin. He returned to his primary care phy-
sician the next day because of persisting sore throat and
worsening difficulty swallowing and breathing, and he was hos-
pitalized. On examination, the patients oral temperature was
38.3C, and he had copious nasopharyngeal secretions. Direct
laryngoscopic examination revealed ulceration, with yellowish
exudate on the posterior pharynx. His initial WBC count was
1500 cells/mm3, with 66% polymorphonuclear cells, 5% band
cells, and 23% lymphocytes. During the first 3 days of hospi-
talization, the patient received intravenous clindamycin. On the
fourth day after hospital admission, the drug was replaced with
metronidazole, ciprofloxacin, and vancomycin, after the local
laboratory reported that culture of throat specimens grew 4+
diphtheroids that did not show typical C. diphtheriae mor-
phology by methylene blue staining and after diphtheria was
excluded as a likely diagnosis. Although the patient had signs
of a diphtheria-like illness, diphtheria antitoxin was not re-
covered. The patient developed dyspnea and underwent intu-
bation after an episode of aspiration. His condition rapidly
deteriorated, with development of pulmonary edema and evi-
dence of cardiogenic shock. Despite nasotracheal intubation
and mechanical ventilation, the patient died on the following
day.
The patient had a significant history of Felty syndrome and
had been receiving daily 10-mg doses of oral methylpredni-
solone for the preceding 11 years. He had no travel history
outside of the United States, but he had spent 23 days visiting
friends on a farm in Minnesota 10 days prior to the onset of
his illness. The patient had no history of interacting with anyone
who had recently traveled abroad or any person with skin ul-
cers. He had reportedly received a booster tetanus and diph-
theria vaccination 112 years prior to this illness.
Postmortem examination demonstrated a thick, gray
membrane that extended from the throat into the bronchial
tree and into the esophagus. The membrane had sloughed in
some areas, and there was narrowing of the airways due to
edema. No significant inflammatory changes were noted in the

396 CID 2008:46 (1 February) Tiwari et al.

Table 2. Published case reports of diphtheria-like illness caused by Corynebacterium ulcerans, 19702006.

Patient characteristic
Country of Source of Dairy
Patient Year residence Sex Age Hospitalized Outcome infection exposure Reference(s)
1 2007 United Kingdom M 50 years No Recovered Unknown No [22]
2 2006 France F 72 years Yes Recovered Dog No [4]
3 2006 United Kingdom F Adult Yes Recovered Unknown Unknown [23]
4 2005 France F 47 years Yes Recovered Dog No [5]
5 2004 Germany F 53 years Yes Recovered Unknown Unknown [3]
6 2004 United Kingdom F 58 years No Recovered Unknown No [24]
7 2003 Japan F 52 years Yes Recovered Probably a cat No [25]
that died
8 2003 Italy F 75 years Yes Recovered Unknown Unknown [26]
9 2002 Switzerland F 71 years Yes Recovered Unknown No [27]
10 2002 The Netherlands F 59 years Yes Recovered Unknown No [28]
11 2002 Germany M 77 years Yes Died Unknown No [8, 29]
12 2000 United Kingdom F Adult Yes Died Unknown No [30]
13 2000 United Kingdom F Adult No Recovered Unknown No [30]
14 2000 United Kingdom F Girl No Recovered Unknown No [30]
15 1997 United States F 54 years Yes Recovered Unknown No [31]
16 1995 Denmark M 53 years Yes Recovered Unknown Unknown [32]
17 1994 Germany F 42 years Yes Recovered Unknown Unknown [33]
18 1994 United Kingdom F 9 years No Recovered Unknown No [34]
19 1992 United Kingdom F 44 years Yes Recovered Unknown Unknown [35]
20 1990 Switzerland F 63 years Yes Recovered Unknown Unknown [36]
21 1990 United Kingdom F 73 years No Died Unknown Unknown [37]
22 1987 Denmark M 9 years No Recovered Unknown No [38]
23 1985 United Kingdom M 78 years Yes Died Unknown Unknown [39]
24 1984 United Kingdom F 25 years No Recovered Cows Yes [19]
25 1984 United Kingdom F Child No Recovered Cows Yes [13]
26 1984 United Kingdom M 12 years No (carrier) Cow Yes [13]
27 1979 United Kingdom M 59 years Yes Recovered Unknown No [40]
28 1970 United Kingdom M 60 years Yes Recovered Unknown No [41]

myocardium or in peripheral nerves. Postmortem specimens
from the larynx, trachea, and lungs were obtained for culture
and conventional PCR testing [45].
Culture of throat specimens obtained during the laryngo-
scopic examination revealed heavy growth of diphtheroids (4+)
on day 3 of hospitalization. The isolates were forwarded to the
Washington State Department of Health Public Health Labo-
ratory (Shoreline, WA), where the agent was identified as C.
ulcerans 4 days after the patient died. The agent was resistant
to clindamycin and erythromycin but susceptible to penicillin,
sulfamethoxazole, ciprofloxacin, vancomycin, and cephalospo-
rins. The CDC confirmed these results and demonstrated the
presence of toxigenic C. ulcerans by the modified Elek test [46]
and by positive conventional PCR [45] for subunit A and sub-
unit B of the diphtheria toxin gene (tox). In addition, the
conventional PCR results were positive for the tox gene in
postmortem formalin-fixed tissue specimens from the larynx
and trachea but were negative in lung tissue specimens. Real-
time PCR [47] performed on this isolate revealed atypical am-
plification of subunit A and no amplification of subunit B of
the tox gene.
Patient B (Tennessee). In 2005, a 66-year-old white, non-
Hispanic woman complained of fatigue, sore throat, and dif-
ficulty in swallowing. Her symptoms worsened, and on the
following afternoon, she presented to the emergency depart-
ment of a local hospital. She was afebrile (oral temperature,
37.1C) and had sinus tachycardia, with a heart rate of 105
beats per min. A throat examination revealed an erythematous
palate and edematous pharynx and uvula, with a covering ex-
udate that extended into the nasopharynx. CT of the neck
confirmed marked edema of the uvula and soft palate and
demonstrated near obliteration of the nasopharynx but did not
suggest epiglotitis or a retropharyngeal abscess. The result of a
rapid streptococcal test was negative.

Diphtheria-Like Illnesses Due to C. ulcerans CID 2008:46 (1 February) 397

Table 3. Results of contact investigations of case patients A and B.
Variable
No. of household contacts
Result of culture of throat swab specimens obtained from contacts
(no. of persons with the result/no. of persons tested)
Postexposure antimicrobial prophylaxis
Vaccination
Animal contacts (no. of patients with the contact)
Results of culture of swab specimens obtained from animal contacts
Minnesota farm investigation
Farm household contacts
Results of culture of nasal and throat swab specimens obtained
from contacts
Vaccination
Prophylaxis
Results of culture of swab specimens obtained from dairy animals
The patient was hospitalized and initially received methyl-
prednisolone, ceftriaxone, and clindamycin and, later, eryth-
romycin and ampicillin/sulbactam. At hospital admission, her
WBC count was 12,600 cells/mm3, with 86% granulocytes and
7% lymphocytes. During the night, the patient developed re-
spiratory difficulty, with oxygen desaturation to 68%. There
was no clinical evidence of neurological abnormality or cardiac
abnormality by electrocardiogram. By the following morning,
the palatine erythema and edema had worsened, her voice be-
came more muffled, and her breathing became noisy. The pa-
tient underwent emergency intubation and taken to the op-
erating room, where tracheostomy was performed. During
tracheostomy, an extensive, thick, yellowish, fibrinous, slough-
ing membrane was noted to cover the lower half of the uvula,
extensively coating the posterior aspect of the soft palate and
the entire nasopharynx and extending into the trachea. The
membrane measured about 5 3 cm. It was gradually removed
by peeling and suctioning, leaving behind an intact mucosa
with mild, punctate bleeding. Direct laryngoscopic examination
demonstrated a normal hypopharynx, larynx, and epiglottis.
There was marked swelling of the soft palate and pharynx. The
attending physician suspected diphtheria and treated the patient
with 60,000 U of diphtheria antitoxin (DAT) obtained on the
same day from the CDC. Throat swab specimens were obtained
for C. diphtheriae testing. The patient had an uneventful
recovery.
At the Tennessee State Health Department laboratory (Nash-
ville, TN), cultures of throat specimens grew black colonies on
tellurite media that were suggestive of Corynebacterium species.
The isolate and membrane specimen were identified as C. ul-
cerans at the CDC. The organisms were susceptible to penicillin,
398 CID 2008:46 (1 February) Tiwari et al.
Case patient A Case patient B
(Washington) (Tennessee)
6 6
Negative (6/6) Negative (6/6)
Intramuscular benzathine penicillin Oral erythromycin
Tetanus and diphtheria vaccine Tetanus and diphtheria vaccine
given to all given to all
None Horses (4), dogs (2)
Negative for
Corynebacterium ulcerans
11
Negative for C. ulcerans
Tetanus and diphtheria vaccine
given to 5 adults
Not offered
Negative for C. ulcerans
erythromycin, clindamycin, ceftriaxone, and ciprofloxacin. Re-
sults of conventional PCR were positive for both subunit A
and subunit B of the tox gene. However, real-time PCR revealed
atypical amplification of subunit A and no amplification of
subunit B. Toxin production in the isolate was demonstrated
by a positive modified Elek test result. A commercial laboratory
reported the serum antibody level to diphtheria toxin to be
0.036 IU/mL (protective level, 0.1 IU/mL) in this patient.
The patient had not received vaccination against diphtheria
during the previous 30 years. She lived in a farmhouse with
her husband and had not traveled during the 2-week period
before onset of illness. She seldom had direct contact with the
animals, although she owned 4 horses and 2 dogs; she did not
own dairy animals. Her close and frequent contacts included
her children and their families. One daughter had frequent close
contacts with immigrants from Central America. Members of
her church had recently returned from a 1-week cruise to the
Caribbean that included island stops.
Contact investigation. As shown in table 3, no specimen
from human and animal contacts of either case patient grew
C. ulcerans.
DISCUSSION
Several published case reports have linked human C. ulcerans
infections to consuming unpasteurized milk from infected cows
or having close contact with infected dairy animals [13, 18,
19]. However, in the majority of reports, patients neither con-
sumed raw milk nor had contact with dairy animals (table 2).
In 2 recent reports, human infection followed contact with dogs
with chronic labial ulceration, rhinorrhea, and sneezing [4, 5];
in 1 report, the same C. ulcerans strain was isolated from both
the patient and her dog [5]. Although a human case resulted
from possible exposure to an infected stray cat with rhinorrhea
[25], in another report, close household contacts of 2 infected
cats with rhinorrhea did not acquire infection [8]. In our re-
ports, nasal and rectal specimens from dairy animals, horses,
and dogs were culture negative for C. ulcerans, suggesting that
there might be other reservoirs and/or novel ways of
transmission.
The clinical features of diphtheria-like illness caused by C.
ulcerans are similar to those of clinical respiratory diphtheria,
and laboratory investigations, treatment, public health re-
sponse, and preventive interventions are identical for the 2 types
of infection. Infection with C. ulcerans or C. diphtheriae should
be considered in the differential diagnosis of membranous
pharyngitis. Culture of throat specimens is the gold standard
for diagnosis of diphtheria-like illness caused by C. ulcerans.
Although no special culture medium is required for growth,
media such as Tinsdale or tellurite agar are useful for rapidly
identifying potentially pathogenic Corynebacterium species.
Growth of diphtheroids not showing typical morphology for
C. diphtheriae by methylene blue staining does not rule out
clinical diphtheria or exclude C. ulcerans. A modified Elek test
is used to confirm toxin production. A positive result of con-
ventional PCR of isolates or tissue specimens detects the pres-
ence of subunits A and B of the tox gene but does not confirm
whether the strain is producing toxin. PCR may be particularly
useful to detect the presence of a strain containing the tox gene
when antimicrobial therapy is initiated prior to specimen col-
lection. A newly developed but not commercially available real-
time PCR test [47] is used at the CDC to provide more rapid
results than conventional PCR for C. diphtheriae. However, in
this report, real-time PCR analysis of C. ulcerans isolates from
both case patients produced atypical amplification of subunit
A and no amplification of subunit B. Although conventional
PCR to detect the presence subunits A and B of the tox gene
may be useful for screening for C. diphtheriae and C. ulcerans,
these findings indicate that additional studies are required to
determine the role of real-time PCR testing of toxigenic C.
ulcerans isolates.
C. ulcerans causes severe diphtheria-like illness, and patients
often require hospitalization (table 2). As for clinical diphtheria,
the mainstay of treatment is equine DAT. Providers should
promptly administer DAT to a patient with respiratory diph-
therialike illness, after testing for sensitivity to DAT and with-
out awaiting laboratory confirmation. Failure or delay in ad-
ministering DAT can lead to a fatal outcome. The dose of DAT
varies from 40,000 IU to 100, 000 IU and depends on the site
and extent of the membrane and the duration of symptoms.
In the United States, DAT is available from the CDC under a
US Food and Drug Administrationapproved Investigational
Diphtheria-Like Illnesses Due to C. ulcerans CID 2008:46 (1 February) 399
New Drug protocol and can be obtained by contacting the
Directors Emergency Operations Center at the CDC [48].
Although antimicrobial agents are not a substitute for DAT,
they eliminate C. ulcerans from the respiratory tract and,
thereby, limit toxin production, reduce disease severity if ad-
ministered early, and halt potential transmission. In vitro stud-
ies have demonstrated that C. ulcerans is susceptible to a wide
range of antimicrobial agents [49]. The recommended anti-
microbial agents and their dosage for treatment and postex-
posure prophylaxis are the same as those for treatment of clin-
ical diphtheria. Generally, erythromycin and penicillin are
effective and are the preferred antimicrobial agents for treat-
ment of respiratory diphtherialike illness caused by C. ulcerans.
To our knowledge, this is the first report of respiratory diph-
therialike illness caused by a C. ulcerans strain that was re-
sistant to erythromycin and clindamycin but susceptible to pen-
icillin, vancomycin, ciprofloxacin, sulfamethoxazole, and
cephalosporins. The finding of an erythromycin-resistant strain
of toxigenic C. ulcerans highlights the importance of testing
strains of this organism for susceptibility to antimicrobials used
for treatment and/or postexposure prophylaxis.
Because of the rare possibility of transmission to close con-
tacts from patients with diphtheria-like illness caused by C.
ulcerans [50], contact investigations can be limited to household
members and other persons who have intimate physical contact
or direct exposure to respiratory secretions of a case patient or
to animals infected with C. ulcerans. In this report, C. ulcerans
was not isolated from any close contacts (human or animal),
and this finding is consistent with other case reports [35, 22
41]. Nevertheless, close face-to-face contacts of patients should
receive postexposure chemoprophylaxis after nasopharyngeal
and throat swab specimens are obtained for culture and should
be placed under surveillance for a week for evidence of disease
[51].
Up-to-date immunization with a diphtheria toxoid vaccine
will prevent diphtheria and diphtheria-like illness caused by C.
ulcerans by maintaining adequate levels of antibodies to diph-
theria toxin. In this report, both case patients were older adults
who were not up-to-date with booster immunization against
diphtheria. Because diphtheria or diphtheria-like illness caused
by C. ulcerans may not provide an adequate protective immune
response, case patients should receive an age-appropriate diph-
theria toxoid vaccine during the convalescent period. Close
contacts of case patients should also receive an age-appropriate
diphtheria toxoid vaccine according to the childhood, adoles-
cent, and adult immunization schedules, as recommended by
the Advisory Committee on Immunization Practices. The Ad-
visory Committee on Immunization Practices recommends that
all children receive a routine series of a pediatric diphtheria
toxoid vaccine (diphtheria and tetanus toxiods and acellular
pertussis antigen vaccine and diphtheria and tetanus toxiods)
at ages 2, 4, 6, and 12 months and between 4 and 6 years of
age. Adolescents should receive a booster dose with tetanus
toxoid and reduced diphtheria toxoid and acellular pertussis
vaccine, preferably between 11 and 12 years of age, and then
tetanus and diphtheria vaccine every 10 years thereafter during
adulthood [52, 53]. For added protection against pertussis,
adults who have not previously received a dose of tetanus toxoid
and reduced diphtheria toxoid and acellular pertussis vaccine
should receive a single dose of such vaccine to replace the next
dose of tetanus and diphtheria vaccine [54].
In summary, heightened clinical awareness of respiratory
diphtherialike illness caused by C. ulcerans is critical for early
recognition and prompt administration of treatment with DAT
and appropriate antimicrobial agents. Finding of a strain re-
sistant to first-line antimicrobials highlights the need for an-
timicrobial susceptibility testing of C. ulcerans. Using real-time
PCR to rapidly confirm the presence of the tox gene in C.
ulcerans may lead to false-negative results, and this test requires
further evaluation for toxigenic C. ulcerans isolates. Lastly, age-
appropriate vaccination with diphtheria toxoid vaccines and
timely decennial boosters should be encouraged to prevent
disease.
Acknowledgments
We thank Dr. Marsha Goldoft, Mary Perry, Heidi Kassenborg, Lori Stork,
Sue Johnson, Dr. Valerie Boaz and the staff of the Chattanooga/Hamilton
County Health Department, Henrietta Hardin, Chung Kim Marston, Eliz-
abeth Mothershed, and Dr. Pekka Nuorti.
Potential conflicts of interest. All authors: no conflicts.
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