Paediatrics and International Child Health

ISSN: 2046-9047 (Print) 2046-9055 (Online) Journal homepage: http://www.tandfonline.com/loi/ypch20

Fatal diphtheria myocarditis in a 3-year-old

girl—related to late availability and administration
of antitoxin?

Karlijn Van Damme, Natasja Peeters, Philippe G. Jorens, Tine Boiy, Marjan
Deplancke, Hilde Audiens, Marek Wojciechowski, Jozef De Dooy, Margreet te
Wierik & Erika Vlieghe

To cite this article: Karlijn Van Damme, Natasja Peeters, Philippe G. Jorens, Tine Boiy,
Marjan Deplancke, Hilde Audiens, Marek Wojciechowski, Jozef De Dooy, Margreet te Wierik
& Erika Vlieghe (2017): Fatal diphtheria myocarditis in a 3-year-old girl—related to late
availability and administration of antitoxin?, Paediatrics and International Child Health, DOI:
10.1080/20469047.2017.1378796

To link to this article: http://dx.doi.org/10.1080/20469047.2017.1378796

Published online: 29 Sep 2017.

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 Paediatrics and International Child Health, 2017
https://doi.org/10.1080/20469047.2017.1378796

Fatal diphtheria myocarditis in a 3-year-old girl—related to late availability and

administration of antitoxin?
Karlijn Van Dammea‡, Natasja Peetersb‡, Philippe G. Jorensb, Tine Boiya, Marjan Deplanckec, Hilde Audiensc,
Marek Wojciechowskia, Jozef De Dooyb, Margreet te Wierikd and Erika Vlieghee
a
Department of Paediatrics, Antwerp University Hospital, University of Antwerp, Edegem, Belgium; bDepartment of Paediatric Critical Care
Medicine, Antwerp University Hospital, University of Antwerp, Edegem, Belgium; cDepartment of Paediatrics, AZ Sint Maarten, Mechelen,
Belgium; dCentre for Infectious Disease Control, National Institute for Public Health and the Environment, Bilthoven, The Netherlands;
e
Department of General Internal Medicine, Infectious and Tropical Diseases, Antwerp University Hospital, University of Antwerp, Edegem,
Belgium

ABSTRACT ARTICLE HISTORY

Sporadic cases of diphtheria are very rare throughout Europe. A 3-year-old incompletely
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Received 4 April 2017

vaccinated girl was admitted with pharyngotonsillitis caused by diphtheria. On day 9 of her Accepted 15 August 2017
illness, renal and cardiac failure with a third-degree AV-block occurred. Unfortunately, she died KEYWORDS
within 36 h of admission to intensive care, despite pacemaker placement, the administration of Diphtheria; myocarditis;
antibiotics and diphtheria antitoxin. The delayed antitoxin administration 7 days after admission fatality; antitoxin;
to hospital was related to a lack of availability and knowledge of its availability in Europe and this Corynebacterium
is likely to have contributed to the unfavourable outcome. diphtheria

Introduction its resurgence in the 1990s, the incidence of diphtheria

decreased by over 95% between 2000 and 2009, spo-
Diphtheria is an acute and fulminant infectious disease
radic cases are still reported throughout Europe, particu-
caused by toxicogenic strains of corynebacteria, i.e.
larly in 10 countries [3]. In Belgium between 2009 and
Corynebacterium diphtheriae, Corynebacterium ulcerans
2013, only two cases of toxicogenic strains of C. ulcerans,
and Corynebacterium pseudotuberculosis. C. diphtheriae
not C. diphtheriae, had been confirmed by the Belgian
is the most common toxicogenic strain and is associated
reference laboratory until the present case in 2016 [6].
with person-to-person spread [1–3]. Respiratory diph-
A case of fulminant diphtheria myocarditis is reported
theria is usually characterised by a variable degree of
in whom delayed administration of antitoxin related to
pharyngitis followed by the formation of unilateral or
lack of availability and of knowledge of its availability
bilateral tonsillar pseudomembranes. More severe illness
may have contributed to the unfavourable outcome.
can be associated with inflammation and oedema of the
surrounding cervical lymph nodes, causing a bull-neck
appearance. When it enters the bloodstream, the highly Case report
potent exotoxin may cause serious systemic complica-
A previously healthy 3-year-old, incompletely vaccinated
tions, including myocarditis, which is often fatal, and
girl (she had only received the legally required four doses
peripheral neuropathy [1–4].
of polio vaccine) was admitted to a regional hospital in
Since the commencement of mass immunisation
Belgium following 4 days of fever, anorexia and a sore
campaigns in the 1940s and 1950s and the introduction
throat. Clinical examination revealed an extensive phar-
of childhood immunisation, this previously endemic dis-
yngotonsillitis, for which treatment with intravenous
ease has become rare in high-income countries, although
antibiotics (amoxicillin/clavulanic acid) was commenced.
diphtheria remains endemic in many low- and middle-in-
Because of a progressive increase of cervical lymphade-
come countries [1–4]. Whereas most fatalities occur in
nopathy and neck swelling, the attending paediatrician
countries where diphtheria is still endemic, case-fatality
transferred her to the paediatric intensive care unit (PICU)
rates are highest in countries where it is rare and a lack
of our university hospital on day 4 of the illness with the
of familiarity with the disease leads to delayed diagnosis
clinical suspicion of diphtheria. The parents volunteered
and treatment, and it is increasingly difficult to obtain
that the child had been born in Belgium and that they
diphtheria antitoxin (DAT) in time [3,5]. Although, after

CONTACT  Philippe G. Jorens  Philippe.Jorens@uza.be

‡
These authors contributed equally to this work.

© 2017 Informa UK Limited, trading as Taylor & Francis Group

 2   K. V. DAMME ET AL.
were of a Russian ethnic background. The child had not
travelled outside Belgium but one of the parents had
recently been to Russia, a diphtheria-endemic country.
The patient had not been vaccinated against diphtheria
because the parents had decided against it.
On admission, she appeared alert and haemody-
namically stable. Temperature was 36.9  °C, the heart
rate was 98/minute and regular and blood pressure
was 97/61 mm Hg. Inspection of the mouth and throat
demonstrated large inflamed tonsils with a white and
blood-stained membrane. There was diffuse swelling
and redness of the neck with enlarged lymph nodes.
The airway was not compromised. Clinical examination
of heart, lungs and abdomen was normal and there were
no neurological abnormalities.
Investigations
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Haemoglobin was 11.2 g/dL, white cell count 7.8 × 109/L
(neutrophils 50% and lymphocytes 40%) and plate-
let count 18 × 109/L (150–450). C-reactive protein was
790 nmol/L (<28). Serum electrolytes and liver function
tests were normal. Throat swabs had been taken at the
previous hospital and sent to a reference laboratory
where the first result displayed no growth of patho-
genic bacteria and no viruses. Serology for a wide range
of infectious agents including Epstein–Barr virus was
negative.
Because of the oedema and redness of the neck, intra-
venous clindamycin was added to cover group A strep-
tococcal infection. Platelets were administered for the
persisting thrombocytopenia. Because diphtheria was
part of the differential diagnosis, a search for DAT was
commenced in Belgium and throughout Europe, initially
without success.
As the patient improved rapidly and markedly soon
after admission and the initial search for DAT was unsuc-
cessful, the search for antitoxin was not intensified
and she was transferred to a paediatric ward on day 2
of admission. She continued to improve until day 5 of
admission when she suddenly developed worsening
generalised oedema and hypotension with a diminished
urine output. Acute renal failure was manifested by pro-
teinuria (1.6 mg/mg creatinine) and a rise in serum cre-
atinine to 83 μmol/L and falling serum albumin (17 g/L).
Albumin (1  g/kg bodyweight) was administered. Over
the next couple of hours the patient deteriorated and
developed a third-degree AV-block. At that point it was
confirmed that the throat swab was positive for C. diph-
theriae, biovar gravis, sensitive to penicillin, erythromy-
cin and clindamycin, after which all family members and
healthcare workers at risk received antibiotic prophylaxis
with penicillin or erythromycin. The throat swabs of both
parents did not demonstrate C. diphtheria.
The patient was transferred back to the PICU.
Isoprenaline was commenced, after which she developed
a junctional rhythm. Echocardiography demonstrated
an acceptable cardiac function with a left ventricular
ejection fraction of 60%, mitral regurgitation grade 2/4,
tricuspid regurgitation grade 3/4 and a hyper-echogenic
myocardium, and a temporary transvenous pacemaker
was inserted. After 2 h the heart rhythm reverted to sinus
tachycardia, 135 bpm. Phenylephrine was commenced in
order to maintain a systolic blood pressure above 80 mm
Hg.
However, her urine output remained low and, after
another infusion of albumin, a continuous infusion of
furosemide was commenced to stimulate diuresis. She
remained haemodynamically stable and was awake
and responsive but showed decreasing interest in her
surroundings. Continuous cardiac monitoring demon-
strated a normal sinus rhythm, but the temporary pace-
maker remained in place as backup.
Following confirmation of the diagnosis of diphtheria,
the search for DAT was immediately resumed and inten-
sified. It appeared that DAT was not available either in
Belgium or in a wide range of European countries. After
an extensive search, it was eventually procured through
the Dutch National Institute for Public Health and the
Environment (RVIM). Within 3 h, it was made available
to our unit. To exclude a possible allergic reaction as it
was equine DAT, a sensitivity test using diphtheria anti-
toxin was performed (a prick test combined with an
intradermal test); both tests were negative. The patient
received DAT within 24 h of her second admission to the
PICU. Despite this, her medical condition deteriorated.
Over the course of a few hours she developed a high
temperature with increasing oxygen demand and she
became anuric. Because of her increasing need of oxy-
gen, progressive difficulty of breathing and exhaustion,
she was intubated. This was followed by a cardiac arrest
with an initial rhythm of pulseless electrical activity.
She was resuscitated for over an hour and although the
pacemaker was still in place and had good capture, there
was no cardiac output and no return of spontaneous cir-
culation. The option of extra-corporal life support was
explored during resuscitation but, given the duration of
attempted resuscitation, it was not considered a viable
option. Eventually, resuscitation was withdrawn and she
was declared dead 36 h after admission to the PICU and
11 days after onset of her illness (Figure 1). The parents
did not give consent for an autopsy.
Discussion
In the pre-vaccination era, diphtheria was one of the
most serious childhood infections with a mortality rate
of 5–10%. It was only in 1883, that C. diphtheriae was
identified as the causative agent [1–3]. Once known as
‘the strangling angel of children’, diphtheria is considered
a major, yet preventable, disease of childhood associated
with high morbidity and mortality [3].

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Figure 1. Time-line of the case report.
Mass immunisation campaigns in the 1940s and
1950s and improved socio-economic conditions led to
a decrease in cases with almost complete elimination
in high-income countries, but even in countries where
diphtheria is rare, the threat remains. Migrating popula-
tions and travellers are an important risk for the spread
of diphtheria to countries in which the disease is no
longer endemic. A lack of booster vaccinations and of
natural immunity render the adult population more sus-
ceptible, and incomplete childhood vaccination, as in
this case, puts a child at serious risk [1,3–5]. In Flanders
(Belgium), vaccination against diphtheria is offered at 2,
3, 4 and 15 months and boosters at 6 and 14 years. One
of the parents had recently travelled to Russia, a diph-
theria-endemic country. This case is similar to another
report describing asymptomatic adults carrying the dis-
ease from Russia to Finland, resulting in the death of an
unvaccinated infant [7].
Because of its rarity, most clinicians in industrialised
countries are no longer familiar with the disease’s clinical
course, and diphtheria might not be suspected until the
disease has reached an advanced stage [5,8]. Clinicians
might also feel reassured by initial improvement of the
clinical condition and not realise that it is the late toxin
effect which can be fatal.
The major virulence factor for diphtheria is the potent
diphtheria toxin [8]. Toxic diphtheric myocarditis, as seen
in this case, occurs in 10–25% of diphtheria cases, most
commonly in the second week of the disease (range
1–6 weeks) [9]. Other cardiac manifestations are brad-
yarrhythmias and tachyarrhythmias, but the most severe
one is complete heart block which is fatal in almost all
cases, despite ventricular pacing [10,11]. The diphthe-
ria toxin affects the myocardium and the conduction
system owing to acute inflammation of sino-atrial and
PAEDIATRICS AND INTERNATIONAL CHILD HEALTH   3
atrioventricular nodes. Toxin-mediated inhibition of pro-
tein synthesis is the causative mechanism. Interstitial
inflammation as well as hyaline degeneration and necro-
sis is seen in the affected myocardium. These systemic
manifestations lead to death in 60% of those affected
[4,11,12].
The cornerstone of treatment for diphtheria is
rapid administration of antibiotics and DAT. When the
toxin is bound to tissue, DAT will no longer be effec-
tive. Although WHO recognises that DAT is an essential
drug—which means it should be available at all times—
it is often difficult to obtain because of scarce supplies.
This has been reported by several countries, but, to date,
no lasting solution has been found [5]. Because diph-
theria is no longer common in some regions and the
economic value of producing DAT is low, several coun-
tries no longer produce it. Furthermore, production for
export has also been reduced or has been discontinued
in most countries. This has led to supplies being past
their ‘use-by’ date or a complete lack of the antitoxin in
several countries [5,8].
This case demonstrated that DAT is not available in
Belgium and throughout most of Europe; it was only
after an extensive search that DAT was found to be
readily available through the RVIM in the Netherlands.
Moreover, the late administration of the antitoxin related
also to lack of availability or knowledge of its availabil-
ity may have contributed to the unfavourable outcome
[13]. Studies have shown that patients may die despite
having received DAT; a Latvian study demonstrated that
DAT may be ineffective if administered after the second
day of symptoms [5]. A similarly unfavourable outcome
occurred in a recent case reported from France because
of the lack of available DAT in that country which resulted
in it being administered 7 days after admission [5,8].
 4   K. V. DAMME ET AL.
Administration of DAT is not without risk since it is
an equine derivative with a risk of acute and delayed
hypersensitivity reactions [14]. Although research has
been undertaken to find an alternative (e.g. with mon-
oclonal antibodies), none is available as yet [15]. In the
past, various suggestions were put forward, including
maintaining a central European stock of DAT or main-
taining an easily accessible list of DAT suppliers, but both
could still cause delay in obtaining DAT because it has to
be transported to the patient [5,8].
Vaccination remains the most important means of
preventing and eventually eradicating diphtheria, and
coverage levels in Flanders are high [16,17]. A recent
study indicated that, in 2016, 93% (95% CI 90.5–95.0) of
children in Flanders aged 18–24 months had received all
four doses of diphtheria–tetanus–pertussis vaccine [17].
It is essential that the public and healthcare workers are
Downloaded by [Australian Catholic University] at 14:47 30 September 2017
kept aware of the importance of immunisation in order
to prevent further cases of diphtheria and other vac-
cine-preventable diseases. When treating similar cases,
it is important to keep in mind that close contacts and
family members should be assessed for the risk of devel-
oping the disease, receive antibiotic prophylaxis (as in
our case) and/or booster vaccination according to inter-
national guidelines [13,18]. This case also emphasises the
importance of receiving appropriate vaccination when
travelling to endemic countries; travellers visiting friends
and relatives abroad are at particular risk of under-im-
munisation [13,18].
Acknowledgments
We are grateful to the collaborators of the National Institute
for Public Health and the Environment, Bilthoven, The
Netherlands who promptly provided the antitoxin upon
request.
Authors’ contributions
Karlijn Van Damme, Natasja Peeters, Philippe G. Jorens, Tine
Boiy, Marianne Deplancke, Hilde Audiens, Marek Wojciechowski,
Jozef De Dooy and Erika Vlieghe took care of the patient.
Karlijn Van Damme, Nathasja Peeters, Tine Boiy, Philippe G.
Jorens and Marek Wojciechowski initially wrote the manuscript.
Margriet te Wierik supplied the antitoxin.
All co-authors reviewed the manuscript.
Disclosure statement
No potential conflict of interest was reported by the authors.
Ethics approval
All data on this patient are anonymised. Informed consent to
publish was given by the parent.
Notes on contributors
Karlijn Van Damme is senior resident in paediatrics, Antwerp
University Hospital.
Natasja Peeters is last year resident in anaesthesiology/critical
care medicine, Antwerp University Hospital.
Philippe Jorens is chairman of the Department of Paediatric
Critical Care and member of the Faculty of Medicine and
Health Sciences, University of Antwerp.
Tine Boiy is senior staff member of the Department of
Paediatrics, Antwerp University Hospital with a broad experi-
ence, particularly in infectious diseases.
Marjan Deplancke is senior staff member of the Department
of Paediatrics in a large private hospital.
Hilde Audiens is senior staff member of the Department of
Paediatrics in a large private hospital.
Marek Wojciechowski is senior staff member of the
Department of Paediatrics, Antwerp University Hospital with
a broad experience, particularly in infectious diseases. He was
head of the department until his recent retirement.
Jozef De Dooy is senior staff member of the Department of
Paediatric Critical Care and member of the Faculty of Medicine
and Health Sciences, University of Antwerp.
Margreet te Wierik (Centre for Infectious Disease Control,
The Netherlands) is author and co-author of several manu-
scripts on public health, outbreaks of diseases (in Europe) and
vaccination.
Erika Vlieghe is head of the Department of Internal Medicine,
Infectious and Tropical Diseases and Professor in the Faculty
of Medicine and Health Sciences, University of Antwerp and
Institute of Tropical Medicine.
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