Journal of Infection and Public Health 11 (2018) 698–701

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Journal of Infection and Public Health

journal homepage: http://www.elsevier.com/locate/jiph

Myocarditis associated with influenza infection in five children

Kubra Aykac a,∗ , Yasemin Ozsurekci a , Pinar Kahyaoglu b , Sevgen T. Basaranoglu a ,
Ilker Ertugrul c , Alpaslan Alp d , Ali B. Cengiz a , Ates Kara a , Mehmet Ceyhan a
a
Department of Pediatric Infectious Diseases, Hacettepe University Faculty of Medicine, Ankara, Turkey
b
Department of Pediatric Diseases, Hacettepe University Faculty of Medicine, Ankara, Turkey
c
Department of Pediatric Cardiology Diseases, Hacettepe University Faculty of Medicine, Ankara, Turkey
d
Department of Medical Microbiology Diseases, Hacettepe University Faculty of Medicine, Ankara, Turkey

a r t i c l e i n f o a b s t r a c t

Article history: Background: Myocarditis is an inflammatory condition located mainly in the myocardium. It is caused
Received 14 August 2017 by a variety of bacterial and viral infections. Influenza is one of the most common relevant viruses that
Received in revised form 3 May 2018 cause myocarditis.
Accepted 6 May 2018
Objectives: We attempted to share our experiences about clinical and laboratory findings, cardiac evalu-
ation, and treatment of children with influenza myocarditis.
Keywords:
Methods: This retrospective study was performed by the Department of Pediatric Infectious Diseases
Myocarditis
at the Faculty of Medicine, Hacettepe University in Turkey. The medical records of patients diagnosed
Influenza
Children
with myocarditis associated with an influenza infection between January 2014 and January 2017 were
systematically reviewed.
Results: Vaccination seems likely to be an important protection strategy for both influenza infections and
complications.
© 2018 The Authors. Published by Elsevier Limited on behalf of King Saud Bin Abdulaziz University
for Health Sciences. This is an open access article under the CC BY-NC-ND license (http://
creativecommons.org/licenses/by-nc-nd/4.0/).

Introduction [6]. The prevalence of myocardial involvement in infections caused

Influenza occurs all over the world, with an annual global
attack rate estimated at 5–10% in adults and 20–30% in children;
unfortunately, annual epidemics are estimated to result in approx-
imately 3–5 million cases of severe illness and approximately
250,000–500,000 deaths [1,2]. In addition to such moderate com-
plications as sinusitis and otitis, myocarditis is one possible serious
complications of influenza [3]. Myocarditis in children is one of the
most important causes of acute cardiovascular death and requires
early diagnosis and aggressive treatment to save the patient [4]. It
is caused primarily by numerous infection agents, but it may also
accompany autoimmune disease, hypersensitivity reactions, and
toxins [5]. Influenza is one of the common relevant viruses caused
by myocarditis, as well as Coxsackie B, adenovirus, echovirus, and
cytomegalovirus. The actual incidence of influenza myocarditis in
the general population is unknown because of the variable clinical
presentation in a wide range—from asymptomatic electrocardio-
graphic changes to fulminant heart failure with fatal arrhythmias
∗ Corresponding author.
E-mail address: kubraklnc@hacettepe.edu.tr (K. Aykac).
by influenza virus ranges from 0 to 11%, and the clinical appearance
of influenza myocarditis is not common [7–9]. In the literature, few
pediatric cases with influenza myocarditis were reported.
With this report, we attempted to share our experiences, which
include a description of clinical findings, laboratory findings, and
cardiac evaluation and treatment, with five children who had
influenza myocarditis over three years.
Material and methods
This retrospective study was performed by the Department of
Pediatric Infectious Diseases at the Faculty of Medicine, Hacettepe
University in Turkey. The medical records of patients diagnosed
with myocarditis associated with influenza infection between
January 2014 and January 2017 were systematically reviewed. The
diagnosis of acute myocarditis was confirmed according to criteria
reported in “Guidelines for Diagnosis and Treatment of Myocardi-
tis” as (1) a history of flu-like symptoms, (2) pathologic cardiac
findings on physical examination, (3) abnormal electrocardiogra-
phy (ECG), (4) abnormal ECHO findings, (5) elevated myocardial
constitutive proteins, (6) changes in cardiac findings on physical
examination within a few hours and myocardial constitutive pro-

https://doi.org/10.1016/j.jiph.2018.05.003
1876-0341/© 2018 The Authors. Published by Elsevier Limited on behalf of King Saud Bin Abdulaziz University for Health Sciences. This is an open access article under the
CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
 K. Aykac et al. / Journal of Infection and Public Health 11 (2018) 698–701 699

Recovered

Recovered

Recovered
teins, (7) exclusion of acute myocardial infarction, (8) abnormal
histological findings on endomyocardial biopsy, and (9) detection
Sonuç

Dead

Dead
of a virus [10]. Relevant information, such as demographics, clinical
laboratory findings, and cardiac findings, were recorded on pre-
pared forms. All laboratory tests had been performed in our local
Antiviral

laboratory, and echocardiography (ECHO) was performed on all

drug

Yes

Yes

Yes

Yes
patients. Respiratory viruses were isolated from nasopharyngeal
No

specimens, and the samples were analyzed by multiplex reverse

Yes (0,3 g/kg/day, 3

transcription polymerase chain reaction (RT-PCR) to detect viral

Yes (1 g/kg/day, 3

Yes (1 g/kg/day, 3
pathogens. We tested samples for 15 viruses (IFV A-B, PIV 1-2-3,
hAD, RSV A, RSV B, CoV, EV, hRV, hBoV, CoV 229/NL63, and CoV
OC43/HKU1). Nucleic acid isolation was performed with a GeneAll
days)

days)

days)
Ribospin vRD II Isolation Kit (Seoul, Korea). A real-time PCR method
Antibacterial IVIG

No

No

was carried out using a Seegene RV16 Detection Kit (Seoul, Korea).
The study was approved by the Ethical Committee of the Hacettepe
University (number: GO 17/88).
drugs

Yes

Yes

Yes

Yes

Yes
Results

Demographic, epidemiological, and clinical features

20 days
2 days

5 days

6 days

3 days
Timeb

During the period between January 2014 and January 2017, 5

patients (3 female, 2 male) with a median age of 5 years were
Filiform pulse, hypotension

diagnosed with myocarditis associated with influenza infection

Lower extremity strength

Filiform pulse, increased

İncreased capillary refill

among 241 patients with influenza infection. Only 1 patient had

Physical examination

no underlying disease; the others had metabolic disease, dilated

capillary refill time

cardiomyopathy, neurologic disease, and chronic granulomatous

Hepatomegaly

Filiform pulse

Hypotension
Hypotension
Dehydration

disease, respectively. The most frequently reported presenting

Tachycardia

Respiratory
Depression

symptoms were fever and cough (100%); vomiting was seen in 2

(40%) of the patients, and only 1 patient had dyspnea. None of these
time
Pale
3/5

patients were previously vaccinated with influenza. The demo-

graphic, epidemiological, and clinical features of these 5 patients
vomitting, diarrhea
Cough, rhinorrhea

are summarized in Table 1.

myalgia, malasia,
Cough, fever,

Cough, fever,

Cough, fever,

Cough, fever,

Laboratory
vomitting

dyspnea
Clinic

All 5 children had a positive RT-PCR test result from a nasopha-

ryngeal swab sample that was subsequently confirmed as influenza
Neurologyc disease

at Hacettepe University Microbiology Laboratory. Two patients had

Underlying disease

myocardtis history
Metabolic disease,

cardiomyopathy

both influenza A and B virus; 1 patient had only influenza B virus; 1

one year before

granulomatous
No underlying

patient had RSV A and influenza B virus; and 1 patient had parain-
fluenza 1, RSV A, and the influenza A virus (Table 1).
Chronic
disease

disease
Dilated

Diagnosis
Influenza B, RSV A

The first patient (Case 1) had elevated cardiac enzymes with

Parainfluenza 1,

pericardial effusion and mild valve deficiency. The second patient

Influenza A,

Influenza A,

Influenza A,
Influenza B
influenza B

influenza B

(Case 2), who also had dilated cardiomyopathy, had a decreased

Patient who had ECMO, IVIG: intravenous immunoglobulin.
Virus type

ejection fraction from 54% to 31%. Afterwards, he had the influenza

RSV A

Time to myocarditis findings from influenza findings.

infection, ejection fraction returned to 46% on ECHO. Global dysk-

inesia was detected on this patient’s cardiac magnetic resonance
imaging (see Supplementary Video S2 in the online version at
17 years/F
9 years/F

5 years/F
4 year/M

1 year/M

DOI: 10.1016/j.jiph.2018.05.003). The third patient (Case 3) had a

Age/sex

decrease in ejection fraction from 48% to 30%; after the influenza

Demographic and clinic data of patients.

infection, this was 73% on ECHO. Mitral valve regurgitation also

recovered. The fourth patient (Case 4) had fulminant myocarditis
with sudden onset of cardiac symptoms. This rapidly progressed to
January 2014

January 2017

January 2017

January 2017

January 2017

severe hemodynamic deterioration with severe heart failure. This

patient’s ECG showed ST elevation and prolonged QRS. The patient’s
Season

ECHO showed reduced systolic function (Fig. 1, see Supplementary

Year

Video S1 in the online version at DOI: 10.1016/j.jiph.2018.05.003).

The last patient (Case 5) had subclinic myocarditis, as did the first
Patient no.

patient, with elevated cardiac enzymes (Tables 1 and 2).

a

We were able to do a biopsy in only Case 1, who had fulminant

Case 1

Case 2

Case 3

Case 4

Case 5
Table 1

myocarditis. However, it was reported that the biopsy material was

a

not suitable for the examination of myocardial tissue. It is known

700 K. Aykac et al. / Journal of Infection and Public Health 11 (2018) 698–701

Table 2
Laboratory data of patients.

Patient no. Troponin Myoglobin CK MB BNP ECHO WBC (/mm3 ) ANS (/mm3 ) ALS (/mm3 ) CRP (mg/dL) Sedimentation
(ng/ml) (ng/ml) (ng/ml) (pg/ml) (mm/h)

Case 1 0,08 4024 308 69,7 EF:69, minimal 17,000 12,700 2.200 11.8 15
pericardiac
effusion
Case 2 0.1 32 8.2 4110,2 EF:31, minimal 10,300 6100 3.400 0.2 2
pericardiac
effusion
Case 3 2 1353 6.3 3840,3 EF:30 16,900 11,600 4.800 0.1 2
Case 4 1.5 83 29 926,5 EF:30 12,400 8700 3.100 0.2 2
Case 5 0.7 86 41 1983 EF:66 800 600 100 16.1 19

CK MB: creatine kinase MB.

BNP: brain natriuretic peptide.
WBC: white blood cell.
AST: aspartate aminotransferase.
ALT: alanine aminotransferase.
CRP: C-reaactive protein.

myocarditis [11,13]. Two (40%) of five patients died in our study,

Fig. 1. ECG of this patient showed ST elevation.
that the presence of abnormal myocardium confirms the actual
diagnosis; however, the absence of such findings does not exclude
the possibility of myocarditis [10].
Treatment and prognosis
Oseltamivir as an antiviral treatment was started in 4 patients.
We did not start oseltamivir in 1 of patients because one week
passed after the influenza symptoms started. Three patients were
treated with intravenous immunoglobulin (IVIG) treatment; unfor-
tunately, 2 of them died. Extracorporeal membrane oxygenation
(ECMO) was applied to 1 patient in the first hours of admission
to the hospital because of acute-onset heart failure and cardio-
genic shock. Detailed treatment information is given in Table 1.
Despite IVIG, oseltamivir, and cardiac support in addition to ECMO,
the patient died. Two patients of the five died (Tables 1 and 2).
Discussion
Cardiotoxicity due to viral infections, which can lead to signifi-
cant impairment of cardiac function and mortality, is a well-defined
entity; however, only a few reports have been linked to influenza
myocarditis in children [7,11,12]. Cardiovascular involvement in
acute influenza infection can occur through the direct effects of
the virus on the myocardium or through the exacerbation of exist-
ing cardiovascular disease [6]. Some patients with good prognoses
were treated with aggressive hemodynamic support in influenza
despite the antiviral IVIG treatment in both patients and the ECMO
treatment in one of them. A national survey from Japan shows that,
despite the intensive treatment, the mortality rate may reach up to
39% in fulminant myocarditis associated with the influenza virus
[14].
The Centers for Disease Control and Prevention (CDC) deter-
mined that certain risk groups (children, adults 65 years of age
and older, pregnant women, long-term care facilities, and people
with chronic medical conditions) are at risk for influenza com-
plication; however, the risk factors for developing myocarditis
during influenza infection are unclear [15–17]. Two (40%) of our
patients had cardiac disease history. Three of them had no prior
history of cardiac disease. Only 1 patient had no underlying disease
and, 4 children had chronic diseases. In terms of age, 2 patients
(40%) were under 5 years of age; the others were older. Groups
at high risk for influenza-related complications included children
younger than 5, but especially younger than 2 years of age [15].
With regard to the severe complications caused by an infection
with influenza, the CDC recommends annual influenza vaccination
for all persons aged ≥6 months who do not have contraindica-
tions [18]. None of these patients were previously vaccinated with
influenza.
The most frequently reported presenting symptoms were fever
and cough, and only 1 patient had myocarditis symptoms such
as dyspnea. Because it is known that most patients with viral
myocarditis are asymptomatic or minimally symptomatic. In symp-
tomatic patients, the clinical presentation of viral myocarditis
varies from non-specific electrocardiographic abnormalities in the
setting of normal left ventricular systolic function to acute hemo-
dynamic decompensation or sudden cardiac death [6,19].
Oseltamivir was started in 4 patients. The CDC recommends
antiviral treatment as early as possible for patients with confirmed
or suspected influenza who have a severe, complicated, or progres-
sive illness; who require hospitalization; or who are at high risk
for serious influenza-related complications [20]. The hemodynamic
support is based on the use of inotropic drugs and vasopressor
therapy in combination with inotropic therapy in the treatment
of myocarditis [21]. Four of our patients needed cardiac support.
ECMO was applied to only one patient. It is known that mechanical
circulatory support systems are used to maintain cardiac output
and organ perfusion and to minimize the need for inotropic sup-
port until myocardial recovery [22]. Some cases rescued with ECMO
support were reported in the literature [11,13,23]. Although ECMO
was applied in the first hours of hospitalization, our patient died
because she had fulminant myocarditis, which has a mortality rate
as high as 48%, as reported by Saji et al. [24].
 K. Aykac et al. / Journal of Infection and Public Health 11 (2018) 698–701
Some studies indicate that IVIG may have a favorable thera-
peutic effect in myocarditis [25–27]. However, patient deaths in
the present study were also treated with IVIG. In contrast, it was
revealed in a study from the United States that IVIG did not affect
survival. A Cochrane review concluded that IVIG should not be
given routinely in any cases of pediatric or adult patients with
presumed viral myocarditis [28,29].
In conclusion, physicians should be aware of the possibility for
circulatory decompensation in children with influenza infection
and should recognize patients with influenza myocarditis who had
subtle cardiac symptoms and signs, which may be overshadowed
by systemic manifestations of the underlying influenza infection in
many clinical cases. Unfortunately, mortality and morbidity may
be seen, despite early cardiac support and antiviral treatment. Our
data show that vaccination seems likely to be an important protec-
tion strategy for both influenza infection and its complications.
Funding
No funding sources.
Competing interests
None declared.
Ethical approval
Not required.
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