Accepted Manuscript

Cardiac complications in diphtheria and predictors of outcomes

Sunil Samdani, Avani Jain, Vinod Meena, C.B. Meena

PII: S0165-5876(17)30509-8
DOI: 10.1016/j.ijporl.2017.10.032
Reference: PEDOT 8750

To appear in: International Journal of Pediatric Otorhinolaryngology

Received Date: 25 August 2017

Revised Date: 18 October 2017
Accepted Date: 20 October 2017

Please cite this article as: S. Samdani, A. Jain, V. Meena, C.B. Meena, Cardiac complications in
diphtheria and predictors of outcomes, International Journal of Pediatric Otorhinolaryngology (2017), doi:
10.1016/j.ijporl.2017.10.032.

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 ACCEPTED MANUSCRIPT
CARDIAC COMPLICATIONS IN DIPHTHERIA AND PREDICTORS OF
OUTCOMES

AUTHORS-

1. DR. SUNIL SAMDANI (MS) - Professor, Department of Otolaryngology (ENT),

Sawai Man Singh Medical College and attached group of Hospitals, Jaipur, Rajasthan,

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India.
2. DR. AVANI JAIN (MS) - Senior Resident
3. DR. VINOD MEENA (MS) – Senior Resident

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4. DR. CB MEENA (MD) - Professor, Department of Cardiology, Sawai Man Singh
Medical College and attached group of Hospitals, Jaipur, Rajasthan, India.

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Corresponding Author-

Dr Avani Jain
Flat no C-8, Tower 1,
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New Moti Bagh,

New Delhi- 110023
India
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Contact no- +919910341347

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Email id- avanijain87@hotmail.com

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Conflicts of interest and source of funding (for all the authors) - none declared.
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ABSTRACT

OBJECTIVE: To study the cardiac complications in diphtheria patients and to study

the predictors of outcomes.

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STUDY DESIGN: Single centre prospective analysis of cardiac complications in
diphtheria patients

RESULTS: In this study, there were 60 patients diagnosed with diphtheria with ECG

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changes. The ECG changes seen were sinus tachycardia (68.3%), T wave inversion
(20%), ST segment depression (13.3%), right bundle branch block (5%), multiple

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atrial ectopics (3.3%). The case fatality rate in our study was 25% (15 patients).
High CPK-MB, myoglobulin and cardiac troponin levels were associated with cardiac
mortality. In our study, cardiac troponin T had the highest sensitivity (80%) and CK-

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MB had the highest specificity (95.56%).
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CONCLUSION: Cardiac involvement is a common complication of infection with C.
diphtheria and is associated with high mortality. As diphtheria can be prevented by
adequate vaccination, efforts should be maximized for high vaccine coverage with booster
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doses.
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Key words: diphtheria; myocarditis; cardiac troponin; outcomes

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INTRODUCTION

Diphtheria is a vaccine preventable but potentially fatal infectious disease with

multisystem involvement, caused by toxigenic strains of Corynebacterium diphtheria.
Although its incidence has declined, it continues to be endemic in many developing
countries, including India.1 The cardiac involvement in diphtheria is characterized by
severe impairment of cardiac contractility, which can be reversible with successful
treatment. Myocarditis may occur in about 10-25% of patients with respiratory
diphtheria and has been reported to cause high mortality.2 The patients with cardiac

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involvement may be asymptomatic (ECG changes) or symptomatic (features of heart
failure).

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The objective of this study was to investigate the cardiac complications in
diphtheria patients and to study the predictors of outcomes. As per our knowledge,

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this is the first study till date that describes the use of serum cardiac markers as
predictors of outcome in diphtheria patients.

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METHODS

This study is a prospective analysis of cardiac complications in diphtheria

patients admitted at a tertiary level institute over a period of 3 years. All patients
diagnosed with diphtheria were evaluated with respect to demographic details,
immunization status, clinical features, complications and outcomes. Written consent
was taken from all the parents/guardians of the patients. Ethical approval was taken
prior to initiating the study.

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All patients underwent routine blood investigations and ECG at the time of
admission and repeated as and when required. Throat swab for Alberts stain
confirmed diphtheria in all the cases. Each patient was monitored closely for any

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breathlessness, chest discomfort, hypotension and palpitation. Patients with anticipated/
established cardiac involvement underwent detailed work up for cardiac complications

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including serial electrocardiography (ECG), echocardiography and serum cardiac
markers: creatine kinase- MB (CK-MB), cardiac troponin T, myoglobin. The normal
levels of serum CPK-MB, myoglobulin, and cardiac troponin T were taken as <4.3

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ng/mL, <107 ng/mL and <0.4 ng/mL respectively . Outcomes were recorded in all
patients with cardiac complications.
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All patients were treated with intravenous anti-diptheritic serum (ADS), benzyl
penicillin and oral erythromycin. The duration of hospitalization was noted and
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patients were followed up for 6 months following discharge.

The collected data was tabulated and statistical analysis was done. Statistical
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analysis with the student’s t-test and Chi square test, were used to identify the
predictors of outcome. The criteria for statistical significance was p<0.05. Serum level
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of CPK-MB of 4.3 ng/mL, myoglobulin of 107 ng/mL , and cardiac troponin T of

0.4 ng/mL were taken as cut-off points for calculating the sensitivity and specificity
with 95% confidence interval. The positive and negative predictive values of various
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parameters were calculated and tabulated.

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RESULTS

There were a total of 158 patients with a clinical diagnosis of respiratory

diphtheria over a period of 3 years. Out of these, 60 patients (37.9%) were diagnosed
with ECG changes (Table 1). The age ranged from 0-15 years of age, and the most
common age group affected was 0-5 years of age (50%). The male:female ratio was
1.6:1.

As per the immunization records, most of the children were not immunized

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(41.6%), followed by 26.6% being partially immunized. The most common clinical
features were fever and throat pain. Other clinical features were dysphagia (58.3%),
bull neck (45%), stridor (11.6%) and bleeding from pseudomembrane (8.3%). All the

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7 patients with stridor required emergency tracheotomy. There were no
symptoms/signs suggestive of heart failure.

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The ECG changes (Table 2) seen were sinus tachycardia (68.3%), T wave
inversion (20%), ST segment depression (13.3%), right bundle branch block (5%),
multiple atrial ectopics (3.3%). The case fatality rate in our study was 25% (15
patients).
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In our study, the CPK-MB level was more than 4.3 in 11 patients, out of
which 9 patients died. A high CPK-MB level was associated with 60% of the
mortality, and was found to be statistically significant (chi square= 23.1911, p value<
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0.0001). Therefore, CPK-MB level more than 4.3 ng/mL is associated with a high
mortality (Table 3).
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Out of 60 patients, 17 had high myoglobulin levels, out of which, 11 died.

This was found to be statistically significant (chi square= 19.9453, p value< 0.00010).
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High myoglobulin levels were associated with 73% of the mortality. Therefore,
myoglobulin level of more than 107 ng/mL is associated with a high mortality
(Table 3).
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In our study, 15 out of 60 patients had high cardiac troponin-T levels, out of
which, 12 died. This was found to be statistically significant (chi square= 32.2667, p
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value< 0.00010). High cardiac troponin levels were associated with 80% of the
mortality. Therefore, cardiac troponin level more than 0.4 ng/mL is associated with a
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high mortality (Table 3).

The sensitivity, specificity, positive predictive value and negative predictive

value of these parameters, for predicting cardiac mortality, in our study is shown in
Table 4. Among these, cardiac troponin T had the highest sensitivity (80%) and CK-
MB had the highest specificity (95.56%).

The patients were admitted for a period of 5-12 days, with an average of 7
days. They were followed up for 6 months after discharge. On follow up, 5 patients
had non specific, asymptomatic ECG changes which resolved spontaneously within 4-6
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weeks. Also, 2 patients had palatal palsy and 1 had muscular weakness. These 3
patients recovered with conservative management.

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DISCUSSION

Diphtheria continues to remain endemic in developing countries, including

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India. The endemicity of this disease in India despite Universal Immunization
Programme is possibly due to inadequate vaccination, overcrowding, reduced efficacy
of the administered vaccine and improper vaccine preservation. Diphtheria exotoxin
inhibits elongation factor-2 activity in protein synthesis and causes DNA fragmentation
and cytolysis causing both local and systemic manifestations.3 The absorbed toxin can

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affect various organs including heart, kidney, liver, adrenal glands and nervous
system.

About half to two-thirds of the patients with diphtheria infection have ECG

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changes. Electrocardiographic changes include non-specific ST-T wave changes, heart
blocks and arrhythmias.4 Conduction system involvement has been shown to be due

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to acute inflammation of sinoatrial and atrioventricular nodes.5 Clinical signs include
diminished heart sounds, gallop rhythms and systolic murmurs. Even after the
recovery period, patients can have persistent or progressive conduction defects.

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Clinically significant myocarditis develops in only 10-25% of the patients and is more
severe when the onset is early.4 It may develop during the acute phase of illness or
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it may begin insidiously after several weeks.6 Children may present with features
ranging from non specific fatigue and malaise to congestive cardiac failure. Other
symptoms may include fever, breathlessness, chest pain and palpitations. Clinical signs
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include tachycardia which is disproportionate to the fever with or without signs of

ventricular dysfunction. Early changes in diphtheric myocarditis include cloudy
swelling of muscle fibres and interstitial edema. Within weeks, this is followed by
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hyaline and granular degeneration of muscle fibres progressing to myolysis and finally
to the replacement of lost muscle with fibrosis causing permanent cardiac damage.7
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Apart from supportive measures, treatment options in diphtheria myocarditis are

limitied. If the treatment is started early, the myocardial changes are completely
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reversible. Antitoxin has value only in the early stages of the disease, as it has
limited action against penetrating toxin or toxin already absorbed into the cell.
Continuous monitoring, including serial ECG and supportive care including fluids,
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airway protection, ventilation support and treatment of heart failure are crucial, if
indicated.8 Patients who present with extensive membrane and bull neck usually have
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more incidence of cardiac involvement.9 So, early and adequate administration of ADS
is helpful to prevent cardiac arrhythmia.

Inflammation of the myocardium leads to a release of both CK-MB and

troponin T in a time dependent manner. Cardiac troponins are highly specific markers
of myocardial injury.10 It has been postulated that, unlike other markers of
myocardial injury, troponins could be elevated in reversible myocardial injury and the
myocardial necrosis doesn’t have to occur for troponins to be released from
myocytes.10-11
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` It has been shown that clinical severity and ECG changes are correlated with
transaminase (SGOT) levels. High levels have been recorded with major blocks with
a grave prognosis.12-13 As per our knowledge, this is the first study in literature that
describes the use of serum cardiac markers as predictors of outcomes in patients with
diphtheria. In this study, we described the use of serum CK-MB, myoglobulin and
cardiac troponin levels as predictors of outcomes in diphtheria patients with ECG
changes. It was found that high levels of serum CK-MB, myoglobulin and cardiac
troponin are associated with high mortality. These are simple parameters that appear

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to be fairly reliable indicators of outcome and mortality in diphtheria patients. This is
particularly useful in developing countries where diphtheria is endemic, and continuous
ECG recording is not practical.

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In India, the incidence of diphtheric myocarditis varies from 16-66%. In a
study by Havaldar et al14, 13 patients had left or right bundle branch blocks, or

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second degree or complete atrio-ventricular block associated with 58% mortality.
Stockins et al15 reported a mortality of 50% in patients with bundle branch block.
Celik et al16 also demonstrated that the patients with left bundle branch block and T

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wave inversion had lower survival rates than that of patients without these ECG
changes. In our study, the mortality rate was 25%.
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The incidence of diphtheria and mortality due to it has declined drastically
over the last few decades due to higher vaccination coverage, improved health care
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facilities, easy availability of ADS and higher standards of living. However, diphtheria
is still endemic in some parts of the world, particularly developing countries, and is
still lethal due to its associated complications. Therefore, a high index of suspicion
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must be maintained in those with sore throat, tonsillar membrane and bull neck
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associated with unexplained tachycardia or neuropathy and in such cases antitoxin

must be administered immediately, pending diagnostic confirmation. This can help in
reducing cardiac complications and mortality in diphtheria patients.
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4. Ledbetter MK, Benson CA. The electrocardiogram in diphtheric myocarditis. Am
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9. Jayashree M, Shruthi N, Singhi S. Predictors of outcome in patients with diphtheria
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13. Havaldar PV, Patil VD, Siddibhavi BM, Sankpal MN, Jagadish. Fulminant
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14. Havaldar PV. Diphtheria in the Eighties: Experience in a South Indian District
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Table 1. Clinical characteristics of diphtheria patients

Clinical characteristic Number of patients (%)

Age
0-5 years 30 (50%)
6-10 years 23 (38.3%)
11-15 years 7 (11.6%)
Immunization status
Unimmunized 25 (41.6%)

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Partially immunized 19 (31.6%)
Adequately immunized 12 (20%)
Unknown 4 (6.7%)

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Clinical features
Fever 59 (98.3%)
Throat pain 54 (90%)

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Dysphagia 35 (58.3%)
Bull neck 27 (45%)
Stridor 7 (11.6%)
Bleeding from pseudomembrane 5 (8.3%)

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Table 2. ECG changes in diphtheria patients
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ECG changes Number of patients (%)

Sinus tachycardia 41 (68.3%)
T wave inversion 12 (20%)
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ST segment depression 8 (13.3%)

Right bundle branch block 3 (5%)
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Multiple atrial ectopics 2 (3.3%)

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Table 3. Predictors of outcome

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Number of cases p value

Survived Deaths Total
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CK-MB levels (ng/mL) < 0.0001

0-4.3 43 6 49
>4.3 2 9 11
Myoglobulin levels (ng/mL) < 0.0001
0-107 39 4 43
>107 6 11 17
Cardiac troponin- T levels (ng/mL) < 0.0001
0-0.4 42 3 45
>0.4 3 12 15
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Table 4. Sensitivity, specificity, positive and negative predictive value of parameters
in our study

Serum markers Sensitivity (%) Specificity (%) Positive predictive Negative predictive
value (%) value (%)
CK-MB 60 95.56 81.82 87.76
(32.29 - 83.66) (84.85 - 99.46) (52.19 - 94.88) (79.35 - 93.04)

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Myoglobulin 73.3 86.67 64.71 90.7
(44.9 - 92.21) (73.2 - 94.95) (45.04 - 80.39) (80.69 - 95.79)
Cardiac troponin T 80 93.3 80 93.3

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(51.9 - 95.7) (81.7 - 98.6) (56.57 - 92.47) (83.53 - 97.48)

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