Accepted Manuscript 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 Received Date: Date: 25 August August 2017 Revi Revise sed d Dat Date: e:
18 Oc Octo tobe berr 201 2017 7
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), (2017), doi: 10.1016/j.ijporl.2017.10.032.
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CARDIAC COMPLICATIONS IN DIPHTHERIA AND PREDICTORS OF OUTCOMES
AUTHORS-
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CARDIAC COMPLICATIONS IN DIPHTHERIA AND PREDICTORS OF OUTCOMES
AUTHORS1. DR. SUNIL SAMDANI (MS) - Professor, Department of Otolaryngology (ENT), Sawai Man Singh Medical College and attached group of Hospitals, Jaipur, Rajasthan, India. 2. DR. AVANI JAIN (MS) - Senior Resident 3. DR. VINOD MEENA (MS) – Senior Resident 4. DR. CB MEENA (MD) - Professor, Department of Cardiology, Sawai Man Singh Medical College and attached group of Hospitals, Jaipur, Rajasthan, India.
Corresponding AuthorDr Avani Jain Flat no C-8, Tower 1, New Moti Bagh, New Delhi- 110023 India Contact no- +919910341347 Email id-
[email protected]
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. STUDY DESIGN: Single diphtheria patients
centre prospective analysis of
cardiac complications in
RESULTS: In this study, there were 60 patients diagnosed with diphtheria with ECG 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 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 CKMB had the highest specificity (95.56%). 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 doses.
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 1 countries, including India. 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 2 diphtheria and has been reported to cause high mortality. The patients with cardiac involvement may be asymptomatic (ECG changes) or symptomatic (features of heart failure). 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, 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. 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 breathlessness, chest discomfort, hypotension and palpitation. Patients with anticipated/ established cardiac involvement underwent detailed work up for cardiac complications 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 ng/mL, <107 ng/mL and <0.4 ng/mL respectively . Outcomes were recorded in all patients with cardiac complications. All patients were treated with intravenous anti-diptheritic serum (ADS), benzyl penicillin and oral erythromycin. The duration of hospitalization was noted and patients were followed up for 6 months following discharge. The collected data was tabulated and statistical analysis was done. Statistical 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 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 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 (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 7 patients with stridor required emergency tracheotomy. There were no symptoms/signs suggestive of heart failure. 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). In our study, the CPK-MB level was more than 4.3 in 11 patients, which 9 patients died. A high CPK-MB level was associated with 60% mortality, and was found to be statistically significant (chi square= 23.1911, p 0.0001). Therefore, CPK-MB level more than 4.3 ng/mL is associated with mortality (Table 3).
out of of the value< a high
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). 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). 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 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 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 CKMB 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 1 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 3 and cytolysis causing both local and systemic manifestations. The absorbed toxin can 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 changes. Electrocardiographic changes include non-specific ST-T wave changes, heart 4 blocks and arrhythmias. Conduction system involvement has been shown to be due 5 to acute inflammation of sinoatrial and atrioventricular nodes. Clinical signs include diminished heart sounds, gallop rhythms and systolic murmurs. Even after the recovery period, patients can have persistent or progressive conduction defects. Clinically significant myocarditis develops in only 10-25% of the patients and is more 4 severe when the onset is early. It may develop during the acute phase of illness or 6 it may begin insidiously after several weeks. 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 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 hyaline and granular degeneration of muscle fibres progressing to myolysis and finally 7 to the replacement of lost muscle with fibrosis causing permanent cardiac damage. Apart from supportive measures, treatment options in diphtheria myocarditis are limitied. If the treatment is started early, the myocardial changes are completely 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, airway protection, ventilation support and treatment of heart failure are crucial, if 8 indicated. Patients who present with extensive membrane and bull neck usually have 9 more incidence of cardiac involvement. 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 10 of myocardial injury. 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 10-11 myocytes.
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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 12-13 a grave prognosis. 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 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. In India, the incidence of diphtheric myocarditis varies from 16-66%. In a 14 study by Havaldar et al , 13 patients had left or right bundle branch blocks, or second degree or complete atrio-ventricular block associated with 58% mortality. 15 Stockins et al reported a mortality of 50% in patients with bundle branch block. 16 Celik et al also demonstrated that the patients with left bundle branch block and T wave inversion had lower survival rates than that of patients without these ECG changes. In our study, the mortality rate was 25%. 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 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 must be maintained in those with sore throat, tonsillar membrane and bull neck 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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REFERENCES 1. Jain A, Samdani S, Meena V, Sharma MP. Diphtheria: It is still prevalent!!! Int J Ped Otorhinolaryngol. 2016; 86: 68-71. 2. Singh J, Harit AK, Jain DC, Panda RC, Tewari KN, Bhatia R, et al. Diphtheria is declining, but continues to kill many children: Analysis of data from a sentinel center in Delhi, 1997. Epidemiol Infect 1999;123:209-15. 3. Collier RJ. Diphtheria toxin: mode of action and structure. Bacteriol Rev 1975; 39:54 – 85. 4. Ledbetter MK, Benson CA. The electrocardiogram in diphtheric myocarditis. Am Heart J 1964;68:599– 611. 5. Smith S. Heart rhythm in diphtheria. JAMA 1922;77:765-71. 6. Hoyne A, Welford N. Diphtheric myocarditis: a review of 496 cases. J Pediatr 1934;5:642– 53. 7. Hadfield TL, McEvoy P. The pathology of diphtheria. J Infect Dis 2000; 181:S116– 20. 8. Lakkireddy DR, Kondur AK, Chediak EJ, Nair CK, Khan IA. Cardiac troponin I release in non-ischemic reversible myocardial injury from acute diphtheric myocarditis. Int J Cardiol. 2005; 98: 351-354. 9. Jayashree M, Shruthi N, Singhi S. Predictors of outcome in patients with diphtheria receiving intensive care. Indian Pediatr 2006;43: 155-60. 10. Chu WW, Dieter RS, Stone CK. Evolving clinical applications of cardiac markers: a review of the literature. Wisc Med J 2002;101: 49– 55. 11. Herrmann J, Volbracht L, Haude M, Eggebrecht H, Malyar N, Mann K, et al. Biochemical markers of ischemic and non-ischemic myocardial damage. Med Klin 2001;96:144–56. 12. Tahernia AC. Elctrocardiographic abnormailities and serum transaminase levels in diphtheric myocarditis. J Pediatr. 1969; 75: 1008-14. 13. Havaldar PV, Patil VD, Siddibhavi BM, Sankpal MN, Jagadish. Fulminant diphtheritic myocarditis. Indian Heart J 1989; 41: 265-269. 14. Havaldar PV. Diphtheria in the Eighties: Experience in a South Indian District Hospital. Journal Of Indian Medical Association. 1992; 90: 155-156. 15. Stockins, BA, Lanas, FT, Saavedra, JG, Opazo, JA. Prognosis in Patients with Diphtheric Myocarditis and Bradyarrhythmias: Assessment of Results of Ventricular Pacing. British Heart Journal. 1994; 72: 190-191. 16. Celik T, Selimov N, Vekilova A, Kursaklioglu H, Iyisoy A, et al. Prognostic Significance of Electrocardiographic Abnormalities in Diphtheritic Myocarditis after Hospital Discharge: A Long-Term Follow-Up Study. Ann Noninvasive Electrocardiol. 2006; 11: 28-33.
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Table 1. Clinical characteristics of diphtheria patients Clinical characteristic Age 0-5 years 6-10 years 11-15 years Immunization status Unimmunized Partially immunized Adequately immunized Unknown Clinical features Fever Throat pain Dysphagia Bull neck Stridor Bleeding from pseudomembrane
Number of patients (%) 30 (50%) 23 (38.3%) 7 (11.6%) 25 (41.6%) 19 (31.6%) 12 (20%) 4 (6.7%) 59 (98.3%) 54 (90%) 35 (58.3%) 27 (45%) 7 (11.6%) 5 (8.3%)
Table 2. ECG changes in diphtheria patients ECG changes Sinus tachycardia T wave inversion ST segment depression Right bundle branch block Multiple atrial ectopics
Number of patients (%) 41 (68.3%) 12 (20%) 8 (13.3%) 3 (5%) 2 (3.3%)
Table 3. Predictors of outcome Number of cases Survived Deaths Total CK-MB levels (ng/mL) 0-4.3 >4.3 Myoglobulin levels (ng/mL) 0-107 >107 Cardiac troponin- T levels (ng/mL) 0-0.4 >0.4
p value < 0.0001
43 2
6 9
49 11 < 0.0001
39 6
4 11
43 17 < 0.0001
42 3
3 12
45 15
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Table 4. Sensitivity, specificity, positive and negative predictive value of parameters in our study
Serum markers
Sensitivity (%)
Specificity (%)
CK-MB
60
95.56
(32.29 - 83.66)
(84.85 - 99.46)
73.3 (44.9 - 92.21) 80 (51.9 - 95.7)
86.67
Myoglobulin Cardiac troponin T
(73.2 - 94.95)
93.3 (81.7 - 98.6)
Positive predictive value (%) 81.82 (52.19 - 94.88) 64.71 (45.04 - 80.39) 80 (56.57 - 92.47)
Negative predictive value (%) 87.76 (79.35 - 93.04) 90.7 (80.69 - 95.79)
93.3 (83.53 - 97.48)
