INTRODUCTION
Diphtheria remains an important cause of pediatric mortality in developing countries. The mortality rate is still ∼10% and has changed little over the past 20 years with particular reference to developed world ¹. A resurgence of diphtheria has been observed in developing nations, are largely attributed to waning vaccine immunity and social taboos leading to poor immunization coverage in children especially above 5 years of age. Acute mortality is due to toxin-mediated diphtheritic cardiomyopathy, suffocation by the pseudomembrane, disseminated intravascular coagulation, and renal failure ^2,3. The incidence of diphtheritic cardiomyopathy following diphtheria is 10%–20%, and some Indian studies reported the occurrence of myocarditis is 16-66% and the associated mortality is ∼50%. Myocarditis in diphtheria is reported to be the sole independent predictor of death with an adjusted Odds ratio 25, (95% confidence interval (CI) 3.4-210.3)⁴. Clinical signs of diphtheritic cardiomyopathy become apparent by the end of 2^nd week of infection but, in severe cases, may be a presenting feature ⁵. Severe conduction abnormalities including tachy or brady-arrhythmias or complete heart block are reported in 50% of patients presented with diphtheria cardiomyopathy and reported to be uniformly fatal for children^6,7. Most of the large series describing the clinical and electrocardiographic features of diphtheria were reported in old studies, before the availability of modern electrocardiographic, echocardiographic and bio chemical measurements ⁸. These studies found that the development of severe conduction defects on the 12-lead electrocardiograph were associated with a poor prognosis ⁹. We have recently observed on the prognostic and predictor utility of combined echocardiographic and electrocardiography and have shown that, in some cases of diphtheritic cardiomyopathy, intervention with temporary cardiac pacemaker or off label use of IV methylprednisolone may improve the outcome. The ability to predict from simple and readily available measures whether myocarditis will develop would aid in triage and clinical management.

We aimed to examine clinical spectrum of diphtheric cardiomyopathy and diagnostic tools (serum markers, ECG, Echocardiography) to assess particular findings that might predict the development of diphtheritic cardiomyopathy and poor survival. Identification of such factors would help in planning focused screening of such patients so that they can be picked early and may be fatal outcome can be changed. This will not only decrease chances of life threatening complications but also minimize cost used to treat them. It will also help us

to decrease psychosocial trauma to family.

MATERIAL AND METHOD

This cohort study was conducted at the Department of Cardiology, The Children Hospital and pediatric medicine department DHQ/Allied hospital Faisalabad, Pakistan, over a period of 3years from 1^st January 2018 till 31^st December 2020. These are tertiary care centers in the province of Punjab with a population of over 120 million ^10’11 where we get referral from other tertiary care hospitals in the region as well both for diagnostic and management point of view. Institutional Review Board of the hospital approved the study protocol. All patients presenting to the hospital for the first time and diagnosed as diphtheria were evaluated for inclusion in the study. After obtaining informed consent from patient’s parents, evaluation was performed with confirmation of diagnosis through clinical and laboratory (throat swab, serial ECG’s and echocardiography) The demographic profile, residence, vaccination status, clinical spectrum, ECG interpretation and echocardiographic findings were recorded on a specially designed questionnaire proforma by the author (UR,RN) from direct caregivers including mother, father or the guardian and ECG and echocardiographic interpretation by a consultant pediatric cardiologist. The diagnosis of diphtheria was made using either one or both of the criteria i-e clinically either if the patient had a febrile illness with a characteristic adherent pseudomembrane visible in the nasopharynx or if the patient presented later (after pseudomembrane clearance) with a history of recent severe sore throat and signs of cardiomyopathy or if throat culture proven for the Corynebacterium diphtheriae ⁸. Diphtheric cardiomyopathy was defined either as Symptomatic diphtheritic cardiomyopathy, the patients who developed symptoms of, and examination findings consistent with, heart failure and abnormal findings on 12-lead electrocardiography (Partial or complete right bundle branch block with “M” pattern in V1 and “W” pattern in V6, ST segment elevation or depression, complete heart block)( Fig 1) or echocardiography or Asymptomatic diphtheritic cardiomyopathy, includes  children with no symptoms of heart failure, but with either clinically detected rhythm disturbances or abnormal findings on 12-lead electrocardiography or LV dysfunction on echocardiography, according to contemporary standards of pediatric cardiology ^12. Diphtheria severity score system was defined as: “mild,” local symptoms (involving the nasopharyngeal region) only; “moderate,” patient is systemically unwell with a “toxic” facial appearance and having fever with systemic features of neck swelling; “severe,” patient is bed-bound, is unable to drink, has difficulty breathing or inspiratory stridor , needs tracheostomy or has alteration in mental status⁸. Partial immunization was defined as the children who got only 1 or 2 doses of vaccine at early infancy and did not get all the doses recommended by EPI in Pakistan. Children were considered adequately immunized if they had received three or more doses of diphtheria toxoid containing vaccine by age 2 years ⁴.

Patients having growth of other bacteria on throat culture even suspected clinically as diphtheria were excluded from the study. Several variables were compared among the survivors and non-survivors to define the predictors of outcome. Outcome was defined as either developed cardiomyopathy or not.

STATISTICAL ANALYSIS

Data was entered in SPSS version 20 and analyzed using its statistical package. Frequency was calculated for qualitative variables including gender, vaccination status, and cardiomyopathy. Data was presented as mean, SD and median. Between groups comparison was done using Chi-square test for categorical data and Students’ t-test and Mann Whitney U test for parametric and non-parametric data respectively Univarient and multivarient analysis were performed to determine significance and to identify the predictors having a significant association with cardiomyopathy and mortality. Odd’s ratio with 95% CI was computed for the significant variables. All variables found to be significant on univariate analysis (P<0.05).

RESULTS

Sixty-seven subjects presented with diphtheria were recruited in the study in a 3 year period. There were 47 (70.1%) boys and 20 (29.9%) girls with boys to girl’s ratio of 2.4:1. Median age at the time of presentation was 106 months (range 24-172 months). Median day of presentation to a tertiary care hospital was 3 days (range 1-9 days). Nearly 58.2% patients belong to rural areas. In total 38 (56.7%) subjects presented with diphtheria were non-vaccinated for diphtheria vaccine and 18 (26.9%) were completely vaccinated and 11(16.4%) were partially vaccinated. None of the subject in this cohort was given a booster vaccine at 5y of age. Total 70.1% patients had a nasopharyngeal membrane during initial presentation and 28.4% (n=19) had a neck swelling initially at presentation and 11.9% presented with stridor. All the patients who presented with stridor at initial clinical manifestation need a tracheostomy at subsequent days due to overt or impending upper airways obstruction. Majority (83.6%) of children presented with mild severity of the disease. Only 1.5% patients presented with severe disease and toxic look.

Table 1: Comparison between cardiomyopathy VS no cardiomyopathy

In all the affected cases 25.4% patients had a positive throat culture for the Corynebacterium diphtheriae. Both the electrocardiography (ECG) and echocardiography were different at initial presentation and subsequent follow up. Out of these 76.1% (n=51) had a normal ECG at initial presentation (65.7% at subsequent ECGs), 4 (6.0%) had a right bundle branch block (RBBB), 3% had a 1^st degree heart block (10.4% on subsequent ECGs), 1.5% had complete heart block (3% on subsequent ECGs), 1.5% had VT (4.5% on subsequent ECGs). Forty-nine patients (73.1%) had a normal echocardiography at presentation, 23.9% (n=16) had septal paradoxes at initial echocardiography and 3% (n=2) had a LV systolic dysfunction (22.4% on subsequent echocardiography).

Twenty-five (37.3%) had a cardiac involvement in the form of diphtheria cardiomyopathy or arrhythmia. The mean interval between onset of respiratory symptoms and myocarditis was 5.9 ± 2.4 days (range 2-11 days).  Among the cardiac involvement with LV dysfunction 52% had a mild LV dysfunction (EF>45%) on echocardiography and 18.8% had a moderate LV dysfunction (EF 35-45%). 7.5% (N=5) patient expired on follow up. Among total 25 patients who had diphtheria cardiomyopathy 20% expired during follow up. All the patients who expired had moderate to severe LV dysfunction and expired primarily due to cardiomyopathy and two patients had an associated arrhythmia in the form of VT that ultimately lead to their death. All the patients were managed with inotropes (Milrinone infusion) and for VT antiarrhythmic drugs (Amiodarone, Lignocaine) were used but alternate tachy-bradyarrhythmia ultimately leads to the bad prognosis of these patients. The analysis among both the groups were given in Table 1 .

Male had more commonly cardiac involvement as compared to female with a male: female 3:1 as compared to 2:1 among non-cardiomyopathy patients. Almost half (52%) were unimmunized in the group involve the heart but it is not statistically significant (p=0.213). patients who had neck swelling as initial presentation had a more cardiac involvement as compared to no neck swelling (44% vs 19%). Eight patients (32%) of patient who had a tracheostomy subsequently had cardiac involvement.

There were many predictors that predict the subsequent cardiac involvement and ultimately the outcome of the patient’s. Septal paradoxes was an important marker in the prediction of the cardiomyopathy in patients with diphtheria. Septal paradoxes had 76% sensitivity and 100% specificity with a positive predictive value (PPV) of 100%. Nasopharyngeal membrane had a PPV of 40.4% (P=0.42). Neck swelling had a PPV of 57.9% (P=0.02). Moderate severity score of diphtheria disease had a PPV of 90% and severe disease had a PPV of 100%. Tracheostomy at presentation having a PPV of 100% (p=0.001). Some parameters had a very strong positive predictor value regarding outcome of the disease in the form of death. Ventricular tachycardia (VT) at presentation or on subsequent ECG had a PPV of 94% and complete heart block had a PPV of 82%.

Out of 25 patients with myocarditis 5 (20%) died (Odd’s ratio 14.3, 95% CI 3.1-68.5, P = 0.0001);. Presence of arrhythmia was associated with the highest mortality (OR 18.1; 95% CI 2.7-73.9; P = 0.0001). Presence of septal paradoxes on echo had association with the cardiac involvement (OR 10.1: 95% CI 1.2-84.6; P = 0.0005) Table 2

Table2: Comparison of Survivors vs Non-survivors (Complications) and risk

Fig 1= ECG changes partial RBBB (i) and ST segment changes (ii) in diphtheria cardiomyopathy