Abstract
Diphtheria, a vaccine preventable disease in children, is still being reported from India. Details of 99 children with a clinical diagnosis of diphtheria admitted to a paediatric tertiary care teaching and referral hospital between January 2008 and December 2015 were collected retrospectively and analysed. The median (interquartile range [IQR]) age of the study group was 7.0 years (IQR = 5.0–8.0 years). Nearly two-thirds were unimmunised. Clinical features included fever (97%), dysphagia (82%), sore throat (67%), bull neck (54%), stridor (40%), neuropathy (27%) and nasal discharge (14%). Throat swab for Albert stain was positive in only 21% of cases and C. diphtheriae was isolated in only 28%. Complications included airway compromise (61.7%) followed by myocarditis (35.4%), acute kidney injury (22.3%), thrombocytopenia (25.3%) and neuropathy (27.3%). In all, 66% survived, 23% died and 11% opted for discontinuity of care owing to unfavourable prognoses. On multivariable logistic regression analysis, shorter duration of symptoms before presentation to our hospital was an independent predictor of unfavourable outcome (adjusted odds ratio = 0.88, 95% confidence interval = 0.79–0.99, P = 0.03).
Background
Diphtheria has become a disease of the past in most parts of the world, owing to highly effective immunisation programmes. However, the disease continues to be a significant public health problem for India, accounting for nearly 50% of all reported cases of diphtheria worldwide. Although its incidence has decreased from 39,231 cases in 1980 to 3380 in 2016, 1 there is an epidemiological shift to older age groups (>5 years) and higher mortality. India introduced the DPT (diphtheria, whole cell pertussis, tetanus) vaccine in its Expanded Programme of Immunization (EPI) in 1978. Since then, despite different nomenclature of immunisation programmes and efforts to improve vaccine coverage, the target of covering 90% of children with all three doses of the DPT vaccine has not been successfully achieved.1,2 Both improved surveillance and lower vaccination rate in certain areas probably contribute to the increase in reported diphtheria cases from India.
Available literature with regards to diphtheria is primarily limited to case series with an emphasis on clinical profile and outcome.3–7 One such study from our centre in 2006, showed that the majority of affected children were unimmunised with a mean (standard deviation [SD]) age of 5.1 years (2.08) and these were associated with high mortality (56%). 8 However, this cohort comprised critically ill children admitted to an intensive care unit. 8 In the ensuing 10–12 years, we found that the disease burden is still sizeable and associated with higher complication rates. Being the tertiary care referral and teaching hospital in the region, our centre caters for five neighbouring states and hence witnesses a huge disease burden. However, periodic updates with follow-up studies are required to identify the changing trends in epidemiology as these will guide management and help allocate healthcare resources appropriately. We therefore planned this analysis to identify a change in epidemiology, if any, and to study the clinical profile, vaccination status and predictors of mortality in an era of intensified routine immunisation.
Method
Case records of children with a clinical diagnosis of diphtheria (as defined) from January 2008 to December 2015 were retrieved from the Hospital Medical Records Department and analysed retrospectively. Data with respect to demography, immunisation status, clinical features, treatment received, complications and outcome were recorded on a pre-designed proforma. Outcome was defined as unfavourable if the child died or care was discontinued owing to poor prognosis.
The diagnosis of diphtheria was made according to the World Health Organization (WHO) clinical description, which defines an illness characterised by laryngitis, pharyngitis or tonsillitis, with an adherent greyish white membrane over the oropharynx, larynx or nasal passage, combined with laboratory diagnosis (diphtheria isolation of C. diphtheriae from a clinical specimen). 9 A diagnosis of probable diphtheritic polyneuropathy was made in those who developed multiple cranial or limb neuropathy having a history within the preceding six weeks of having an illness suggestive of clinical diphtheria. Because of such late presentation, laboratory diagnosis was not attempted in these cases. All children with a clinical diagnosis of diphtheria were monitored for the occurrence of myocarditis, which usually occurs during the second week of illness, supported by electrocardiographic changes, raised enzyme (troponin-T) or falling ejection fraction on echocardiography.
Suspected cases were treated in isolation and throat swabs were sent for Albert staining and culture. Blood samples were drawn for serum electrolyte, urea-creatinine levels and haematological tests. Other investigations were tailored according to the clinical course and presence or absence of complications. The children were managed according to the unit’s standard protocol which included administration of anti-diphtheritic serum (ADS) and antibiotics (erythromycin or penicillin), apart from those who presented with only post-diphtheritic polyneuropathy without any signs of active infection. ADS was given in the recommended dose according to site and extent of involvement. 10 Details of these cases were shared with the community health department of our institution, who appraised the district immunisation official regarding occurrence of diphtheria cases in their district, leading to a reinforcement of efforts to improve primary immunisation in these areas.
Statistical analysis
Data are presented as mean (SD for parameters variables) and median (interquartile range [IQR] for non-parametric variables). The χ 2 test was applied for comparison between groups with categorical data. Student’s t-test or Mann–Whitney U tests were applied for parametric and non-parametric continuous data, respectively. Cases were compared based on outcome to identify factors associated with unfavourable outcome. Multivariable logistic regression analysis was applied to those variables which were found to be significant on univariate analysis to identify predictors of unfavourable outcome.
Results
A total of 99 cases of clinical diphtheria were admitted from August 2008 to January 2015. Of these, 83 were diagnosed clinically. Sixteen cases presented later with symptoms of polyneuropathy with a diagnosis of diphtheritic neuropathy. Boys (n = 63) outnumbered girls with a ratio of 1.8:1. The median age of affected children was seven years (IQR = 5–8 years). The maximum number of cases occurred during months of August to December every year (Figure 1). None of the children had completed the DPT vaccine schedule according to the National Immunization Schedule (NIS) of India; 65.7% had not received even one dose of the DPT vaccine and the rest were only partially immunised. Geographic clustering of cases was observed, with 35.3% hailing from one district of a neighbouring state.
Distribution of diphtheria cases by month.
Demography and clinical characteristics of study cohort (n = 99).
Airway compromise was the most common complication; 61 patients had features of airway obstruction in the form of stridor at presentation of whom 57 required advanced airway support (tracheotomy in 46 and endotracheal intubation in 11 cases) with 34 requiring positive pressure ventilation.
Complications in diphtheria cases (n = 99).
Polyneuropathy was seen in 27 cases, of whom 16 had symptoms of neuropathy at presentation. The median duration between onset of illness and neuropathy was 25 days (IQR = 7.75–35 days). Albert stain was performed in all cases but was positive in only 21% cases. Throat swab culture showed growth of C. diphtheriae in 28% cases.
Anti-diphtheritic serum (ADS) was administered in 84 patients at a mean dose of 150,000 IU. Of these, 81 had a classic pseudomembrane in the throat. In two children, the pseudomembrane was absent, symptoms were suggestive of diphtheria, vaccination was incomplete and the Albert stain throat swab was positive for diphtheria. One child who presented with probable diphtheritic polyneuropathy in the chronic stage also received ADS. The other 15 children who did not receive ADS in our hospital had presented with polyneuropathy with mean interval of four weeks between symptom onset and presentation. Antibiotic treatment was administered as benzyl penicillin in 64 patients and erythromycin in 31 patients.
Comparison between children with good and unfavourable outcomes.
P < 0.05 significant.
Mann–Whitney U test.
Discussion
Our study shows that diphtheria still remains a life-threatening illness among children, having a seasonal peak from August to December, every year. At our centre, the disease is purely one of an unvaccinated population, residing in certain pockets, where immunisation rates continue to be poor. Airway compromise and myocarditis were the commonest complications, contributing to death.
Patterns of epidemiology are known to change over time because of vaccination as well as change in socioeconomic conditions. 11 Our study shows that the age of susceptibility has shifted upwards with the disease being seen more commonly among children aged >5 years, the median age being seven years (IQR = 5–8 years). One explanation for this observation might be partial immunisation of children; while there is high coverage for first and second doses of the DPT vaccine, coverage falls for the third dose and subsequent booster doses. 1 Children at older ages therefore remain susceptible. A rapid Government survey of Indian children in 2013–2014 showed that 74.8% children had received all three doses of the DPT vaccine. 12 However, the coverage rates were in the range of 35.3–95.2% among various Indian states 12 and this patchy coverage may explain geographic clustering in certain areas. This persisting poor immunisation coverage in certain pockets of the country is truly a matter of concern. Targeting these populations needs directed special strategies and a high level of commitment
Tracheostomy is the standard of care for patients with a compromised airway; care is less risky than endotracheal intubation. Moreover, there is always a potential risk of dislodging the friable membrane while intubating, thus causing tracheal obstruction or bleeding into the airways during the procedure.
Myocarditis has been reported at higher rates elsewhere as 16–70%;7,8,11,13–15 in our series, its onset was slightly earlier (10 ± 4 days) than the classical end of the second week onset. Early onset myocarditis is often fatal. 16 Completely unimmunised children have a great tendency to develop myocarditis compared to those who are partially immunised. 8 In our cohort, too, 82% of children who had myocarditis were unimmunised. Bradycardia was more common than tachyarrhythmias as elsewhere;8,11,14,15 although there is no specific treatment for diphtheritic myocarditis, recent studies show a 25% improved survival among patients with severe conduction abnormalities following temporary pacing.16,17 We cannot comment on the statistic as temporary pacing was done in one child in our series, but did not affect the outcome. Mortality with myocarditis was indeed high (40%), particularly if it was associated with complete heart block (100%).
A lower rate of recovery of diphtheria bacilli has also been reported in other studies,8,11,18 possibly from inadequate sampling either due to an uncooperative child or sampling from an inappropriate site, improper storage and transport or prior antibiotic use, which was a significant issue in our study as approximately two-thirds were prescribed antibiotics before referral. A shorter duration of symptoms before presentation being associated with poor outcome appears a logical consequence of higher disease severity. Retrospective data collection is one of the major limitations of our study; furthermore, the tertiary referral hospital tends to collect more severe forms of disease.
Conclusion
What can be inferred with moderate certainty is that the disease now commonly affects children aged >5 years. In addition, it still has a very high mortality rate, with airway obstruction and myocarditis remaining the most frequent complications. The changing epidemiology appears to represent partial immunisation, especially in certain pockets. Therefore, efforts must be directed towards identifying and promoting good cover vaccination in these areas.
Footnotes
Declaration of conflicting interests
The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding
The author(s) received no financial support for the research, authorship, and/or publication of this article.