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predictors of outcome in children with DOI: 10.1177/0049475518823657
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diphtheria: a study from northern India

Nabaneeta Dash1, Sanjay Verma2 , Muralidharan Jayashree3,

Rakesh Kumar2, Pankaj C Vaidya2 and Meenu Singh3

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 ¼ 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 ¼ 0.88, 95% confidence
interval ¼ 0.79–0.99, P ¼ 0.03).

Keywords
Diphtheria, children, epidemiology, predictors of outcome, northern India

clinical profile and outcome.3–7 One such study from

Background our centre in 2006, showed that the majority of affected
Diphtheria has become a disease of the past in most children were unimmunised with a mean (standard
parts of the world, owing to highly effective immunisa- deviation [SD]) age of 5.1 years (2.08) and these were
tion programmes. However, the disease continues to be associated with high mortality (56%).8 However, this
a significant public health problem for India, accounting cohort comprised critically ill children admitted to an
for nearly 50% of all reported cases of diphtheria world- intensive care unit.8 In the ensuing 10–12 years, we
wide. Although its incidence has decreased from 39,231 found that the disease burden is still sizeable and asso-
cases in 1980 to 3380 in 2016,1 there is an epidemio- ciated with higher complication rates. Being the tertiary
logical shift to older age groups (>5 years) and higher care referral and teaching hospital in the region, our
mortality. India introduced the DPT (diphtheria, whole centre caters for five neighbouring states and hence
cell pertussis, tetanus) vaccine in its Expanded witnesses a huge disease burden. However, periodic
Programme of Immunization (EPI) in 1978. Since updates with follow-up studies are required to identify
then, despite different nomenclature of immunisation
programmes and efforts to improve vaccine coverage, 1
Senior Resident, Department of Pediatrics, PGIMER, Chandigarh, India
the target of covering 90% of children with all three 2
Professor, Department of Pediatrics, PGIMER, Chandigarh, India
3
doses of the DPT vaccine has not been successfully Professor, Department of Pediatrics (Emergency and Critical Care),
achieved.1,2 Both improved surveillance and lower vac- PGIMER, Chandigarh, India
cination rate in certain areas probably contribute to the
Corresponding author:
increase in reported diphtheria cases from India. Sanjay Verma, Additional Professor, Room 3126, Level 3, Block A,
Available literature with regards to diphtheria is pri- Advanced Pediatric Center (APC), PGIMER, Chandigarh 160012, India.
marily limited to case series with an emphasis on Email: sanjay06verma@yahoo.com
2 Tropical Doctor 0(0)

the changing trends in epidemiology as these will guide regarding occurrence of diphtheria cases in their dis-
management and help allocate healthcare resources trict, leading to a reinforcement of efforts to improve
appropriately. We therefore planned this analysis to primary immunisation in these areas.
identify a change in epidemiology, if any, and to
study the clinical profile, vaccination status and pre-
Statistical analysis
dictors of mortality in an era of intensified routine
immunisation. Data are presented as mean (SD for parameters vari-
ables) and median (interquartile range [IQR] for
non-parametric variables). The 2 test was applied for
Method comparison between groups with categorical data.
Case records of children with a clinical diagnosis of Student’s t-test or Mann–Whitney U tests were applied
diphtheria (as defined) from January 2008 to for parametric and non-parametric continuous data,
December 2015 were retrieved from the Hospital respectively. Cases were compared based on outcome
Medical Records Department and analysed retrospect- to identify factors associated with unfavourable out-
ively. Data with respect to demography, immunisation come. Multivariable logistic regression analysis was
status, clinical features, treatment received, complica- applied to those variables which were found to be sig-
tions and outcome were recorded on a pre-designed nificant on univariate analysis to identify predictors of
proforma. Outcome was defined as unfavourable if unfavourable outcome.
the child died or care was discontinued owing to poor
prognosis.
Results
The diagnosis of diphtheria was made according to
the World Health Organization (WHO) clinical A total of 99 cases of clinical diphtheria were admitted
description, which defines an illness characterised by from August 2008 to January 2015. Of these, 83 were
laryngitis, pharyngitis or tonsillitis, with an adherent diagnosed clinically. Sixteen cases presented later with
greyish white membrane over the oropharynx, larynx symptoms of polyneuropathy with a diagnosis of diph-
or nasal passage, combined with laboratory diagnosis theritic neuropathy. Boys (n ¼ 63) outnumbered girls
(diphtheria isolation of C. diphtheriae from a clinical with a ratio of 1.8:1. The median age of affected chil-
specimen).9 A diagnosis of probable diphtheritic poly- dren was seven years (IQR ¼ 5–8 years). The maximum
neuropathy was made in those who developed multiple number of cases occurred during months of August to
cranial or limb neuropathy having a history within the December every year (Figure 1). None of the children
preceding six weeks of having an illness suggestive of had completed the DPT vaccine schedule according to
clinical diphtheria. Because of such late presentation, the National Immunization Schedule (NIS) of India;
laboratory diagnosis was not attempted in these cases. 65.7% had not received even one dose of the DPT vac-
All children with a clinical diagnosis of diphtheria were cine and the rest were only partially immunised.
monitored for the occurrence of myocarditis, which Geographic clustering of cases was observed, with
usually occurs during the second week of illness, sup- 35.3% hailing from one district of a neighbouring state.
ported by electrocardiographic changes, raised enzyme Fever and dysphagia were the most common pre-
(troponin-T) or falling ejection fraction on senting symptoms in 96 and 81, respectively.
echocardiography. Pseudomembrane was seen in 80. Bull neck as a pre-
Suspected cases were treated in isolation and throat senting sign was present in only 53, sore throat in 66,
swabs were sent for Albert staining and culture. stridor in 40 and nasal discharge in 14 (Table 1).
Blood samples were drawn for serum electrolyte, Airway compromise was the most common compli-
urea-creatinine levels and haematological tests. Other cation; 61 patients had features of airway obstruction in
investigations were tailored according to the clinical the form of stridor at presentation of whom 57 required
course and presence or absence of complications. The advanced airway support (tracheotomy in 46 and endo-
children were managed according to the unit’s standard tracheal intubation in 11 cases) with 34 requiring posi-
protocol which included administration of anti- tive pressure ventilation.
diphtheritic serum (ADS) and antibiotics (erythro- Myocarditis was the second most common compli-
mycin or penicillin), apart from those who presented cation observed in our cohort in 35 patients. This was
with only post-diphtheritic polyneuropathy without diagnosed by ECG (heart blocks/bradycardia/
any signs of active infection. ADS was given in the prolonged PR interval) and using echocardiography
recommended dose according to site and extent of (low ejection fraction) (Table 2). The mean (SD) dur-
involvement.10 Details of these cases were shared with ation between its onset and the start of illness was 8.5
the community health department of our institution, days (3–16). Eleven children (11.1%) with myocarditis
who appraised the district immunisation official developed cardiogenic shock.
Dash et al. 3

Figure 1. Distribution of diphtheria cases by month.

Table 1. Demography and clinical characteristics of study Table 2. Complications in diphtheria cases (n ¼ 99).
cohort (n ¼ 99).
Complications n (%)
Age (years) (median (IQR)) 7.0 (5.0–8.0)
Airway compromise 61 (62)
Sex ratio (boys:girls) 1.7:1
Myocarditis 35 (35)
Religion (n (%))
ECG abnormalities 25 (71)
Islam 44 (44.4)
Conduction abnormality and heart block 9
Hindu 37 (37.4)
ST depression 5
Sikh 18 (18.2)
Ventricular tachycardia (VT) 7
Place of residence (n (%))
Ventricular premature beats 2
Uttar Pradesh 42 (42.4)
Prolonged PR interval 2
Chandigarh 3 (3)
Acute kidney injury 22 (22)
Punjab 28 (28.3)
Thrombocytopenia 25 (25)
Haryana 17 (17.2)
Neuropathy 27 (27)
Other 9 (9.1)
Multi-organ failure 6 (6)
Vaccination status (n (%))
No DPT vaccine received 65 (65.7)
At least 1 dose of DPT 34 (34.3)
Presenting complains (n (%)) only 21% cases. Throat swab culture showed growth
Fever 96 (96.9)
of C. diphtheriae in 28% cases.
Anti-diphtheritic serum (ADS) was administered in
Sore throat 66 (66.7)
84 patients at a mean dose of 150,000 IU. Of these, 81
Dysphagia 81 (81.8)
had a classic pseudomembrane in the throat. In two
Bull neck 53 (53.5) children, the pseudomembrane was absent, symptoms
Stridor 40 (40.4) were suggestive of diphtheria, vaccination was incom-
Nasal discharge 14 (14.1) plete 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
Polyneuropathy was seen in 27 cases, of whom 16 receive ADS in our hospital had presented with poly-
had symptoms of neuropathy at presentation. The neuropathy with mean interval of four weeks between
median duration between onset of illness and neur- symptom onset and presentation. Antibiotic treatment
opathy was 25 days (IQR ¼ 7.75–35 days). Albert was administered as benzyl penicillin in 64 patients and
stain was performed in all cases but was positive in erythromycin in 31 patients.
4 Tropical Doctor 0(0)

A poor outcome was seen in 34 patients, 23 of whom and myocarditis were the commonest complications,
died and 11 discontinued care (decided to return home) contributing to death.
owing to a probable fatal prognosis. Ventricular tachy- Patterns of epidemiology are known to change over
cardia was the immediate cause of death in four time because of vaccination as well as change in socio-
patients, heart block and bradycardia in ten, refractory economic conditions.11 Our study shows that the age of
shock in three patients, pulmonary complications (pro- susceptibility has shifted upwards with the disease being
gressive pneumonia, pulmonary haemorrhage and seen more commonly among children aged >5 years,
pneumothorax) due to manual ventilation in four the median age being seven years (IQR ¼ 5–8 years).
patients and healthcare-associated infections in two One explanation for this observation might be partial
patients. When comparing children with unfavourable immunisation of children; while there is high coverage
outcomes with survivors, the former were more fre- for first and second doses of the DPT vaccine, coverage
quently associated with a shorter duration of symptoms falls for the third dose and subsequent booster doses.1
before presentation in hospital and airway compromise Children at older ages therefore remain susceptible.
at admission (Table 3). On multivariable analysis, this A rapid Government survey of Indian children in
was the independent predictor of unfavourable out- 2013–2014 showed that 74.8% children had received
come. If the 16 children who presented with probable all three doses of the DPT vaccine.12 However, the
diphtheritic polyneuropathy to our hospital are coverage rates were in the range of 35.3–95.2%
excluded from the analysis, requirement of emergency among various Indian states12 and this patchy coverage
intubation to protect the airway became an independ- may explain geographic clustering in certain areas. This
ent predictor of poor outcome (adjusted odds ratio persisting poor immunisation coverage in certain pock-
[OR] ¼ 10; 95% confidence interval [CI] ¼ 1.3–77.3; ets of the country is truly a matter of concern.
P ¼ 0.026). Targeting these populations needs directed special stra-
tegies and a high level of commitment
Tracheostomy is the standard of care for patients
Discussion with a compromised airway; care is less risky than
Our study shows that diphtheria still remains a life- endotracheal intubation. Moreover, there is always a
threatening illness among children, having a seasonal potential risk of dislodging the friable membrane
peak from August to December, every year. At our while intubating, thus causing tracheal obstruction or
centre, the disease is purely one of an unvaccinated bleeding into the airways during the procedure.
population, residing in certain pockets, where immun- Myocarditis has been reported at higher rates
isation rates continue to be poor. Airway compromise elsewhere as 16–70%;7,8,11,13–15 in our series, its onset

Table 3. Comparison between children with good and unfavourable outcomes.

Good Unfavourable Multivariable regression analysis

outcome outcome
Variable (n ¼ 65) (n ¼ 34) P value OR (95% CI) P value

Age (years) (median (IQR)) 7 (5–10) 6 (4–8) 0.09*

Duration of symptom before presentation 7 (5–15) 5 (4–8) 0.03* 0.88 (0.79–0.99) 0.03
(days) (median (IQR))
<7 (n (%)) 26 (55) 21 (45)
7–14 (n (%)) 22 (65) 12 (35)
>14 (n (%)) 16 (94) 1 (6)
Unimmunised (n (%)) 43 (66.2) 22 (64.7) 0.87
Bull neck (n (%)) 33 (50.8) 23 (44) 0.36
Myocarditis (n (%)) 21 (32.3) 14 (41.2) 0.32
Acute kidney injury (n (%)) 12 (18.5) 10 (29.4) 0.17
Thrombocytopenia (n (%)) 16 (24.6) 19 (26.6) 0.71
Respiratory distress (n (%)) 20 (30.8) 12 (35.3) 0.65
Airway compromise requiring advanced 32 (49.2) 25 (73.5) 0.01 0.51 (0.15–1.7) 0.28
airway (n (%))
P < 0.05 significant.
*Mann–Whitney U test.
Dash et al. 5

was slightly earlier (10  4 days) than the classical References

end of the second week onset. Early onset myocarditis 1. Burton A, Monasch R, Leutenbach B, et al. WHO and
is often fatal.16 Completely unimmunised children UNICEF estimates of national immunization coverage:
have a great tendency to develop myocarditis compared methods and processes. Bull World Health Organ 2009;
to those who are partially immunised.8 In our 87: 535–541.
cohort, too, 82% of children who had myocarditis 2. Busteo F, Okwo-Bele JM and Kamara L. World Health
were unimmunised. Bradycardia was more common Organization perspectives on the contribution of the
than tachyarrhythmias as elsewhere;8,11,14,15 although global alliance for vaccines and immunization on redu-
there is no specific treatment for diphtheritic myocardi- cing child mortality. Arch Dis Child 2015; 100(Supp. 1):
tis, recent studies show a 25% improved survival S34–S37.
among patients with severe conduction abnormalities 3. Bitragunta S, Murhekar MV, Hutin YJ, et al. Persistence
of diphtheria, Hyderabad, India, 2003–2006. Emerg
following temporary pacing.16,17 We cannot comment
Infect Dis 2008; 14: 1144–1146.
on the statistic as temporary pacing was done in one
4. Nath B and Mahanta TG. Investigation of an outbreak in
child in our series, but did not affect the outcome. Borborooah block of Dirbrugarh district, Assam. Indian
Mortality with myocarditis was indeed high (40%), J Community Med 2010; 35: 436–438.
particularly if it was associated with complete heart 5. Shaffi M, Nayar KR and Lal SS. Diphtheria deaths in
block (100%). Kerala signs of impending crisis. Econ Polit Wkly 2015;
A lower rate of recovery of diphtheria bacilli has also 50. Available at: http://www.epw.in/journal/2015/43/
been reported in other studies,8,11,18 possibly from inad- reports-states-web-exclusives/diphtheria-deaths-
equate sampling either due to an uncooperative child or kerala.html).
sampling from an inappropriate site, improper storage 6. Basavaraja GV, Chebbi PG and Joshi S. Resurgence of
and transport or prior antibiotic use, which was a sig- diphtheria: clinical profile and outcome - a retrospective
nificant issue in our study as approximately two-thirds observational study. Int J Contemp Pediatr 2016; 3:
were prescribed antibiotics before referral. A shorter 60–63.
duration of symptoms before presentation being asso- 7. Dravid MN and Joshi SA. Resurgence of diphtheria in
ciated with poor outcome appears a logical consequence Malegaon and Dhule regions of north Maharashtra.
Indian J Med Res 2008; 127: 616–617.
of higher disease severity. Retrospective data collection
8. Jayashree M, Shruthi N and Singhi S. Predictors of out-
is one of the major limitations of our study; furthermore,
come in patients with diphtheria receiving intensive care.
the tertiary referral hospital tends to collect more severe
Indian Pediatr 2006; 43: 155–160.
forms of disease. 9. World Health Organization. WHO recommended surveil-
lance standards, 2nd ed. Geneva: World WHO, 1999,
Conclusion Available at: http://www.who.int/iris/handle/10665/
65517.
What can be inferred with moderate certainty is that 10. Singhi SC, Jayashree M, Straumanis J, et al. Toxin-
the disease now commonly affects children aged related diseases. In: Nichols DG and Shaffner DH (eds)
>5 years. In addition, it still has a very high mortality Rogers’ Textbook of Pediatric Intensive Care. 5th ed.
rate, with airway obstruction and myocarditis remain- Philadelphia, PA: Lippincott Williams and Wilkins,
ing the most frequent complications. The changing epi- 2016, pp. 1547–1571.
demiology appears to represent partial immunisation, 11. Singh SN, Singh A and Chandra S. Clinical profile
especially in certain pockets. Therefore, efforts must be and predictors of poor outcome of hospitalized diph-
directed towards identifying and promoting good cover theria cases in children from Lucknow region of North
India. Clinic Epidemiology and Global Health 2014; 2:
vaccination in these areas.
75–79.
12. Ministry of Women and Child Development Government
Declaration of conflicting interests of India. Rapid survey on Children (RSOC) 2013–2014.
The author(s) declared no potential conflicts of interest with Fact sheet: India. Available at: http://wcd.nic.in/sites/
respect to the research, authorship, and/or publication of this default/files/State%20RSOC.pdf (accessed on 15 March
article. 2018).
13. Hoyne A and Welford N. Diphtheritic myocarditis, a
Funding review of 496 cases. J Pediatr 1934; 5: 642–653.
The author(s) received no financial support for the research, 14. Havaldar PV, Sankpal MN and Doddannavar RP.
authorship, and/or publication of this article. Diphtheritic myocarditis: clinical and laboratory param-
eters of prognosis and fatal outcome. Ann Trop Paediatr
2000; 20: 209–215.
ORCID iD
15. Kole AK, Roy R and Kar SS. Cardiac involvement in
Sanjay Verma http://orcid.org/0000-0001-5064-2325 diphtheria: Study from a tertiary referral infectious
6 Tropical Doctor 0(0)

disease hospital. Ann Trop Med Public Health 2012; 5: of a cardiac pacemaker. Clin Infect Dis 2002; 35:
302–306. 1425–1429.
16. Varghese MJ, Ramakrishnan S, Kothari SS, et al. 18. Meera M and Rajarao M. Diphtheria in Andhra
Complete heart block due to diphtheritic myocarditis in Pradesh – a clinical-epidemiological study. Int J Infect
the present era. Ann Pediatr Cardiol 2013; 6(1): 34–38. Dis 2014; 19: 74–78.
17. Dung NM, Kneen R, Kiem N, et al. Treatment of
severe diphtheritic myocarditis by temporary insertion