DOI: 10.7860/JCDR/2022/54907.

16376
Original Article

Diphtheria in Children- Clinical Profile of Cases

Paediatrics Section

during an Outbreak in Kerala, India

Thekkile Gangadharan Sindhu1, Madhava Vijayakumar2, Peethambaran Geetha3,

Chandran Priya4, Puduvail Moorkoth Anitha5

ABSTRACT Results: Among 76 children, 62(81.6%) were from Malappuram

Introduction: Diphtheria is an acute potentially fatal infectious and Kozhikode districts, which have relatively low immunisation
disease caused by the toxigenic strains of Corynebacterium coverage. Most admissions were in July 2016. Majority 58 (76.3%)
diphtheriae. Acute respiratory obstruction, toxic myocarditis of children belonged to Muslim community. The mean age was
and neurologic weakness are the most important complications 8.1 years with male to female ratio 1.53:1. Most of the children
of diphtheria. The clinical presentation and severity of diphtheria 47 (61.8%) were unimmunised or partially immunised. Cultures
vary in immunised and non immunised children. Early diagnosis were positive for C. diphtheriae in 20 children. Complications
and prompt treatment including administration of diphtheria were noted in 36 children, which included asymptomatic
antitoxin and antibiotics minimise mortality. myocarditis in 31, symptomatic myocarditis in one, palatal palsy
in nine, loss of accommodation in four and distal weakness
Aim: To observe the changing trends in the clinical presentation
in five. Only one child who received antitoxin within 72 hours
of diphtheria during the 2016 outbreak and its association with
of disease onset developed neurological complications.
immunisation status and antitoxin administration.
Complications were common in children who received less than
Materials and Methods: This longitudinal prospective study minimum three doses of diphtheria vaccines compared to those
was conducted among children admitted to Government Medical who received three or more doses (54% vs. 44%). There was
College, Kozhikode, Kerala, a tertiary care centre with a diagnosis no mortality.
of diphtheria during January 2016 to December 2016. Details of
Conclusion: There was an upward shift in age of affected
socio-demographic data, clinical presentation, investigations,
children. Neurological complications were significantly less in
immunisation status, treatment and complications were collected
those who received antitoxin within 72 hours of disease onset.
using a semi-structured performa. These children were managed
Regular monitoring helped to detect asymptomatic myocarditis.
by an interim guideline provided by the state authorities. They
The outbreak highlighted the need to improve awareness about
were followed-up for 3 months i.e. till March 2017. The data was
diphtheria and better vaccination coverage, especially in older
analysed using Statistical Package for Social Sciences (SPSS),
children.
version 18.0.

Keywords: Clinical presentation, Complications, Diphtheria antitoxin, Immunisation status, Vaccination

INTRODUCTION The aim of this study was to find out the changing trends in the
Diphtheria is an acute potentially fatal infectious disease caused clinical presentation and complications of diphtheria in children
by the toxigenic strains of Corynebacterium diphtheriae [1]. during the epidemic. The study also had attempted to find out the
In the pre-vaccine era, more than 40% of cases occurred in association of complications seen in the epidemic with immunisation
children below five years. Recently an upward shift in age is status and the time of antitoxin administration.
observed both in developed and developing countries [2,3].
Acute respiratory obstruction, toxic myocarditis and neurologic MATERIALS AND METHODS
weakness are the most important complications of this disease. This longitudinal prospective study was conducted in the Paediatric
Cardiac involvement may be asymptomatic {characterised only Infectious Disease Unit at Government Medical College, Kozhikode,
by changes in Electrocardiogram (ECG) and/or raised cardiac Kerala, India (tertiary care teaching institute in North Kerala). The
enzymes) or symptomatic (with clinical features of heart failure)} study period was from January 2016 to March 2017. All children
[4]. The main modality of treatment is administration of diphtheria satisfying the inclusion criteria were included in the study. This study
antitoxin and antibiotics. The rapidity of seeking medical care was approved by Institutional Ethical Committee of Government
and administering specific treatment is known to decrease the Medical College Kozhikode (Ref No: GMCKKD/RP 2016/ EC/171).
mortality [1]. Immunisation status of the individual affects the Informed consent was obtained from parents.
clinical presentation and severity of the disease [5]. The operational definition for clinical diphtheria was taken as an
An outbreak of diphtheria was reported from the northern districts illness characterised by laryngitis, pharyngitis or tonsillitis and an
of the state of Kerala India in 2016, starting from June 2016. A total adherent membrane on the tonsils, pharynx or nose as per World
of 533 cases were reported accounting for about 7% of globally Health Organisation (WHO) case definition or a child with clinically
reported cases [6]. But this was based on surveillance data alone and compatible history with typical complications such as palatal palsy,
did not analyse the clinical features or treatment response. This was myocarditis or peripheral neuropathy [7].
the largest epidemic in Kerala over the last decade. Majority of cases Inclusion criteria: All children below 12 years of age who met the
were reported from Kozhikode, Malappuram, and Kannur districts operational definition of diphtheria and were admitted to Paediatric
where the routine immunisation coverage was low at that time. Infectious Disease Unit from January 2016 to December 2016 were
Journal of Clinical and Diagnostic Research. 2022 May, Vol-16(5): SC19-SC23 19
 Thekkile Gangadharan Sindhu et al., Diphtheria in Children: A longitudinal Prospective Study www.jcdr.net

included in the study. A total of 80 children met the clinical case strains with the antitoxin released from the filter paper, between the
definition. disk and the inoculum was taken as positive.
Exclusion criteria: Children in whom an alternate diagnosis was made
during evaluation were excluded. So, two cases were diagnosed STATISTICAL ANALYSIS
The data was analysed using Statistical Package for Social
subsequently as infectious mononucleosis, one case as streptococcal
Sciences (SPSS) version 18.0. Chi-square test was used as test of
pharyngitis, and one turned out to be a case of acute lymphoblastic
significance for qualitative variables. A p-value <0.05 was considered
leukaemia, were excluded from the study.
as statistically significant.
Procedure RESULTS
Details of socio-demographic data, clinical presentation, laboratory Total of 80 children met the clinical case definition. Among these,
investigations, immunisation status, treatment and complications four children were excluded from the study as they had an alternate
were collected using a semi-structured proforma and from the diagnosis during the hospital stay. Of these, two cases were
hospital records. Immunsation status was documented after diagnosed subsequently as infectious mononucleosis, one case as
crosschecking with the available records. Those children who had streptococcal pharyngitis, and one turned out to be a case of acute
completed recommended age-appropriate doses of diphtheria lymphoblastic leukaemia. The remaining 76 children were followed-up
toxoid as per national immunisation schedule were considered for 3 months and details were analysed. The mean age of the study
as completely immunised [8]. Those who did not receive even a population was 8.1 years, and the youngest child was 7 months old.
single dose were considered as non immunised and those who had There were more boys with a male to female ratio 1.53:1. Most of
received less than the recommended doses for age were classified these children were from Malappuram and Kozhikode districts. The
as partially immunised. epidemic started in June with the first case admitted on 13th June
Clinical examination: Detailed clinical examination was done to 2016. Maximum numbers of cases were admitted in July 2016, at
determine the degree of involvement and presence of cardiac and the peak of monsoon season in this state. Thereafter cases started
neurological complications. A child with clinical diphtheria and ECG declining and reached a plateau by November 2016 [Table/Fig-1].
showing non specific changes and or raised cardiac enzymes in the
absence of clinical features of cardiac failure was classified as having
asymptomatic myocarditis. Throat was examined to determine the
type and extent of the diphtheritic membrane.
Laboratory test: The laboratory tests includes complete  blood
counts, Erythrocyte Sedimentation Rate (ESR), hepatic transaminases,
renal function tests and urinalysis were done in all children at
the time  of admission and during clinical deterioration. ECG was
taken soon after admission and was repeated on every alternate
day during the inpatient stay, at the time of discharge and during
follow-up visits. Further investigations including echocardiography
and nerve conduction study was done for cases with features of
cardiac or neurological involvement. Troponin-I assay was done in
32 children with ECG abnormalities. [Table/Fig-1]: Month wise distribution of diphtheria cases 2016.
Management and follow-up: All cases were managed as per the
interim guidelines provided by the Directorate of Health Services, Among the study subjects, 22 children were unimmunised and
Kerala state [9] at the time of outbreak. The details of treatment with 25 partially immunised [Table/Fig-2]. None of the older children
antitoxin (dose, route, and day of administration) and antibiotics were received Tetanus and adult Diphtheria (Td) vaccination since it was
documented. These children were followed-up at 4 and 6 weeks and not included in the immunisation schedule at that time.
at 3 months.
Male Female Total Non Partially Fully
Throat swab culture: Throat swabs for Corneybacteria were Details (n=46) (n=30) (N=76) ­immunised immunised ­immunised
collected and cultured immediately on blood agar and potassium Age group
tellurite agar. Cultures were done soon after admission and repeated
0-5 years 15 4 19 (25.0)* 5 5 9
on days 15 and 16. The isolates were confirmed from World Health
6-10 years 24 15 39 (51.3) 10 17 12
Organisation Vaccine Preventable Disease Surveillance Laboratory
at Thiruvananthapuram using Polymerase Chain Reaction (PCR) 11-12 years 7 11 18 (23.7) 7 3 8

and standard biochemical tests. Sugar fermentation tests were Total

46 30
76 (100) 22 25 29
(60.5) (39.5)
done using Hiss’s serum sugar media. Other biochemical reactions
tested included urease test, nitrate  reduction test, catalase and District-wise distribution

oxidase reaction. The toxigenicity was detected by PCR for tox+ Malappuram 19 13 32 (42.1) 12 10 10
gene (tox A and tox B) and the phenotypic expression was confirmed Kozhikode 17 13 30 (39.5) 4 12 14
using modified Elek’s gel precipitation test [10,11]. Real-time PCR Kannur 3 4 7 (9.2) 4 1 2
(qPCR) assays were done using hydrolysis probes (TaqMan, Applied Palakkad 1 0 1 (1.3) 1 0 0
Biosystems). The qPCR targets for the RNA polymerase β-subunit-
Wayanad 4 0 4 (5.3) 0 2 2
encoding gene (rpoB) and the tox A gene were used. Extraction of DNA
Kasarkode 2 0 2 (2.6) 1 0 1
was performed using Magna pure 24 System (Roche Life Science).
Religion
Oligonucleotide primers and probe were designed using the software
Primer 3 to target rpoB and the tox gene [12]. Elek’s test was done Christian 2 0 2 (2.6) 0 1 1

with Elek’s test agar base supplemented with calf serum. A sterile filter Hindu 7 9 16 (21.1) 1 1 14
paper with 10 IU/mL of antitoxin was used. The test organisms were Muslim 37 21 58 (76.3) 21† 23 14
streaked at 10 mm from the disk along with positive and negative [Table/Fig-2]: Epidemiological details of children admitted during the diphtheria
controls. The plates were observed after 24 hour incubation at 37°C. outbreak.
*The number in parenthesis show percentages; †p-value=0.001
Formation of precipitin lines, due to binding of toxins produced by the
20 Journal of Clinical and Diagnostic Research. 2022 May, Vol-16(5): SC19-SC23
www.jcdr.net Thekkile Gangadharan Sindhu et al., Diphtheria in Children: A longitudinal Prospective Study

In this study, 25 (32.9%) cases were diagnosed within 48 hours of the 72 hours of the onset of the disease. Fourteen children had allergic
disease onset. One child presented around third week of illness with reactions following antitoxin administration. Three of them developed
palatal palsy and another one presented with generalised weakness severe allergic reactions and needed desensitisation. Full dose of
after one month of illness. All of them had pharyngo-tonsillar lesions the antitoxin could not be administered to these three children.
[Table/Fig-3]. Bull neck was present in 15 (19.7%) cases [Table/Fig-4]. Complications were noted in 36 children while on treatment or
Type of involvement Number of children* (n,%)
follow-up [Table/Fig-7]. Palatal palsy was noted in 9 (11.8%)
children of whom two developed weakness in the first week itself
Pharyngo-tonsillar 76 (100)
and 7 after second week. Five children developed distal weakness
Laryngeal 2 (2.63) during 4-6 weeks of illness. One child required ventilator support
Nasal 1 (1.32) for 5 days. Four children developed loss of accommodation reflex
Cutaneous 0 during follow-up visit but improved without any sequelae. None had
[Table/Fig-3]: Type of diphtheria (N=76). any airway compromise. None had jaundice or features of hepatic
*More than one type observed in some children failure. There was no mortality.

Clinical feature Number of children* (n,%) Major Number of

­complications cases (n,%) Non Partially Fully
Fever 75 (98.7) observed* N=76 ­immunised ­immunised ­immunised
Sore throat 74 (97.4) Asymptomatic
31 (40.8) 11 9 11
Dysphagia 34 (44.7) myocarditis

Bull neck 15 (19.7) Symptomatic

1 (1.3) 1 0 0
myocarditis
[Table/Fig-4]: Clinical features (N=76).
*More than one symptom observed in many children Palatal palsy 9 (11.8) 6 1 2
Symmetric
5 (6.6) 5 0 0
Corynebacterium diphtheriae was isolated from throat swabs of polyneuropathy
20 children (26.3%). All isolates were sensitive to penicillin and Accommodation
4 (5.3) 2 1 1
erythromycin. Repeat cultures after 14 days of treatment were palsy
negative except in one child who became culture-negative after a Proteinuria 1 (1.3) 1 0 0
course of erythromycin for 14 days. Culture positive cases included Thrombocytopenia 2 (2.6) 2 0 0
five fully immunised children as well. Thirty four (44.7%) children had [Table/Fig-7]: Complications observed.
leukocyte count above 15000. Erythrocyte Sedimentation Rate (ESR) *More than one complication was observed in some children

was above 50 mm in 28 (36.8%) children. Ten (13.2%) of them had

elevated Alanine Aminotransferase (ALT) level [Table/Fig-5]. These children were followed-up till 3 months after the onset of
illness. New complications noticed during the follow-up visits as
Laboratory parameter Mean Range Standard deviation well [Table/Fig-8]. All affected children recovered completely by
Haemoglobin (gm/dL) 11.6 8.6-13.9 0.87 three months.
Total count (cells/mm3) 15459 7500-49930 6739
No of Newly detected complications*
Platelet count (lakh cells/mm3) 3.21 1.03-6.90 1.27 Time of children
follow- came for Asymptomatic Palatal Loss of Distal
Erythrocyte sedimentation up visit follow-up myocarditis palsy ­accommodation weakness
49 3-125 27
rate (mm at 1st hour)
4th week 75 1 3 2 2
Alanine aminotransferase (U/L) 28 10 -204 32
6 week
th
73 1 3 2 3
Creatinine (mg/dL) 0.56 0.3-0.9 0.11
3rd month 76 0 0 0 0
[Table/Fig-5]: Laboratory investigations (N=76).
[Table/Fig-8]: Details of follow-up visits.
*More than one complication was observed in some children
Injection crystalline penicillin was given in a dose of 150000 units /kg/
day in four divided doses for 14 days to all subjects (including those Association between day of administration of antitoxin and
who presented late) except one who developed hypersensitivity complications: Only one child who received antitoxin within
reaction to penicillin. This child was treated with erythromycin 40 mg/ 72  hours of disease onset developed neurological complications
kg/day four divided doses for 14 days. Diphtheria antitoxin was and this was statistically significant (p-value <0.05).
administered to 74 children but could not be given to two since they Association between immunisation status and complications:
were admitted two weeks after the onset of symptoms. Antitoxin Complications were common in children who received less than 3
was given in varying doses (20,000 to 1,00,000 units) depending doses of diphtheria toxoid compared to those who received three or
on the day of presentation and the severity of the illness [Table/ more doses (54 vs 44%). However, this was not statistically significant
Fig-6]. For all the children antitoxin was administered intravenously. (p-value=0.2). Children who received five doses of vaccine did not
Less than half 34 (44.7%) of the children received antitoxin within develop diphtheritic polyneuropathy or accommodation palsy.
Those children with bull neck had developed more complications
Quantity of Diphtheria antitoxin (units/kg/day)
administered intravenously No. of children (N=76)
and it was statistically significant (p-value=0.001).
0 2
DISCUSSION
20,000 27
Out of the 533 reported diphtheria cases in Kerala in 2016, 76
30,000 1 cases were admitted in this hospital [Table/Fig-9]. This includes 58
40,000 26 children in the under 10 years of age. The upward shift in age in the
50,000 1 study by Sangal L et al., is evident in our study as well with relatively
60,000 10 lesser number of children in the 0-5 year age group [6]. The upward
shift of age was reported from various parts of the world [2,3,13].
80,000 8
Some areas of India continue to have a predilection to younger age
1,00,000 1
groups. In a hospital-based study conducted by Maheriya KM et
[Table/Fig-6]: Details of antitoxin administration.
al., [14] from Ahmadabad (Gujarat), children in the 0-5 year age
Journal of Clinical and Diagnostic Research. 2022 May, Vol-16(5): SC19-SC23 21
 Thekkile Gangadharan Sindhu et al., Diphtheria in Children: A longitudinal Prospective Study www.jcdr.net

category were more affected. More boys were affected in current Diphtheritic polyneuropathy is under reported in India [20]. The
study, which was consistent with the above study. Majority of latency of the diphtheritic polyneuropathy can vary from 10 days to
cases were from Malappuram and Kozhikode districts, which have 3 months [21]. In this study, neurological complications appeared
relatively low immunisation coverage for even primary doses of within 6 weeks of illness, during follow-up. Lack of follow-up may
Diphtheria Pertussis Tetanus (DPT) (80.8% and 86.9%; NFHS 4). be the reason for under reporting of neurological complications.
Accommodation palsy is not a reported complication in other
Total reported cases in Kerala Case in present study studies [Table/Fig-10]. It was noted that neurological complications
District by Sangal L et al., [6] (N=533*) (N=76) Number (%)
were significantly low for those who had received antitoxin early.
Malappuram 229 32 (14%) This observation underscores the importance of early initiation of
Kozhikode 190 30 (15.8%) antitoxin in suspected cases (even before a definite diagnosis is
Kannur 64 7 (1.6%) established by bacterial culture).
Wayanad 16 4 (25%) Cardiac involvement was present in 32 children (42%) of which
Palakkad 15 1 (6.7%) all except one had asymptomatic myocarditis noted in routine
Kasaragod 3 2 (66.7%)
electrocardiogram monitoring. Other studies from India have reported
varying incidence of myocarditis from 16 to 66% [4,5,14,22]. This
Other Districts †
16 0
highlights the importance of routine ECG monitoring in all children
[Table/Fig-9]: District wise breakup of Diphtheria cases in 2016.
†
(Thrissur, Ernakulam, Alappuzha, Thiruvananthapuram)
suspected to have diphtheria.
Most of the Indian studies have reported a high case fatality rate
Twenty nine (38.15%) immunised children developed the disease. varying from 23.67% to 56.3% [5,14,15,16]. There was no mortality
This is contrary to most of the studies from India where many in current study. The reasons may be due to relatively higher
were unimmunised [Table/Fig-10] [14,15]. But in a recent (2015) immunisation status, early administration of antitoxin and antibiotics
epidemic reported from Delhi, a significant number of immunised and a protocol based institutional case management for all children
children developed the disease [16]. More than 90% of children with suspected diphtheria.
developed protective level of antibodies against diphtheria following
three primary doses [17]. But Gowin E et al., demonstrated that Limitation(s)
only 70% polish children developed protective antibodies after Since this was a hospital-based study, true nature of illness in the
adequate immunisation pointing to the fact that variation can occur community would not be reflected here.
in protective antibody production in different populations [18]. So,
in the present study, the observation of occurrence of the disease CONCLUSION(S)
in children adequately immunised points the need for population- Occurrence of diphtheria in various parts of India including states
based studies for estimating protective antibody levels in India. like Kerala where immunisation coverage in children is significantly
Recent change in the national policy to give Td instead of Tetanus high compared to other states, is a matter of grave public health
Toxoid (TT) at 10-year, 15 year and during pregnancy may decrease concern. It is important to note that diphtheria may occur in
the disease in these age groups [19]. This also reminds us that immunised children as well. The clinical profile is also changing
the protection through immunisation is not an absolute one. Thus, with an increased incidence in older children. It is gratifying to
any child presenting with fever and sore throat must be carefully note that mortality can be prevented or reduced significantly
examined for the presence of a diphtheritic membrane irrespective with institutional care and protocol-based management, which
of the immunisation status. It is especially important in an epidemic includes routine screening for the development of complications.
setting in the background of low immunisation coverage in the Administration of diphtheria antitoxin within 72 hours of presentation
community. Bull neck was more common among who had received decreases the development of neurological complications. Regular
less than five doses of vaccine. Higher mortality of children with bull anticipatory screening for cardiac involvement has a specific role in
neck had been described in an earlier study [16]. management.

Maheriya KM et Dandinarasaiah M Acknowledgement

Variables al., [14] et al., [15] Present study, 2022
The authors would like to acknowledge Puthezhath S. N Menon
Period of study 2013 1997 to 2007 2016
Consultant Paediatrician for final preparation of the manuscript. The
Place of study Hubli, Karnataka Ahmedabad, Gujarat Kozhikode, Kerala
also would like to acknowledge faculty members, the resident doctors
Study design Prospective Retrospective Prospective and the nursing staff of the Department of Paediatrics who provided
Total cases 38 52 76 all basic support for the diagnosis and management of patients seen
Age <5 years 22 (58%)* 21 (40.38%) 19 (25%) during the outbreak. They would like to acknowledge the help and
Fully immunised 6 (16) 6 (11.53%) 29 (38.15%) advice received from the Directorate of Health Services, Kerala.
Male female ratio 1.8:1 1:1.7 1.53:1
Season August to December Not mentioned January to December
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PARTICULARS OF CONTRIBUTORS:
1. Additional Professor, Department of Paediatrics, Government Medical College, Kozhikode, Kerala, India.
2. Professor, Department of Paediatrics, Government Medical College, Manjeri, Kerala, India.
3. Additional Professor, Department of Paediatrics, Government Medical College, Kozhikode, Kerala, India.
4. Additional Professor, Department of Community Medicine, Government Medical College, Kozhikode, Kerala, India.
5 Professor, Department of Microbiology, Government Medical College, Manjeri, Kerala, India.

NAME, ADDRESS, E-MAIL ID OF THE CORRESPONDING AUTHOR: PLAGIARISM CHECKING METHODS: [Jain H et al.] Etymology: Author Origin
Thekkile Gangadharan Sindhu, •  Plagiarism X-checker: Jan 14, 2022
Additional Professor, Department of Paediatrics, Government Medical College, •  Manual Googling: Mar 16, 2022
Kozhikode, Kerala, India. •  iThenticate Software: Apr 25, 2022 (4%)
E-mail: drsindhuimch@gmail.com

Author declaration:
•  Financial or Other Competing Interests:  None Date of Submission: Jan 12, 2022
•  Was Ethics Committee Approval obtained for this study?  Yes Date of Peer Review: Mar 16, 2022
•  Was informed consent obtained from the subjects involved in the study?  Yes Date of Acceptance: Apr 25, 2022
•  For any images presented appropriate consent has been obtained from the subjects.  No Date of Publishing: May 01, 2022

Journal of Clinical and Diagnostic Research. 2022 May, Vol-16(5): SC19-SC23 23