Diphtheria: a re-emerging infectious disease

Abstract

p class="abstract"> Background: Diphtheria is a fatal bacterial infection which affects the mucous membranes of oropharyngeal and nasal cavity, caused by aerobic gram-positive bacteria Corynebacterium diphtheriae. Clinical diphtheria is on the increase worldwide, mainly affecting developing countries and leading cause of morbidity and mortality. We sought to understand its presentation among patients and also early intervention of the disease. The objective of the study was to study the clinico-demographic profile of cases, the relationship between immunization status and clinical disease, the role of microbiological investigations and to identify complications in diphtheria cases.
Methods: This study is a hospital based observational study from September 2019 - September 2020 at a tertiary care centre, S.Nijalingappa Medical College and HSK hospital, Bagalkot, Karnataka. The cases were analysed with respect to demographic details, clinical features, immunization status, microbiological confirmation and complications of diphtheria cases.
Results: 32 cases were suspected to have diphtheria on clinical examination. The mean age of presentation was 15 years. Fever, sore throat, difficulty in swallowing, neck swelling and pseudomembrane in oral cavity were the common signs and symptoms. Airway compromise, myocarditis and neurological complications were noted. Antidiphtheritic serum (ADS) was tried in all 32 cases and 8 cases had adverse reactions. Case fatality rate was 12.5%.
Conclusions: Shifting of occurrence of diphtheria in the age group of >5 years suggest the need to improve and strengthen the immunization program specially the booster doses.</p

Full text

International Journal of Otorhinolaryngology and Head and Neck Surgery | March 2021 | Vol 7 | Issue 3 Page 475
International Journal of Otorhinolaryngology and Head and Neck Surgery
Suligavi SS et al. Int J Otorhinolaryngol Head Neck Surg. 2021 Mar;7(3):475-480
http://www.ijorl.com
pISSN 2454-5929 | eISSN 2454-5937
Original Research Article
Diphtheria: a re-emerging infectious disease
Shashidhar S. Suligavi1, Divya K. Vishwanath1*, Shilpa Gokale2, S. S. Doddamani1
INTRODUCTION
Diphtheria is an infectious disease caused by the exotoxin
produced by Corynebacterium diphtheriae.1 The
organisms are locally invasive and secrete soluble
exotoxins, which can lead to serious consequences
mainly involving the heart muscle and nervous system.
Death can occur due to circulatory failure within the first
10 days of infection.2 If diagnosed early, the infection
responds to appropriate antibiotics and prompt antitoxin
therapy.
The incidence of diphtheria is high in India, especially in
the region of North Karnataka. Factors contributing to
morbidity and mortality include patient’s immunization
status, age at infection, time of infection, clinical type,
and time of intervention.3 An accurate microbiological
diagnosis of diphtheria is crucial and is always regarded
as being complementary to clinical diagnosis because
diphtheria is often confused with other conditions, such
as severe streptococcal sore throat, Vincent’s angina, or
glandular fever.4
ABSTRACT
Background: Diphtheria is a fatal bacterial infection which affects the mucous membranes of oropharyngeal and
nasal cavity, caused by aerobic gram-positive bacteria Corynebacterium diphtheriae. Clinical diphtheria is on the
increase worldwide, mainly affecting developing countries and leading cause of morbidity and mortality. We sought
to understand its presentation among patients and also early intervention of the disease. The objective of the study
was to study the clinico-demographic profile of cases, the relationship between immunization status and clinical
disease, the role of microbiological investigations and to identify complications in diphtheria cases.
Methods: This study is a hospital based observational study from September 2019 - September 2020 at a tertiary care
centre, S.Nijalingappa Medical College and HSK hospital, Bagalkot, Karnataka. The cases were analysed with respect
to demographic details, clinical features, immunization status, microbiological confirmation and complications of
diphtheria cases.
Results: 32 cases were suspected to have diphtheria on clinical examination. The mean age of presentation was 15
years. Fever, sore throat, difficulty in swallowing, neck swelling and pseudomembrane in oral cavity were the
common signs and symptoms. Airway compromise, myocarditis and neurological complications were noted.
Antidiphtheritic serum (ADS) was tried in all 32 cases and 8 cases had adverse reactions. Case fatality rate was
12.5%.
Conclusions: Shifting of occurrence of diphtheria in the age group of >5 years suggest the need to improve and
strengthen the immunization program specially the booster doses.
Keywords: Diphtheria, Antidiphtheritic serum, Albert stain, Myocarditis
1Department of ENT, 2Department of Microbiology, S. Nijalingappa Medical College, Bagalkot, Karnataka, India
Received: 19 December 2020
Revised: 20 January 2021
Accepted: 21 January 2021
*Correspondence:
Dr. Divya K. Vishwanath,
E-mail: divyavishwanathk@gmail.com
Copyright: © the author(s), publisher and licensee Medip Academy. This is an open-access article distributed under
the terms of the Creative Commons Attribution Non-Commercial License, which permits unrestricted non-commercial
use, distribution, and reproduction in any medium, provided the original work is properly cited.
DOI: https://dx.doi.org/10.18203/issn.2454-5929.ijohns20210681

Suligavi SS et al. Int J Otorhinolaryngol Head Neck Surg. 2021 Mar;7(3):475-480
International Journal of Otorhinolaryngology and Head and Neck Surgery | March 2021 | Vol 7 | Issue 3 Page 476
As per World health organization (WHO) data from 2000
to 2016, over 82% of diphtheria cases occurred in
children above 5 years and over 40% occurred in
individuals over 15 years of age.5 This second shift is due
to the waning immunity as the child grows older and is
the reason why regular booster doses are recommended.
India has the maximum number of diphtheria cases in the
world, from 2011 to 2015 India had a total of 18,350
cases of diphtheria.6 Over 40% of cases reported in India
are from individuals over 15 years and about 20% cases
are reported from children under the age of 5 years.7
Aims and objectives
To study the clinico-demographic presentation of
diphtheria cases. To know the immunization status in
diphtheria cases. To know the role of microbiological
investigations in diphtheria cases. To identify the
complications in diphtheria cases.
METHODS
Place of study
S. Nijalingappa Medical College and HSK Hospital.
Study population
All cases with clinical suspicion of diphtheria admitted in
HSK hospital.
Exclusion criteria
Patient who already treated with antibiotic prior throat
swab
Study period
September 2019 to September 2020.
Type of study
Observational case series study.
The case data was analysed with respect to demographic
details, clinical features, pseudomembrane,
microbiological confirmation, complications and
mortality by using openepi software version 2.3.1.
The management of a patient with suspected diphtheria
includes: administration of antidiphtheritic serum (ADS)
as soon as possible after assessing for hypersensitivity to
horse serum, establishing the diagnosis through
appropriate bacterial cultures, administration of
antibiotics and appropriate supportive care – to maintain
an adequate airway in the presence of laryngeal or
extensive pharyngeal membrane and to careful monitor
for cardiac rhythm disturbances or other manifestations
of myocarditis.
The following data were recorded: age, sex, clinical
symptoms and signs. Patients were categorized into four
age groups: <5, 5–20, 20-40 and >40 years.
Immunization status was documented as per the
information given by the parents/ patients. Those who
had received three primary doses at 4-6 weeks interval
starting at 6 weeks of age, followed by booster doses at
18 months and 5 years were recorded as “Immunized”.
Those who had not received any doses and not known
immunization status were considered as “Unimmunized”/
“Unknown status”. Patients who had missed one or more
of the three primary doses or booster doses were included
as “Partially immunized”.
Microbiological investigations
Sample collection
Under aseptic precautions, two throat swabs were taken
from all suspected cases of diphtheria. Swabs should be
collected underneath the pseudomembrane or a piece of
membrane should be removed. One swab was used for
direct microscopy and the other for culture.
Table 1: Paediatric and Adult ADS (antidiphtheritic
serum) dose.
Diphtheria clinical
presentation
ADS dose in IU (# of
ampoules)
Pharyngeal or laryngeal
disease of 2 days
duration
20000-40000 (2-4)
Nasopharyngeal disease
40000-60000 (4-6)
Extensive disease of 3 or
more days duration, or
any patient with diffuse
swelling of neck
80000-100000 (8-10)
Skin lesions only (rare
case)
20000-40000 (2-4)
Direct microscopy
Gram staining and Albert staining of swab smears were
carried out.
Culture and sensitivity
Throat swab was inoculated on blood agar, Mc conkey
agar and Potassium tellurite agar. Growth after 24-72hr
incubation was identified using standard methods.
Toxigenicity testing
The isolates confirmed by biochemical reaction was sent
to CMC vellore for PCR test and it detects the tox-
bearing gene.
All the patients registered under the study were given
appropriate antibiotics and antidiphtheritic serum (ADS).

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International Journal of Otorhinolaryngology and Head and Neck Surgery | March 2021 | Vol 7 | Issue 3 Page 477
Desensitization was done in case of adverse reaction to
ADS such as rashes, hypotension, serum sickness etc.
1 ml (antitoxin) + 9.0 ml saline = 1:10 dilution
1 ml (1:10 dilution) + 9.0 ml saline = 1:100 dilution
0.1 ml (1:10 diution) + 9.9 ml saline = 1:1000 dilution
1 ml (1:100 dilution) + 9 ml saline = 1:1000 dilution.
Table 2: Desensitization to ADS- intravenous route.
Dose
number
Dilution of ADS
in normal saline
Amount of
injection(cc)
1
1:1000
0.1
2
1:1000
0.3
3
1:1000
0.6
4
1:100
0.1
5
1:100
0.3
6
1:100
0.6
7
1:10
0.1
8
1:10
0.3
9
1:10
0.6
10
undiluted
0.1
11
undiluted
0.2
12
undiluted
0.6
13
Undiluted
1.0
Administer at 15 minute intervals.
RESULTS
Out of 32 patients, 2 patients (6.2%) were less than 5
years age group, 24 patients (75%) were between 5-20
years and 6 patients (18.8%) were above 20 years.
Paediatric age group - 21 cases; adults - 11 cases. 16
patients (50%) were males and 16 (50%) were females.
Table 3: Age distribution.
Age group (years)
Number of patients (%)
>5
2 (6.2)
5-20
24 (75)
20-40
5 (15.5)
>40
1 (3.3)
Total
32 (100)
Immunization status
9 (28.1%) were fully immunized and 17 (53.2%) were
partially immunized and 6 (18.7%) were
unimmunized/unknown status.
Bull neck
Out of 32 patients,19(59.3%) presented with bull neck at
presentation.
Table 4: Immunization status.
Immunization status
Number of patients
(%)
Fully immunized
9 (28.1)
Partially immunized
17 (53.2)
Unimmunized/ Unknown
status
6 (18.7)
Total
32 (100)
Table 5: Clinical presentation.
Clinical presentation
Number of patients (%)
Fever
32 (100)
Throat pain
32 (100)
Cough
18 (56.25)
Bull neck swelling
19 (59.3)
Dysphagia
12 (37.5)
Epistaxis
1 (3.12)
Table 6: Microbiological investigations.
Lab parameter
Data (%)
Albert stain
Positive
18 (56.2)
Negative
14 (43.7)
Throat swab culture
Positive
21 (65.6)
Negative
11 (34.3)
Myocarditis
Out of 32 patients,12 (37.5%) developed myocarditis and
4 (12.5%) patients died.
Figure 1: ADS adverse reaction- rashes over legs.
Microbiological investigations
Albert staining was performed in 32 cases of which 18
(56.2%) were positive. Culture was performed in 32 cases
of which 21 were positive (65.6%). In our study 20
isolates were found to be toxigenic and 1 isolates was
contaminated in the transportation and toxigenicity
testing was not done for that isolate.

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International Journal of Otorhinolaryngology and Head and Neck Surgery | March 2021 | Vol 7 | Issue 3 Page 478
Antidiphtheritic serum (ADS) administration
ADS was administered in all 32 cases out of which 8
patients developed ADS reaction and desensitization was
done.
DISCUSSION
In the pre-vaccine era, disease was common among
children less than 5 years of age due to natural boost to
the development and maintenance of immunity in
adolescence and adults. However, after widespread
immunization in children, lack of or inadequate booster
doses in children and adult and decrease incidence of
cutaneous diphtheria, there is shift of age for the
occurrence of disease in older children and adults. Such a
shifting of age of occurrence was observed in developed
and developing countries including India.8
Figure 2: (A): Pseudomembrane over tonsils; (B): Bull
neck.
Figure 3: (A): Albert’s stain: Smear showing green
colored bacilli with bluish black metachromatic
granules arranged in L or V shape. (B): Potassium
tellurite agar - Black colored colonies.
In present study 93.8% patients were more than 5 years
of age (Table 3). However, Meshram et al (55.32%)
Basavaraja et al (74.1%), Bandichhode et al (66.66%)
also reported resurgence of disease in children of more
than 5 years of age.9-11
In present study, males and females were equally affected
giving sex ratio 1:1 which is almost similar to Meshram
et al.9 Similar types of sex distribution was reported by
many authors, while Mehariya et al observed male
predominance below 10 years of age and few studies
noted predominantly female involvement.12
Most of the patients in the present study were from rural
area and lower socioeconomic class, could be because
our hospital mainly serves to socioeconomically deprived
rural population who have poor access to immunization
and health care system. Similarly, high incidence of
disease in rural and lower socioeconomic class were
reported by Mehariya et al and Singh SN et al.12,13
Present immunization coverage in India is around 61%,
with geographical, religion, rural, urban and gender
variation.14 Minimum immunization coverage of 90% in
children and 75% in adult is required to prevent spread of
diphtheria and current coverage rate in Karnataka is
77.6% which remains inadequate.
Factors contributing to the low immunization coverage
include lack of awareness, misconception, avoiding
immunization for trivial reasons, migration, decline in
enthusiasm to routine immunization, unilateral focus on
pulse polio campaign, short supply of vaccine, not
maintaining proper storage of vaccine (cold chain), poor
clinic organization, non-availability of immunization
services on all day of week, not opening a multidose vial
if enough children are not present and delaying or
postponing vaccination in minor childhood illness.15
In present study, 9 (28.1%) patients were fully
immunized, 17 (53.2%) were partially immunized and 6
(18.7%) were unimmunized/unknown status (Table 4).
This denotes unsatisfactory immunization coverage with
DT/DPT (Diphtheria, Pertussis and Tetanus) vaccine in
respective rural area.
The clinical manifestation can vary from mild to severe
to the life threatening depending on immune status of
host and severity of infection. All patients presented with
fever, pseudomembrane in throat and throat pain (100%)
followed by bull neck 19 (59.3%), dysphagia 12 (37.5%),
epistaxis 1 (3.2%) (Table 5). Similar clinical details were
reported by various authors from various parts of India.
Cases of diphtheria were seen throughout the year but
more number of cases was observed during month of
June to September during rainy season. Some authors
reported peak during the winter season and some in rainy
season.11,16
In our study Albert stain was positive in18 cases (56.2%)
and growth in culture was seen in 21cases (65.6%) out of
32 tested (Table 6). False negative reports are seen
because of prior antibiotic use, difficulties in proper
throat swab collection due to lymphadenopathy, bull neck
and delayed transportation of sample to the laboratory.
Low Corynebacterium yield were reported by Basavaraja

Suligavi SS et al. Int J Otorhinolaryngol Head Neck Surg. 2021 Mar;7(3):475-480
International Journal of Otorhinolaryngology and Head and Neck Surgery | March 2021 | Vol 7 | Issue 3 Page 479
et al (16.1%), Bandichhode et al (33.33%), Singh et al
(30.63%).10-12
Myocarditis was the commonest complication 12 (37.5%)
followed by palatal palsy 3 (9.3%), airway obstruction 2
(6.2%). Case fatality rate was 12.5% and cause of death
was cardiopulmonary arrest. In India, incidence of
diphtheric myocarditis varies from 16 to 66% because
toxin-mediated inhibition of protein synthesis is known to
be the essential mechanism of all complications of
diphtheria, especially myocarditis, as the exotoxin is
directly cardiotoxic and can cause DNA fragmentation
and cytolysis by inhibiting elongation factor-2 activity in
protein synthesis leading to tissue damage.9,17,18
Palatal palsy was characterized by a nasal quality of
voice, nasal regurgitation commonly occurring in second
and third week and is the earliest neurological
complication which may occur alone or in association
with other types of paralysis. However in Meshram et al
study, 7 (14.89%) patients had palatal palsy and 4
(8.51%) had polyneuropathy with or without cranial
nerve involvement.9
In present study we analyzed all the cases of diphtheria
hospitalized in S N Medical College from a period of
September 2019 to September 2020. Data collected
showed mean age of affected is 15 years. In present
study, 32 cases (100%) were found to have a pseudo
membrane. Authors consider a pharyngeal membrane that
is difficult to peel off and leaves a bleeding area on the
mucous membrane after an attempt to remove it
pathognomonic for diphtheria. All patients were treated
with anti-diphtheritic serum as recommended by WHO
and UNICEF. The most commonly administered
antibiotics were penicillin or erythromycin following
recommendations of the WHO and UNICEF. Every
patient in present study had a throat swab taken and
65.6% of cases had microbiologically confirmed disease.
There was 12.5% mortality in present study and one
patient was COVID positive. This observation suggests
that complete vaccination is essential in preventing
fatalities. Diphtheria is still not a lost entity as cases are
coming to tertiary care level. Immunization activity needs
to be improved and strengthened in borderline districts as
most of the cases in present study were from rural areas.
Present study showed complete immunization, high index
of suspicion and microbiological confirmatory diagnosis
and early prompt administration of antitoxin prevent the
complication and mortality.
CONCLUSION
Although, we have reduced the incidence of vaccine
preventable diseases by vaccination, diphtheria is still a
matter of concern for public health. Shifting of
occurrence of disease above 5 years age group suggest
the need for completing the immunization schedule,
especially booster doses. A high degree of suspicion and
early initiation of appropriate management as well as
close monitoring for development of complications are
key factors in successful management of individual cases.
Therefore, serious efforts have to be made to increase
immunization coverage and good surveillance systems
ought to be put into place to enable optimum reporting of
disease.
Funding: No funding sources
Conflict of interest: None declared
Ethical approval: The study was approved by the
Institutional Ethics Committee
REFERENCES
1. Dikid T, Jain SK, Sharma A, Kumar A, Narain JP.
Emerging and re-emerging infections in India: an
overview. Indian J Med Res. 2013;138:19-31.
2. Government of India. Annual report 2012. India:
Ministry of Health. 2012.
3. Meera M, Rajarao M. Diphtheria in Andhra
Pradesh-a clinical–epidemiological study. Int J
Infect Dis. 2014;19:74-78.
4. Efstratiou A, Engler KH, Mazurova IK,
Glushkevich T, Vuopio-Varkila J, Popovic, T.
Current approaches to the laboratory diagnosis of
diphtheria. J Infect Dis. 2000;181:S138-45.
5. Clarke KEN. Review of the Epidemiology of
Diphtheria (2000-2016). US Centers for Disease
Control and Prevention.
6. World Health Organization. Diphtheria vaccine:
WHO position paper, August 2017-
Recommendations. Vaccine. 2018;36(2):199-201.
7. World Health Organisation. WHO vaccine
preventable diseases: monitoring system 2017
global summary.
8. Ujwal MV, Pol RR, Vanaki R, Yelamali BC,
Badakali AV. Resurgence of diphtheria in rural
north Karnataka: Clinical profile and
outcome.International journal of Medical
Paediatrics and Oncology. 2019;5(1).
9. Meshram RM, Patil A.Clinical profile and outcome
of diphtheria in central India: a retrospective
observational. Study Int J Contemp Pediatr.
2018;5(4):1600-605.
10. Basavaraja GV, Chebbi PG, Joshi S. Resurgence of
diphtheria: clinical profile and outcome- a
retrospective observational study. Int J of Contemp
Pediatr. 2016;3(1):60-63.
11. Bandichhode ST, Jatti GM, Anita MS, Nandimath
VA. A clinical study of diphtheria cases in a
pediatric population in tertiary care hospital in
western Maharashtra. Indian J Child Health.
2016;3(3):251-53.
12. Maheriya KM, Pathak GH, Chauhan AV, Mehariya
MK, Agrawal PC. Clinical and epidemiological
profile of diphtheria in tertiary care hospital. Gujarat
medical J. 2014;89(2):105-8.
13. Singh SN, Singh A, Chandra S. Clinical profile and
prediction of poor outcome of hospitalized
diphtheria cases in children from Lucknow region of

Suligavi SS et al. Int J Otorhinolaryngol Head Neck Surg. 2021 Mar;7(3):475-480
International Journal of Otorhinolaryngology and Head and Neck Surgery | March 2021 | Vol 7 | Issue 3 Page 480
North India. Clin Epidemiol Glob Health 2014;2:75-
9.
14. Sharma NC, Banavaliker JN, Ranjan R, Kumar R.
Bacteriological and epidemiological characteristics
of diphtheria cases in and around Delhi-a
retrospective study. Indian J Med Res.
2007;126(6):545-52.
15. Bairwa M, Rajput M, Sachdeva S. Modified
Kuppuswamy’sSocioeconimic scale: Social
researcher should include updated income criteria,
2012. Indian J Community Med 2013;38(3):185-86.
16. Siakia L, Nath R, Saikia NJ, Choudhary G, Sarkar
M. A diphtheria outbreak in Assam, India. Southeast
Asian J Trop Med Public Health. 2010;41:647-52.
17. Verghese MJ, Ramakrishnan SS, Saxsena A.
Complete heart block due to diphtheritic
myocarditis in the present era. Ann Pediatr Cardiol.
2013;6:34-8.
18. Jayasri M, Shruti N, Singhi S. Predictors of outcome
in patients with diphtheria receiving intensive care.
Indian Pediatr. 2006;43:155-60.
Cite this article as: Suligavi SS, Vishwanath DK,
Gokale S, Doddamani SS. Diphtheria: a re-emerging
infectious disease. Int J Otorhinolaryngol Head Neck
Surg 2021;7:475-80.