MODULE-4

DIPHTHERIA

Surveillance Guide for

Vaccine-Preventable Diseases
in the WHO South-East Asia Region

September 2017
Surveillance Guide for Vaccine-Preventable Diseases in the WHO South-East Asia Region
ISBN 978-92-9022-569-0

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 TABLE OF CONTENT

Foreword 4
Diphtheria surveillance 7
Introduction 7

Case detection and reporting 7

Case investigation 8

Unique ID of case 8

Specimen collection 9

Case classification 10

Case management 10

Public health intervention 12

Data management 13

Monitoring indicators 14

Feedback mechanism 16

Annexes 17
ANNEX 01- Diphtheria disease 17

ANNEX 02- Core reporting variables 20

Readings 21
SURVEILLANCE GUIDE FOR VACCINE-PREVENTABLE DISEASES IN THE
WHO SOUTH-EAST ASIA REGION

Foreword
Today, we share a collective vision to have the South-East Asia Region free of vaccine-
preventable diseases, where all countries provide equitable access to high-quality, safe,
affordable vaccines and immunization services throughout the life-course.

Overwhelming evidence demonstrates the benefits of immunization as one of the most

successful and cost-effective health interventions ever known. Over the past several
decades, immunization has achieved many milestones, including the eradication of
smallpox, an accomplishment that has been called one of humanity’s greatest triumphs.
Vaccines have saved countless lives, lowered the global incidence of polio by 99% and
reduced illness, disability and death from diphtheria, tetanus, whooping cough, measles,
Haemophilus influenzae type b disease and epidemic meningococcal A meningitis. We
have been able to make the Region free of polio for the last 6 years and eliminate maternal
and neonatal tetanus.

We have vaccines against more than 25 diseases in the present day world, and this has
increased the need for better surveillance against these diseases to control or eliminate
them. As the essence of this subject matter, I would like to highlight that high vaccination
coverage may not necessarily indicate the case-load or disease burden in a population. We
need to look into the surveillance performance as the key indicators to measure progress
towards disease control and/ or elimination.

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A functional vaccine-preventable disease surveillance system is a key part of public health

decision-making in all countries. Thus, there is an urgent need to build on the current
efforts to strengthen vaccine-preventable disease surveillance with the latest state-of-the-
art technologies at subnational and national levels. This will require a substantial and long-
term commitment of human and material resources, usually beginning with a systematic
assessment of the national vaccine preventable diseased (VPD) surveillance system by
working closely in partnership with all related partners and stakeholders.

I hope that this vaccine-preventable diseases surveillance guide will be well translated into
respective national programmes and add to the efforts to have a high-quality surveillance
system for priority vaccine-preventable diseases and help accelerate progress towards
strengthening vaccine-preventable disease surveillance in our Region.

Finally, every individual in our Region deserves our best work. We all agree that every
family, no matter where residing, has the right to all immunization and health services
that are provided by the respective government, in the spirit of universal health coverage
contributing towards Sustainable Development Goals, especially Goal 3 on health.

Dr Poonam Khetrapal Singh

Regional Director, WHO South-East Asia Region

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LIST OF ABBREBIATIONS LIST OF ABBREBIATIONS

ACS active case search ID identity
aP acellular pertussis IM intramuscular
CCID cell culture infectious dose NPA nasopharyngeal aspirate
CFR case fatality rate NPS nasopharyngeal swab
CHW community health worker NRL national reference laboratory
CI confidence interval outbreak response
ORI
CIF case investigation form immunization
CRF case report form PFU plaque forming units
diphtheria pertussis tetanus reverse transcriptase
DPT RT-PCR
vaccine polymerase chain reaction
DT/dT/ SEAR South-East Asia Region
diphtheria tetanus
Td South-East Asia Regional
SEARO
third dose of diphtheria Office
DTP3
pertussis tetanus vaccine supplementary
SIA
EIA enzyme immunoassay immunization activities
enzymelinked immuno- standard operating
ELISA SOP
sorbent assay procedure
Expanded Programme on tetanus diphtheria and
EPI Tdap
Immunization acellular pertussis
gm gram United States Center for
US CDC
HQ headquarters (WHO) Disease Control, Atlanta

International Classification VPD vaccine preventable disease

ICD WHO World Health Organization
of Diseases
IU international unit

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Diphtheria surveillance
1. Introduction
Diphtheria is a vaccine-preventable disease that has the potential for epidemics. Recent
epidemics have highlighted the need for adequate surveillance and epidemic preparedness.
Diphtheria surveillance would provide region-specific epidemiological data to be able to
formulate appropriate control strategies. Surveillance data can be used to monitor levels
of immunization coverage (target >90%) and disease as a measure of the impact of
immunization programmes.

2. Case detection and reporting

2.1 Case definition
A suspected case of diphtheria is defined as:

An illness of upper respiratory tract characterized by the following:

zz laryngitis or pharyngitis or tonsillitis;

AND
zz adherent membranes of tonsils, pharynx and/or nose.

2.2 Description of case definition

Pharyngitis and tonsillitis: fever with pain and redness of the throat and/or tonsils.

Laryngitis: often presents as hoarseness of voice and cough.

Membrane: initially isolated spots of grey or white exudate appear in tonsillar and
pharyngeal area. These spots often coalesce within a day to form a confluent sharply
demarcated pseudo membrane that becomes progressively thicker, more tightly adherent
to the underlying tissue and darker grey in colour. Dislodging the membrane is likely to
cause bleeding. Unlike the exudate in streptococcal pharyngitis, the diphtheritic pseudo
membrane often extends beyond the margin of the tonsils onto the tonsillar pillars, palate
or uvula.

2.3 Other associated signs and symptoms

The other clinical features that are associated with probability of diphtheria infections
are dysphagia, difficulty in breathing, headache, change of voice (hoarseness or thick
speech), nasal regurgitation and serosanguineous nasal discharge. Some patients may
also present with ‘bull neck’ diphtheria where there is massive cervical lymphadenopathy
with edematous swelling of the submandibular region and surrounding areas. Patients

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of diphtheria may also present with systemic manifestations of diphtheria toxin, such
as myocarditis and polyneuritis. Bulbar dysfunction may present as palatal, pharyngeal,
facial, laryngeal, oculomotor or ciliary paralysis.

2.4 Date of onset

The date of onset for diphtheria should be considered as date of onset of sore throat with
fever.

2.5 Case reporting

The reporting network for diphtheria surveillance should consist of reporting sites such as:

zz medical colleges, district hospitals, subdistrict government health facilities

zz private health facilities where cases of diphtheria are most likely to visit and
personnel should be trained to identify such cases.
All reporting sites should immediately report a suspected case of diphtheria by any
available mode of communication to the concerned health/surveillance authority. The
minimum information required to report a case is patient identification and contact details.

A mechanism of sending weekly reports containing basic information of diphtheria

cases should be established. When no cases are seen in a week, a weekly report
should be sent nevertheless, specifying that ‘zero’ cases were seen. This is called
‘zero reporting’ or ‘nil reporting’. Nil reporting gives confidence that the surveillance
system is operational even if no disease is identified.

3. Case investigation
Trained health staff should be responsible for case investigation preferably within 48 hours
of case reporting. A reported case is investigated using standard Case Investigation Form
(CIF). The CIF should capture certain core variables as given in Annex 02.

4. Unique ID of case
A unique case identification number should be given to each suspected case. This
case number should begin with one or more three-letter combinations to designate the
geographic location, followed by the year and the case number. All communications and
forms related to the case should cite the unique case identification number.

DTH- THA-BKK-16-001: BKK – Province code

DTH- Suspected diphtheria code 16 – Year of onset

THA – Country code 001 – Serial number of diphtheria

case of the province

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5. Specimen collection
Window period from onset 2 days–4 weeks

Type of specimen Throat swab or pieces of membrane

Number 1

Transport media Silica gel /Amies transport media

Storage and transportation 2–8 ºC

5.1 Throat swab sample collection

zz Use any throat swab made up of cotton, polyester or Dacron.
zz Label the specimen tube with the unique identification code, patient’s name and
date of collection.
zz Check the expiry date on the tube and transport media to ensure acceptability of
the material to be used for sample collection.
zz Swab the inflamed area of tonsils, and posterior pharynx. If membrane is visible,
then rub the swab beneath the membrane.
zz Piece of membrane can also be collected on the swab.
zz Immediately place the throat swab sample in the silica gel sachet/Amies transport
media.
zz Procedure to use silica gel sachet:
zz cut open the silica gel packet from the top
zz ensure that the colour of granules inside the packet is blue. If the colour of
granules has turned pink, then it is not fit for use. Open another sachet.
zz now place the loaded throat swab inside the silica gel sachet as shown in the
diagram below
zz fold the top end and secure the opening with cello tape.

Figure. Packing throat swab in silica gel sachet for transportation to laboratory

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zz Procedure to use Amies transport media:

zz immediately insert the swab into the bottom of the media
zz if capped swab, then throw the cap of the tube
zz if uncapped swab, then cut the shaft of the swab to fit into the tube and cap
it securely.
zz Ship the sample to the laboratory at 4 ºC.

6. Case classification
Laboratory confirmed: A case that meets the clinical case definition where samples are
collected and laboratory results are positive for the suspected disease.

Epidemiologically linked: A case that meets the clinical case definition and is
epidemiologically linked to a laboratory-confirmed case.

Clinically compatible: A case that meets the clinical case definition but is neither
laboratory-confirmed nor epidemiologically linked.

Discarded: A case that does not meet the clinical or epidemiological link, or does not meet
case definition on case investigation.

7. Case management
Diphtheria case management has three main components:

7.1 Administration of diphtheria antitoxin

The mainstay of treatment is intramuscular or intravenous administration of diphtheria
antitoxin (a hyper immune anti-serum produced in horses) to neutralize circulating toxin
before it reaches target cells. Early administration after testing for hypersensitivity is
essential as it can neutralize only free toxin.

The minimum therapeutic dose is unknown; recommendations are based on clinical

experience and the assumption that duration of disease and extent of membrane formation
indicate the toxin burden. As a guide, doses range from 10 000 units in tonsillar diphtheria
of short duration, to 40 000–60 000 units in pharyngeal disease, to 100 000–150 000
units in extensive disease of 3 or more days’ duration.

Recommendations differ on the route of administration (intramuscular vs intravenous), but

in severe disease at least some of the dose should be administered intravenously.

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7.2 Antibiotic therapy

Antibiotics have no impact on already established toxin induced lesions but limit further
bacterial growth and the duration of corynebacterial carriage that often persists even after
clinical recovery. Penicillin, 0.6–1.2 gm every 6 hours, or erythromycin, 0.5 gm every
6 hours, is recommended. Antibiotic therapy should be continued for 14 days.

7.3 Supportive measures

Supportive management of complications, with particular attention to the airway and
cardiac manifestations are an important part of case management. Patients should be
nursed in strict isolation and should be attended by staff with documented immunization
histories.

Early in the illness, respiratory and cardiac complications are the greatest threat. These
can be minimized by close monitoring (including regular ECG) and early intervention (e.g.
pacing for conduction disturbances, drugs for arrhythmias). Some experts recommend
tracheostomy or intubation at an early stage to ensure continued patency of a compromised
or potentially compromised airway, and mechanical removal of any tracheobronchial
membrane.

7.4 Immunization
Diphtheria infection does not always confer protective immunity. Individuals recovering
from the disease should therefore complete active immunization by receiving an age-
appropriate booster dose of diphtheria toxoid, or a full primary series if indicated during
convalescence.

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8. Public health intervention

Public health intervention is initiated in response to increased number of suspected cases
of Diphtheria than reported from previous years. However, countries are expected to review
the surveillance data and the disease epidemiology, vaccination coverage and initiate
public health response .

8.1 Active case search in community

Active case search (ACS) in response to identification of diphtheria cases in the
community is very important as there is a probability of finding additional cases among
contacts of diphtheria cases. Besides conducting active case search in households and
neighbourhood, the workplace or school contacts should also be actively assessed for
the illness. A thorough ACS in the community will identify any clustering of cases, and
timely interventions have the potential to curtail the outbreaks and reduce case morbidity
and mortality. An assessment of immunization status of the community should also be
conducted during active case search in the community. Attempts should be made to
conduct active case search soon after identification of a suspected case preferably within
48 hours of case confirmation.

8.2 Prophylaxis
Close contacts, especially household contacts who have lived under the same roof during
the five days prior to the onset of the disease, should receive antibiotics under direct
supervision to the extent possible—benzathine penicillin G (600 000 units for persons
younger than 7 years old and 1 200 000 units for those 7 years old and older) or a 7- to
10-day course of oral erythromycin (40 mg/kg/day for children and 1 g/day for adults).

Management of close contacts with respiratory symptoms

Prophylaxis
Age Immunization
Antibiotic Dose Route Duration
Penicillin G
600 000 units IM Single dose
benzathine
<6 years old DPT or
40 mg/kg in 4
Erythromycin PO 7–10 days
divided doses
Penicillin G
1.2 million units IM Single dose
benzathine
DT/Td/Tdap as
>6 years old or
per availability
1g/day in 4 divided
Erythromycin PO 7–10 days
doses
Note : Azithromycin (10 mg/kg body weight), a long acting oral antibiotic, is also being used as single daily
dose for seven due to its better compliance , however there are no enough evidence on the duration of the
use of Azithromycin.

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8.3 Immunization of patient and other contacts

During convalescence, every patient with clinical diphtheria should receive an age-
appropriate booster dose of diphtheria toxoid, or a full primary series if indicated.

The contacts and susceptible population identified during ACS should be given a dose of
diphtheria containing vaccine appropriate to their age. All children less than 6 years of
age should be immunized by a single dose of diphtheria containing vaccine, such as DPT,
if they have not received such vaccine in the previous 5 years. Persons aged more than
6 years can be given DT, Td (Tetanus with low-dose diphtheria antigen) or Tdap (Tetanus
with low-dose diphtheria and acellular pertussis antigens) as per availability because of
the adverse effects of pertussis component in DPT.

9. Data management
Data collection
Computer technology has greatly facilitated collection and analysis of surveillance data
and should preferably be used in diphtheria surveillance. However, even if the information
system is manual, it should cover case tracking and reporting. Missing or inaccurate data
may limit the usefulness of any analysis. Erroneous or incomplete data do not provide
reliable information so it should be ensured that basic data are captured carefully.

Data analysis
Analysis should be performed at regular intervals using a standard approach. However,
skilful interpretation of data is needed to determine any aberrations and to develop a
focused action plan.

zz Time analysis: Date of onset of symptom is the most critical information on which
time analysis can be based upon. Basic analysis by time can be conducted in
several different ways to detect changes in disease incidence.
zz comparing the number of cases occurring in the current week with the
numbers in the preceding 4 weeks
zz comparing the number of cases during the current period (month, quarter)
with the number reported during the same period in previous years
zz comparing the occurrence of disease by year to analyse long-term (secular)
trends in a disease
zz clustering of cases over the specified period (weeks, months) should
immediately raise an alarm
zz no cases reported during high transmission period should trigger an
appropriate response for verification of information.

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zz Place analysis: Place where the case was residing at the time of onset of
symptoms and during incubation period must be determined for all cases.
Analyse disease occurrence and pattern by time and place simultaneously.
Place analysis is best displayed by plotting the location of cases on a local
map over a specified period of time. Any spatial clustering of cases or silent
areas will immediately become visible to guide interventions. Repeated
occurrence of cases in a particular geographical area over many years helps
in identifying high-risk areas for disease transmission.

Calculation of incidence of reported diphtheria cases

Total number of cases in 1 year in specified

Incidence of reported
geographical area
diphtheria cases = X 100,000
Total population of specified geographical area

This will help in analysing and comparing disease trends over time and place; and identify
high-risk areas.

Person analysis: Analysing surveillance data by characteristics of affected person is also

helpful. Age, sex and religion are the most basic variables to be studied. Other variables,
such as vaccination status, hospitalization, associated risk factors for specific disease,
such as recent travel, exposure in school or work place should also be looked into for
targeted interventions.

10. Monitoring indicators

The various monitoring indicators recommended for diphtheria surveillance are as follows:

1. Proportion of cases with timely notification: This indicator determines the speed
and quality of a surveillance system. Timely notification of suspected cases has many
advantages: sample collection during early phase of disease increases the probability
of laboratory confirmation; early detection of impending outbreaks, case management
and timely public health interventions can reduce the morbidity and mortality rates.
In most cases of diphtheria, membrane appears in 2–4 days after onset and due to
severity of symptoms, there is more likelihood that patients seek early medical care.
The cases reported within 48 hours of disease onset should be considered as timely
notified.

Total number of suspected diphtheria cases reported within 48 hours of onset

X 100
Total number of suspected diphtheria cases

Target of at least 80% timely notification should be achieved. The reasons for delayed
notification should be analysed. These could be due to lack of awareness among health-care
providers, lack of understanding of reporting protocols, reporting network not tuned to pick
early cases or communication channels provided for notification are not free or updated.

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2. Proportion of cases with timely investigation: An investigation is considered timely if

it is done within 48 hours of notification. It is calculated as:

Total number of cases investigated within 48 hours of notification

X 100
Total number of reported cases

Target of timely investigation is at least 90%.

3. Proportion of cases with adequate sample collection: This indicator is

calculated as:

Total number of cases in which adequate sample is collected

X 100
Total number of diphtheria cases

The target of collecting samples should be in at least 80% of suspected cases

of diphtheria.

If large proportion of cases with no samples has been observed, the reasons could be
multiple: late notification of cases outside the window period of sample collection, health-
care provider not confident in sample collection procedure, lack of logistics, death, refusals
and sample spoiled during storage and shipment.

4. Proportion of timely active case search in community: This indicator will help to
monitor the preparedness of the government health system to build up a community
response. It is calculated as:

Total number of ACS conducted within 48 hours of case confirmation

X 100
Total number of diphtheria cases

Target of at least 80% should be achieved for this indicator. Monitoring of this indicator
will promote timely ACS in the community and hence early identification of impending
outbreaks. This indicator will also help in identifying the areas of complacency or areas
requiring support or resources from the district level.

5. Timeliness of weekly reporting: This indicator determines the proportion of reporting

units whose weekly reports are received at the district on time as agreed by national
programme. It is calculated as:

Number of weekly reports received on time

X 100
Total number of reporting units

Target of at least 80% timeliness of weekly reporting should be achieved. This indicator is
an important tool to measure alertness of the reporting network.

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6. Completeness of weekly reporting: This indicator determines the proportion of reporting

units whose weekly reports have been received at the district. It is calculated as:

Number of weekly reports received

X 100
Total number of reporting units

The numerator includes all weekly reports received at the district before next week
irrespective of their timeliness. Target of at least 90% completeness of weekly reporting
should be achieved.

11. Feedback mechanism

Feedback in the form of periodic bulletins and mails that may be combined bulletins for
other vaccine-preventable diseases can be shared. Countries should notify WHO-SEARO
about diphtheria cases and line lists in a weekly frequency.

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Annexes
ANNEX 01- Diphtheria disease
Aetiology
Diphtheria is a bacterial disease caused by exotoxin producing Corynebacterium
diphtheriae. C. diphtheriae is a slender, club-shaped, gram positive bacillus that exists
in four biotypes (gravis, mitis, belfanti and intermedius). Rarely, other Corynebacterium
species (C. ulcerans or C. pseudotuberculosis) may produce diphtheria toxin and may
cause classic respiratory diphtheria-like illness.

Pathogenesis
The pathogenesis of diphtheria involves bacterial exotoxin as well as cell wall components,
such as the O- and K- antigens. The heat-stable O-antigen is common to all corynebacteria.
The heat-labile K-antigen is variable and permits differentiation between individual strains.
While the K-antigen is important for mucosal attachment, invasiveness is facilitated by the
cord factor, a toxic glycolipid. The most important virulence factor of C. diphtheriae is the
exotoxin, a bacteriophage mediated, highly conserved polypeptide encoded by the bacterial
chromosome. Outside the host cell, the exotoxin is relatively inactive, but following cellular
attachment and internalization by its non-toxic fragment B, a highly toxic fragment (A) is
detached that kills cells through inhibition of cellular protein synthesis. Diphtheria exotoxin
causes both local and systemic cell destruction.

Transmission
Transmission is most often person-to-person spread from the respiratory tract through
droplets or direct contact with respiratory secretions. Rarely, transmission may occur from
skin lesions or articles soiled with discharges from lesions of infected persons (fomites). The
incubation period of diphtheria is 1–5 days (range, 1–10 days).

A person is infectious as long as virulent bacilli are present in discharges and lesions. The
period of infectivity is variable, but organisms usually persist 2 weeks, and seldom more
than 4 weeks, without antibiotics. Chronic carriers may shed organisms for 6 months or
more. Effective antibiotic therapy promptly terminates shedding.

Reservoir
Humans are the only known reservoir of C. diphtheriae. In most cases, transmission of C.
diphtheriae to susceptible individuals results in transient pharyngeal carriage rather than in
disease. During outbreaks, high percentages of children are found to be transient carriers.

Occurrence
The disease has almost disappeared from the developed countries as a result of high
immunization coverage. Continued foci of epidemicity and endemicity exist in some parts

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of the world with low-immunization coverage, including the Indian subcontinent and south-
East Asia. In WHO-SEAR, the total cases of diphtheria reported in 2014 were 7647 and
in 2015, total cases were 2737. However, in absence of a robust surveillance system this
might be underreporting.

20 100
18 90
Number of cases in thousands

16 80
14 70

% coverage
12 60
10 50
8 40
6 30
4 20
2 10
0 0
2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016

Diphtheria DTP3 Coverage

Figure:. Diphtheria Cases and DTP3 coverage estimates SEAR, 2001–2015
Source: WHO vaccine-preventable disease: monitoring system 2016, and WHO-UNICEF coverage estimates 2016.

Clinical features and complications

Most infections are asymptomatic or run a relatively mild clinical course. The onset of
respiratory diphtheria is relatively slow and characterized by moderate fever and a mild
exudative pharyngitis leading to sore throat and difficulty in swallowing. The exudate
organizes into a tough, asymmetric, greyish-white pseudo membrane over the tonsils, the
pharynx or larynx. The pseudo membranes are strongly attached to the underlying tissue
and attempts to dislodge usually result in bleeding. They may extend into the nasal cavity
and the larynx causing obstruction of the airways. Laryngeal diphtheria, which sometimes
occurs even without pharyngeal involvement, is a medical emergency that often requires
tracheostomy. Accompanying inflammation of the cervical lymph nodes and surrounding
soft-tissue swelling of the neck give rise to a ‘bull-neck’ appearance and are signs of moderate
to severe disease.

Exotoxin absorbed from the mucosal (or cutaneous) lesions may account for toxic damage to
organs, such as the myocardium, kidneys and nervous system. The extent of toxin absorption
depends largely on the extent of the mucosal lesions. The following WHO-defined clinical
conditions are associated with increasing risk of toxin-induced systemic disease:

i. catarrhal - erythema of pharynx, no membranes;

ii. follicular - patches of exudates over pharynx and the tonsils;
iii. spreading - membranes covering the tonsils and posterior pharynx;
iv. combined - more than one anatomical site involved, for example throat and skin.

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Most complications of diphtheria, including death, are attributable to effects of the toxin.
The most frequent complications of diphtheria are myocarditis and neuritis. Neuritis may
involve bulbar dysfunction, which includes palatal, pharyngeal, facial and oculomotor
paralysis and may also progress to peripheral neuropathy. Pneumonia occurs in more than
50% of fatal cases of diphtheria. Other complications include otitis media and respiratory
insufficiency due to airway obstruction, especially in infants.

Laboratory diagnosis
Gram stain: Diagnosis of diphtheria based upon direct microscopy of smear is not advisable
as false positives and false negatives may occur.

Culture: The clinical specimen for culture should be taken from nose, throat or diphtheritic
membrane. C. diphtheriae requires special culture media containing tellurite to grow and
forms grey to black colonies. The four biotypes (intermedius, belfanti, mitis or gravis)
of C. diphtheriae can be distinguished by colonial morphology and biotyping. Certain
biochemical tests are required to differentiate pathogenic C. diphtheriae from corynebactria
of the normal flora (diphtheroids) in the throat.

Toxigenicity test: All isolates of C. diphtheriae should be subjected to toxigenicity testing

to determine the production of diphtheria toxin. Toxigenicity testing can be done by Elek
test or PCR. Elek test is based on the double diffusion of diphtheria toxin and antitoxin in
an agar medium. The production of diphtheria toxin can be detected within 18 to 48 hours
by the formation of a toxin-antitoxin precipitin band in the agar. Demonstration of toxin
production confirms a case as diphtheria.

Polymerase chain reaction (PCR) testing: Isolation of C. diphtheriae may not always
be possible because many patients will have received antibiotics before a diagnosis of
diphtheria is considered. PCR allows for detection of the regulatory gene for toxin production
(dtxR) and the diphtheria toxin gene (tox) in nonviable organisms. Additionally, primary
isolates can also be screened rapidly for the presence of tox gene by PCR. Some strains
of C. diphtheriae carry inactive toxin gene giving rise to false positive results in this test.

Immunization
Diphtheria toxoid: A modified bacterial toxin that induces protective antitoxin. The
conventional steps of vaccine production include the growth of toxin producing C.
diphtheriae in liquid media, sterilization of exotoxin-containing supernatant, formalin
induced conversion of toxin to toxoid, adsorption to aluminum salt and addition of
thiomersal as preservative in multi-dose vial. The resulting product is tested for potency,
toxicity and sterility. As per WHO requirements, the potency of diphtheria vaccine should
be at least 30 IU per single human dose.

19
SURVEILLANCE GUIDE FOR VACCINE-PREVENTABLE DISEASES IN THE
WHO SOUTH-EAST ASIA REGION

ANNEX 02- Core reporting variables

Variable
Description Field Type Remark
Name
COUNTRY Country of Report Text (ISO3 code) Must be reported
Case identification
CaseID Defined by country Must be reported
number
Province Province Defined by country Must be reported
District District Defined by country Must be reported
Text (Option: DIP; PER;
Agent Agent
NNT; AES;
SEX Sex Text (option: F; M; U) Must be reported
Date: Must be reported (if Age
DOB Date of birth
(format: (DD-MM-YYYY) year/month is not provided)
Must be reported (if DOB is
not provided)
Age in Year
AgeYear Number (format: ####) if <12 months of age,
(completed)
put zero
99=Unknown age
Date of notification
Date: DNOT>=DONSET
DNOT to public health
(format: (DD-MM-YYYY) DNOT>=DOB
system
DOI>=DONSET
Date of Date:
DOI DOI>=DOB
investigation (format: (DD-MM-YYYY)
DOI>=DNOT
Number of vaccine
DosesVac doses received for Number (format: ##) 99=Unknown
the suspect agent
Date of last
Date:
DateLastVac vaccination for the
(format: (DD-MM-YYYY)
suspect agent
Must be reported
Date of onset Date:
DONSET DONSET>=DOB
symptoms (format: (DD-MM-YYYY)
Cannot be future date
Type of laboratory
TypeTest
method
Laboratory test
LabResult
result
Text(Option: Lab confirmed;
Final classification
Classification Epi linked; Compatible;
of case
Rejected)
Text (Option: Death,
Outcome Follow- up
Survival)
Comments Any comments Text

20
 DIPHTHERIA

Readings
1. World Health Organization. Diphtheria Vaccine; WHO position paper. Weekly
Epidemiological Record; 2016. p. 349-364.
2. World Health Organization. Diphtheria Vaccine; WHO position paper. Weekly
Epidemiological Record; 2006. p. 24-32.
3. Tiwari T.S.P.; Manual for the surveillance of Vaccine-Preventable Diseases, 5th
edition, Chapter 1: Diphtheria. Roush S.W.; McIntyre L.; Baldy L.M.; editors. Centers
for Disease Control and Prevention, Atlanta, GA: Centers for Disease Control and
Prevention; 2011.
4. Efstratiou, A.; Engler, K.H.; Mazurova, I.K.; Glushkevich, T.; Vuopio-Varkila, J.;
Popovic, T. Current approaches to the laboratory diagnosis of diphtheria. J Infect Dis.
2000 Feb;181 Suppl 1:S138-145.
5. Sangal L.; Joshi S.; Rathee M.; Surveillance for Vaccine Preventable Diseases:
Diphtheria, Pertussis and Neonatal Tetanus; Field Guide, India. WHO Country Office
India 2014 [Working Draft; unpublished]
6. WHO-recommended standards for surveillance of selected vaccine-preventable
diseases WHO/V&B/03.01. 2003 [Revised 2008]. Available online: http://apps.who.
int/iris/bitstream/10665/68334/1/WHO_V-B_03.01_eng.pdf
7. Sangal L, Joshi S, Anandan S, Balaji V, Johnson J, Satapathy A, et al. Resurgence
of Diphtheria in North Kerala, India, 2016: Laboratory Supported Case-Based
Surveillance Outcomes. Frontiers in Public Health. 2017 2017-August-30;5(218).
English.
8. Sein C, Tiwari T, Macneil A, Wannemuehler K, Soulaphy C, Souliphone P, et al.
Diphtheria outbreak in Lao People’s Democratic Republic, 2012-2013. Vaccine.
2016 Aug 5;34(36):4321-6. PubMed PMID: 27422343. Epub 2016/07/17. Eng.
9. Sharma N, Banavaliker J, Ranjan R, Kumar R. Bacteriological & epidemiological
characteristics of diphtheria cases in & around Delhi -a retrospective study2007
December 1, 2007. 545-52 p.
10. Veeraraghavan B, Anandan S, Rajamani Sekar SK, Gopi R, Devanga Ragupathi NK,
Ramesh S, et al. First Report on the Draft Genome Sequences of Corynebacterium
diphtheriae Isolates from India. Genome Announc. 2016 Nov 23;4(6). PubMed
PMID: 27881543. PMCID: PMC5122685.
11. Murhekar M. Epidemiology of Diphtheria in India, 1996-2016: Implications for
Prevention and Control. Am J Trop Med Hyg. 2017 Aug;97(2):313-8. PubMed PMID:
28722581. Epub 2017/07/19. eng.

21
Acknowledgement
The document was produced under the strategic guidance of the Regional Director, Dr Poonam Khetrapal
Singh; Director, Programme Management, Dr Arun Thapa, and Dr Pem Namgyal, Director FGL
WHO SEARO. The entire process was overseen by Dr Nihal Abeysinghe and Dr Sunil Bahl.
Dr Sudhir Khanal, WHO SEARO, coordinated the development of the technical document in
collaboration with a team of international experts, Dr Jacob T John from India, Dr Naresh Pratap K
C from Nepal, Dr Sujeeva Amarasena from Sri Lanka and Dr Kumnuan Ungchusak from Thailand
along with WHO Consultant Dr Sudhir Joshi who were crucial in the conceptualizing and initial
drafting of the document.
This document also benefited from the dedication, support and expertise of all the participants of the
regional workshop on surveillance standards for measles, rubella and priority vaccine-preventable
diseases in September 2016 at Kathmandu, Nepal, which included National EPI Programme
Managers from Member States as well as a number of WHO and UNICEF country office staff and
external collaborators.
The IVD SEARO team wishes to thank all mentioned above, including the following contributors
whose expert review and guidance made this document possible:
WHO HQ staff: Dr. Minal Patel and Mr. Antoni Sebastien reviewed the draft surveillance standard
document and provided technical inputs.
WHO-SEARO: Dr. Jayantha Liyanage, Dr. Sigrun Roesel, Ms. Sirima Pattamadilok, Dr. Pushpa
Ranjan Wijesinghe, Ms. Uttara Aggarwal, Mr. Tika Sedai and Dr. Aarti Garg reviewed the draft and
provided necessary inputs, including drafting of selected sections.
US CDC: Dr. Jim Goodson, Dr. Heather Scobie and Dr. Susan Wang provided inputs to the various
sections of the document and final draft of the surveillance standard document.
The IVD team would also like to acknowledge the support provided by the entire IVD team for the
administrative work, the R-DOC team, the building management, ICT services, travel unit and all
related staff who played a crucial role at the hind side in the smooth preparation of this report.
WHO-SEARO
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Tel: +91 11 23370804, Fax: +91 11 23370251
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