Review: Tetanus, diphtheria and pertussis: ancient diseases in modern times
Tetanus, diphtheria and pertussis:
ancient diseases in modern times
Johnston L, BPharm
Amayeza Info Centre
Introduction
Pathophysiology
Vaccination is widely considered to be one of the greatest
medical achievements of modern civilisation. Yet,
despite this life-saving innovation, ancient diseases such
as tetanus, diphtheria and pertussis still exist in the 21st
century. In this article, we review the historical facts,
microbiology, pathogenesis, diagnosis, treatment and
prevention of tetanus, diphtheria and pertussis in South
Africa.
Most cases of tetanus result from lacerations, or small
puncture wounds, which become contaminated with
C. tetani spores that germinate and produce toxin.4 The
incubation period from the time of injury to the onset of
symptoms may vary from a few days to weeks, depending
on the site of injury and the infectious dose. Peripheral
wounds generally have a longer incubation period.3
The spores germinate under anaerobic conditions, and
release a neurotoxin called tetanospasmin. Tetanospasmin
is distributed via the lymphatic and vascular circulations
to the end-plates of all nerves, where it then enters the
nervous system peripherally at the myoneural junction,
and is then transported into neurons of the central
nervous system.2
Tetanus
Synonyms for tetanus are lockjaw, klem-in-die-kaak
(Afrikaans) and umhlathingqi (Zulu). Tetanus is a
potentially fatal disease caused by an exotoxin produced
by Clostridium tetani. The disease is characterised by an
acute onset of hypertonia, painful muscular contractions
and generalised muscle spasms. The muscle stiffness
usually involves the neck and jaw, and then becomes
generalised.1,2
Once the toxin becomes fixed to neurons, it can’t be
neutralised by antitoxin, and the neurons become
incapable of neurotransmitter release, leading to the
characteristic symptoms of tetanus. Recovery of nerve
function from tetanus toxins requires development of new
nerve terminals and formation of new synapses.2
History
Records dating as far back as the fifth century BC have
been found to contain descriptions of tetanus. The tetanus
bacterium was discovered in 1884, and later isolated by
Japanese bacteriologist, Shibasaburo Kitasato, in 1889.
Kitasato isolated the bacteria from an infected person,
showed that they caused disease when injected into
animals, and reported that the toxin could be neutralised
by specific antibodies. The protective effect of passively
transferred antitoxin was demonstrated in 1897, and
passive immunisation was later used in humans for
treatment and prophylaxis during World War I. Tetanus
toxoid (TT) was developed in 1924.2
Four types of tetanus have been described:
• Generalised tetanus is the most common form, and
often presents with a descending pattern. Toxin passes
into the blood and lymph, followed by absorption
by motor nerves. Characteristic lockjaw and facial
spasms are followed by generalised painful spasms,
which may be associated with fever and other systemic
symptoms. During spasms, the airway may become
obstructed, resulting in respiratory failure. Spasms
are often initiated by external stimuli which may be
as insignificant as the sound of footsteps or a flash of
light.3,4,5
• In localised tetanus, toxins travel along peripheral
nerves, causing disease confined to the extremities.
Localised tetanus usually resolves spontaneously, but
may last for months.3
• Cephalic tetanus is a rare form of tetanus, which results
Clostridium tetani
C. tenani is an anaerobic Gram-positive rod that forms
terminal spores. These resilient, virtually indestructible
spores are ever present, and can be found in soil, house
dust, animal intestines and human faeces.1,3
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2011;15(2)
Review: Tetanus, diphtheria and pertussis: ancient diseases in modern times
TableI: Tetanus, diphtheria and pertussis vaccinations that are
available in South Africa
from head wounds or otitis media. Patients present with
facial nerve palsies. The infection may be localised, or
may become generalised.3,6
• Neonatal tetanus (NNT) is a major cause of infant
mortality in developing countries. Infection results from
contamination of the umbilical cord during unsanitary
delivery conditions, as well as a lack of maternal
vaccination.6 A review of all hospital admissions in the
Mpumalanga province between 1996-2000, on the case
definition for NNT, found that most cases occurred as
a result of the cultural practice of applying cow dung
or rat faeces to the umbilical stump in the neonatal
period.7 This form of tetanus has a poor prognosis.6
Paediatric formulations
TT: Tetavax®
TT: Tetavax®
Td: Diftavax® ( for use in
persons six years and over)
Only available in public
sector
DTaP: Infanrix®
Tdap:IPV: Adacel® Quadra
(for use in persons six years
and over)
DTaP:HepB:IPV/HiB:
Infanrix® Hexa
DTaP:IPV/HiB: Pentaxim®
DTwP:HepB: Tritanrix®
In 1989, the World Health Assembly called for global
NNT elimination. Elimination is defined as less than
one case of NNT per 1 000 live births in every district of
every country.8 South Africa has achieved and maintained
this goal since 2002.8 (The number of cases of NNT has
dropped from 177 cases in 1988, to a range of six to ten
cases between 1998-2006).9
TT (Tetanus toxoid): Tetavax®, Td (tetanus, diphtheria): Diftavax®, Tdap
(tetanus, diphtheria, acellular pertussis):IPV(inactivated polio): Adacel®
Quadra, DTaP (diphtheria, tetanus, acellular pertussis): Infranrix®,
DTaP (diphtheria, tetanus, acellular pertussis):HepB (Hepatitis B):IPV
(inactivated polio)/HiB (Haemophilus influenzae type B): Infranrix
Hexa®, DTaP (diphtheria, tetanus, acellular pertussis):IPV ((inactivated
polio)/HiB ((Haemophilus influenzae type B): Pentaxim®, DTwP
(diphtheria, tetanus, whole-cell pertussis):HepB (hepatitis B): Tritanrix®
Diagnosis
Diagnosis is clinical, and does not rely on bacteriological
confirmation.1
and again at 18 months, according to the Expanded
Programme on Immunisation (EPI) Schedule. A preschool
booster is administered at the age of six years, followed
by a recently introduced 12-year booster. It is hoped that
if this schedule is maintained, it will not be necessary to
vaccinate pregnant women (in order to prevent neonatal
tetanus) in the future.10
Treatment
All wounds should be cleaned, and foreign or necrotic
tissue removed. Supportive therapy may include
ventilatory support and drugs that treat rigidity,
reflex muscle spasms and tetanic seizures.1,6 Tetanus
immune globulin (TIG) is recommended for persons
with tetanus. It can only help remove unbound tetanus
toxin, possibly shortening the course of disease and
reducing its severity.1,6 Theoretically, antibiotics
such as metronidazole and penicillin G may prevent
multiplication of C. tetani, halting the production
of toxin. However, efficacy is questionable.2 Tetanus
disease does not confer immunity. Persons recovering
from tetanus should complete or commence active
immunisation against tetanus.1
After a primary series of four properly spaced TT vaccines
in children under seven years of age, or three properly
spaced TT vaccines in persons over seven years of age,
almost all recipients will achieve antitoxin levels greater
than the protective level of 0.1 IU/ml.1
Antitoxin levels decrease with time, and as a result, routine
boosters are recommended every 10 years.1 Persons who
sustain a wound that is anything other than clean and
minor, should receive a tetanus booster if more than five
years have elapsed since their last dose, in order to ensure
sufficient protective antitoxin levels.1
Prevention
Prevention
TT is available as a single-antigen preparation (Tetavax®),
combined with diphtheria toxoid as adult tetanusdiphtheria (Td), e.g. Diftavax®, and with diphtheria
toxoid, acellular pertussis and inactivated polio, as
Tdap-IPV (Adacel® Quadra). TT is also available as
combined DTaP-HepB-IPV/Hib (Infanrix® Hexa),
DTaP-IPV/Hib (Pentaxim®), DTaP (Infanrix®) and
DTwP-HepB (Tritanrix®), for paediatric use (refer to
Table I).
The South African Department of Health currently
recommends that TT be given to pregnant woman as per
Table II.11
Post-exposure prophylaxis
All wounds should be thoroughly cleaned and debrided.
Some injuries are considered to be tetanus prone, and
tetanus immunisation should be administered as per
Table III.
In South Africa, primary vaccination against tetanus
is administered at six, ten and fourteen weeks of age,
Prof Nurs Today
Adult formulations
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2011;15(2)
Review: Tetanus, diphtheria and pertussis: ancient diseases in modern times
Table II: Vaccination schedule for the prevention of maternal
and neonatal tetanus
First
pregnancy
Second
pregnancy
Third
pregnancy
TT1 at first
antenatal visit
TT4 single dose
TT5 (tetanus
immunisation
complete)
a
TT2 four weeks
later
to ancient Egypt and Syria.14 In the 17th century, the
disease swept through Europe and Spain, where it became
known as el garatillo (the strangler), as well as to Italy
and Sicily, where it was called “the gullet disease”. In the
18th century, the disease reached the American colonies
and often killed whole families in a few weeks. Here it
was referred to as the “strangling angel of children”.14,15
The name refers to the wing-shaped, white membrane
that formed on children’s tonsils in the early stages of
the disease, and to the way in which it obstructed their
breathing.
TT3 six months
later
Over the last 50 years, the incidence of diphtheria has
declined significantly in the developed world, but still
remains endemic in the developing world. In South
Africa, the number of cases has declined sharply since
the 1980s. In the 1990s, 29 cases were reported, followed
by four cases between 2000-2005.16 All documented
cases in 2008, 2009 and 2010 had fatal outcomes.17,18,19
a = Tetanus toxoid (TT)
• Burns or wounds that require surgery, that is delayed
for more than six hours.
• Burns or wounds that show a significant degree of
devitalised tissue.
• A puncture-type injury, particularly where there
has been contact with soil or manure, and wounds
containing foreign bodies.
• Compound fractures.
• Wounds or burns in patients who have systemic sepsis.12
Corynebacterium diphtheriae
Corynebacterium diphtheriae was first described by Klebs
in 1883.13 In 1890, Emil von Behring, together with his
university friend, Erich Wernicke, developed the first
effective therapeutic serum against diphtheria. In 1901,
Von Behring went on to win the first Nobel Prize in
physiology/medicine.20
Diphtheria
Synonyms for diphtheria are witseerkeel (Afrikaans) and
isifo esivimbanisa umphimbo (Zulu).
C. diphtheriae is an aerobic, noncapsulated, nonmotile,
gram-positive bacillus. Toxin production can only
occur when the bacilli themselves are infected by a
bacteriophage (virus) carrying the genetic information
for the toxin.13,21
History
Diphtheria, meaning “leather hide” in Greek, was first
described by Hippocrates in the fifth century BC.13
However, the earliest references to the disease date back
Table III: Tetanus immunisation following injuries. Adapted from the UK Health Protection Agency (HPA) Immunoglobulin
Handbook.12
Immunisation status
Clean wound
Tetanus-prone wound
Vaccine
Vaccine
Tetanus immunoglobulin
(TIG)
Fully immunised
Not required.
Primary immunisation
complete; boosters
incomplete, but up to date
Not required (unless booster is Not required (unless booster is
due imminently).
due imminently).
a
Primary immunisation
incomplete; or boosters not
up to date
Arrange additional doses
at appropriate intervals to
complete immunisation
schedule.
Arrange additional doses
at appropriate intervals to
complete immunisation
schedule.
One dose of TIG injected at a
different site from the TT.
Not immunised; or unknown
immunisation status
Arrange additional doses
at appropriate intervals to
complete immunisation
schedule.
Arrange additional doses
at appropriate intervals to
complete immunisation
schedule.
One dose of TIG injected at a
different site from the TT.
Not required.
Only if high risk.
a
Only if high risk.
a = A tetanus prone injury is considered to be high risk if there is heavy contamination with substances likely to contain tetanus spores, and/or extensive
devitalised tissue12
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Review: Tetanus, diphtheria and pertussis: ancient diseases in modern times
Pathophysiology
Africa, the Elek test is performed at the Green Point National
Health Laboratory Service in the Western Cape.18,19
Overcrowding, substandard living conditions, poor
health, immunocompromised states, or incomplete
immunisation facilitate susceptibility to diphtheria,
and are risk factors associated with transmission of the
disease.21 Human carriers (usually asymptomatic) are
the main reservoir of infection.13,19 Susceptible persons
acquire toxigenic diphtheria bacteria in the nasopharynx
via respiratory droplets, nasopharyngeal secretions,
and, rarely, via fomites. In cutaneous disease, contact
with exudates may result in disease transmission.21
C. diphtheriae adheres to mucosal epithelial cells and
causes a localised inflammatory reaction, following which
exotoxin is produced, which inhibits cellular protein
synthesis and causes necrosis and membrane formation.
The toxin produced at the site of the membrane is
absorbed into the bloodstream and distributed to other
body tissues.13,21
Treatment
Persons with suspected diphtheria, as well as all close
contacts, should be treated with erythromycin or penicillin.
Treatment should be initiated as soon as possible, as it is
most effective in the early stages of disease, improves the
course of diphtheria, and decreases transmissibility.13,21
The disease is generally not contagious 48 hours after
antibiotics are initiated.13 Diphtheria antitoxin treatment
is only effective if given very early in the course of illness,
and is not available in SA.18 Contacts should be monitored
for symptoms for at least seven days after last exposure,
and booster immunisation should be provided to those
who have not received a booster in the previous 12
months.18
Prevention
The incubation period is two to five days, with a range
of one to 10 days.13 Diphtheria can involve almost any
mucous membrane.
A single-antigen diphtheria toxoid is not available.
Diphtheria toxoid is available, combined with TT as adult
tetanus-diphtheria (Td), e.g. Diftavax®. Diphtheria toxoid
is also available as combined Tdap-IPV (Adacel ®Quadra),
DTaP (Infanrix®), DTaP-HepB-IPV/HiB (Infanrix® Hexa),
TDaP-IPV/HiB (Pentaxim®) and DTwP-HepB (Tritanrix®).
See Table I.
The disease is classified based on the site of infection:13
•
•
•
•
•
Anterior nasal diphtheria;
Pharyngeal and tonsillar diphtheria;
Laryngeal diphtheria;
Cutaneous diphtheria;
Ocular diphtheria.
Paediatric formulations contain three to four times
more diphtheria toxoid than adult formulations. It is
advised that children younger than seven years of age
receive paediatric diphtheria, and that persons over
the age of seven years receive the adult diphtheria
formulations.13
Other sites of infection have included the external ear and
genital mucosa.13,15 Septicaemia caused by C. diphtheriae is
rare, but fatal.15
The pharynx and tonsils are the most common sites of
diphtheria infection. Early symptoms are usually nonspecific, resembling a typical viral upper respiratory tract
infection.13,21
A series of three correctly spaced diphtheria toxoid doses
in adults, or four correctly spaced doses in infants, should
provide a protective level of antitoxin in more than 95%
of individuals. Antitoxin titres do wane with time, and
boosters are recommended 10 years after the last dose.13
Within two to three days, a bluish-white membrane forms
and extends, covering as little as a patch on the tonsils, or
as much as most of the soft palate. Extensive membrane
formation may result in respiratory obstruction. Forcible
attempts to remove the membrane cause bleeding, as it is
adherent to the tissue.13
Pertussis
Synonyms for pertussis are whooping cough, kinkhoes
(Afrikaans) and ugonqogonqo (Zulu).
History
If left untreated, diphtheria can lead to breathing problems,
myocarditis, or nerve damage. Nerve damage may cause
muscle weakness in the arms, legs and throat, or even
paralysis of the muscles that control breathing.22
The earliest known description of pertussis infections
was given by Guillaume De Baillou, who described an
epidemic that occurred in France in 1578. “Kinkehost” is
mentioned in Vita Godrici, from around 1190. It has also
been suggested that the description of the “perinthus”
cough by Hippocrates (around 400 BC) might possibly be
whooping cough, perhaps combined with other diseases
such as viral respiratory infections.23
Diagnosis
The diagnosis can be confirmed by a throat swab culture and
demonstration of toxin by Elek culture plate, or polymerase
chain reaction (PCR) detection, where available. In South
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Review: Tetanus, diphtheria and pertussis: ancient diseases in modern times
Bordetella pertussis
Diagnosis
Bordetella pertussis is an aerobic, non-motile, Gramnegative coccobacillus. Humans are the only reservoirs,
and infection is spread via aerosolised droplets from
coughing by infected individuals.24,25 The disease is highly
contagious, and it is estimated that approximately 80-90%
of susceptible individuals who are exposed will develop
the disease.25
Diagnosis is essentially clinical. Although some
tertiary institutions have the means to do so, laboratory
confirmation is not conducted routinely in South Africa.27
Furthermore, bacteriological confirmation of suspected
pertussis is often missed, as B. pertussis requires special
growth factors to grow on artificial media, and does not
seem to persist far beyond the catarrhal stage.23 PCR
testing is more sensitive than culture, and is the preferred
diagnostic method where available.28
Pathophysiology
B. pertussis bacteria attach to the ciliated respiratory
epithelium, where they produce toxins that paralyse
the cilia and cause inflammation of the respiratory
tract, which interferes with the clearing of pulmonary
secretions.26
Treatment
The macrolide antibiotics, erythromycin, clarithromycin
and azithromycin, are preferred for the treatment of
pertussis in patients older than one month. Azithromycin
is preferred in the treatment of infants less than one month
of age.29
The incubation period of pertussis is usually seven to ten
days, with a range of four to 21 days. The course of the
disease is divided into three stages:26
The South African Standard Treatment Guidelines
and Essential Drug List recommends the use of oral
erythromycin 10-15 mg/kg/dose, six hourly for 14 days
in the treatment of pertussis.30 Infected persons should
be excluded from work, school or daycare for five days
following commencement of antibiotics.28
• The catarrhal phase lasts one to two weeks, and is
characterised by low-grade fever, rhinorrhoea and
progressive cough.23
• The paroxysmal phase lasts several weeks, and is
characterised by episodes of severe and spasmodic
coughing with a dictinctive whoop, often with
cyanosis and vomiting. Paroxysmal attacks occur
more frequently at night, with an average of 15
attacks per 24-hour period. Persons do not appear
to be ill between attacks. 23,26 Young infants may not
have the strength to whoop, but do have paroxysms
of coughing. However, the cough may be absent, and
the infant may present with spells of apnoea and
cyanosis.23,26
• The convalescent phase lasts one to three weeks, and
is characterised by a gradual, but continuous decline
of cough, as the patient returns to normal. Patients
who develop subsequent respiratory infections
months after the onset of pertussis may experience
paroxysms.23
Prevention
A single antigen pertussis vaccine is not available. See
Table I for available preparations. Vaccination is an
essential preventative strategy against pertussis.29 Unless
specifically contraindicated, all children should receive
pertussis vaccines at six, ten and fourteen weeks of age,
followed by additional doses at 18 months, and again
at six years of age. Unfortunately, neither vaccination,
nor natural disease, confer lifelong protective immunity
against pertussis.29 Immunity wanes after five to ten
years from the last pertussis vaccine dose, causing older
children and adults to be susceptible to infection again. It
is therefore assumed that infection frequency is likely to
be highest in adolescents and adults, who as a result, are
the main source of infection in infants.23,29
Compared with older children and adults, infants younger
than six months with pertussis are more likely to have
severe disease, to develop complications, and to require
hospitalisation.24 In addition, pertussis is one of the causes
of sudden infant death syndrome.
Post-exposure prophylaxis
Symptomatic infection of household contacts can be
prevented if administration of post-exposure prophylaxis
is initiated within 21 days of the onset of the cough in
the index patient. The same antimicrobial agents and
dosing regimens used in the treatment of pertussis
are recommended for post-exposure prophylaxis of
pertussis.29
Secondary bacterial pneumonia is the most common
complication, and the cause of most pertussis-related
deaths.26 Complications among adolescents and adults
include syncope, sleep disturbance, incontinence and rib
fractures.24 Less common central nervous system (CNS)
complications, such as seizures and encephalopathy, are
thought to result from severe paroxysm-induced cerebral
hypoxia and apnoea, metabolic disturbances, and small
intracranial haemorrhages.24
Prof Nurs Today
Conclusion
Tetanus, diphtheria and pertussis are serious, potentially
life-threatening, but vaccine-preventable diseases. The
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2011;15(2)
Review: Tetanus, diphtheria and pertussis: ancient diseases in modern times
nursing practitioner may have a pivotal role in preventing
unnecessary illness or deaths by educating and counselling
patients and families to create an awareness of these
illnesses, and to emphasise the importance of vaccination.
18.
19.
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