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15        Diphtheria
s   15.1 Introduction
     s 15.1.1 Diphtheria is an acute infectious disease affecting the upper
     respiratory tract and occasionally the skin. It is characterised by an
     inflammatory exudate which forms a greyish membrane in the
     respiratory tract which may cause respiratory obstruction. The
     incubation period is from two to five days. Patients with disease may be
     infectious for up to four weeks, but carriers may shed Corynebacteria
     diphtheriae for longer. A toxin is produced by diphtheria bacilli which
     affects particularly myocardium and nervous and adrenal tissues. Spread
     is by droplet infection and through contact with articles soiled by
     infected persons (fomites). In countries where hygiene is poor, cutaneous
     diphtheria is the predominant source of infection.

     s 15.1.2 Effective protection against the disease is provided by active
     immunisation. The introduction of immunisation against diphtheria on
     a national scale in 1940 resulted in a dramatic fall in the number of
     notified cases and deaths from the disease. In 1940, 46,281 cases with
     2,480 deaths were notified, compared with 37 cases and six deaths in
     1957. From 1986 to 1995, 38 isolates of toxigenic C. diphtheriae were
     identified by the PHLS Diphtheria Reference Unit. Of these, 19 were
     carriers and 7 were cutaneous infections. There was one death in 1994:
     a 14 year old with no record of immunisation who had visited Pakistan.


                        Immunisation against Infectious Disease             67

                                                                             Notifications of diptheria to ONS
                                                                                    England and Wales (1940-1995)





Immunisation against Infectious Disease
                                                                      1940   1950           1960          1970      1980   1990

15        Diphtheria
     s 15.1.3 The increase in notifications of diphtheria since 1992 has
     been due to a rise in isolations of a non-toxigenic C. diphtheriae var
     gravis. Presentation is usually with a sore throat without signs of

     s 15.1.4 Since 1991, there has been an epidemic of diphtheria in
     Russia, now involving other Newly Independent States of the former
     Soviet Union. In 1995, approximately 52,000 cases of diphtheria and
     1,700 deaths were reported. The causes of this epidemic are low
     immunisation coverage in young children, waning immunity in adults
     and large scale population movements. There have been some
     importations from the former Soviet Union countries into neighbouring
     countries but no evidence of importation into the UK.

     s 15.1.5 The disease and the organism have been virtually eliminated
     from the United Kingdom; the few cases which have occurred in recent
     years have nearly all been imported from the Indian subcontinent or
     from Africa, with minimal spread. There is thus no possibility now of
     acquiring natural immunisation from sub-clinical infection. High
     immunisation uptake must be maintained in order to protect the
     population against the possibility of a resurgence of the disease which
     could follow the introduction of cases or carriers of toxigenic strains
     from overseas.

     s 15.1.6 Recent published data indicate that approximately 38% of
     UK blood donors are susceptible to diphtheria. A significant trend of
     decreasing immunity with increasing age was apparent: 25% of donors
     aged 20-29 were susceptible compared with 53% of those aged 50-59.

s   15.2 Diphtheria vaccine
     s 15.2.1 Diphtheria immunisation protects by stimulating the
     production of antitoxin which provides immunity to the effects of the
     toxin. The immunogen is prepared by treating a cell-free purified
     preparation of toxin with formaldehyde, thereby converting it into the
     innocuous diphtheria toxoid. This however is a relatively poor

     immunogen, and for use as a vaccine it is usually adsorbed on to an
     adjuvant, either aluminium phosphate or aluminium hydroxide.
     Bordetella pertussis also acts as an effective adjuvant.

                        Immunisation against Infectious Disease               69
             15         Diphtheria
                   s 15.2.2 The recommended vaccines for immunisation are:
                   Adsorbed diphtheria/tetanus/pertussis (DTP).
                   Adsorbed diphtheria/tetanus (DT).
                   Adsorbed diphtheria (D).
                   Adsorbed low dose diphtheria vaccine for adults (d).
                   Adsorbed tetanus/low dose diphtheria vaccine for adults (Td).

                   The dose is 0.5ml given by intramuscular or deep subcutaneous

                   Plain vaccines are less immunogenic and have no advantage in terms of
                   reaction rates and are no longer available.

                   Vaccines should be stored at 2-8°C and protected from light. Vaccine
                   which has been frozen should not be used. Disposal should be by
                   incineration at a temperature not less than 1100°C at a registered waste
                   disposal contractor.

             s    15.3 Recommendations
                   s 15.3.1 For immunisation of infants and children up to ten years of

                   a. Primary immunisation

                   Diphtheria vaccine as a component of triple vaccine (diphtheria toxoid,
                   tetanus toxoid and Bordetella pertussis toxoid) is recommended for
                   infants from two months of age. Adsorbed vaccine should be used as it
                   has been shown to cause fewer reactions than plain vaccine which is no
                   longer available. If the pertussis component is contraindicated,
                   adsorbed diphtheria/tetanus vaccine should be used. A course of
                   primary immunisation consists of three doses starting at two months
                   with an interval of one month between each dose (see 11.1). If a course
                   is interrupted it may be resumed; there is no need to start again.

                   b. Reinforcing immunisation

                   Booster doses of vaccine containing diphtheria and tetanus toxoids are
                   recommended for: (i) children before school entry - DT, preferably at
                   least three years after the last dose of the primary course, and (ii) before
                   leaving school at 13 to 18 years of age - Td, both at the same time as

             70      Immunisation against Infectious Disease
15        Diphtheria
     In approximately 25% of children, a fifth tetanus vaccine dose is said to
     have been given by the time the school leaving booster (Td) is due. If a
     child requires a tetanus booster after a tetanus prone wound, after the
     fourth dose has been given (at around 4 years of age) and ten years has
     elapsed, then Td should be given. The school leaving Td dose is then not

     If there is a documented history of a fifth dose of tetanus vaccine having
     already been given when the school leaving booster is due, and supplies
     of a low dose diphtheria vaccine product are readily available (either low
     dose diphtheria vaccine (d) or 0.1 ml of paediatric strength diphtheria
     vaccine (D)), then one of these latter two products should be used. If
     neither is available, then Td should be given with an interval of at least
     one month since the last dose of tetanus vaccine. Recent experience has
     shown that when Td is given to children who have already had 5 doses
     of tetanus vaccine, there is some increase in the number who have local
     reactions and low grade pyrexias, but no increase in the numbers with
     pyrexias over 38.5°C

     s 15.3.2 Immunisation of persons aged ten years or over

     a. Primary immunisation

     Low dose diphtheria vaccine for adults (d) must be used because of the
     possibility of a reaction in an individual who is already immune. Past
     experience showed that when full strength diphtheria vaccine
     preparations (D) were given to adults, there were considerably more
     localised and generalised reactions, such as high fever. Three doses
     (0.5ml) of low dose vaccine for adults (d) should be given by deep
     subcutaneous or intramuscular injection at intervals of one month. When
     this product is not available, then a 0.1 ml injection of the standard
     paediatric diphtheria vaccine (D) may be given as an alternative. For
     adults who have never received either diphtheria or tetanus vaccine
     previously, three doses of Td should be used, each given one month apart.

     b. Reinforcing immunisation

     A single dose of 0.5ml of low-dose diphtheria vaccine (d) must be used
     for all persons aged ten years and over. When this product is not
     available, then a 0.1 ml injection of the standard paediatric diphtheria
     vaccine (D) may be given as an alternative. When a reinforcing dose of
     tetanus vaccine is also required, then Td should be used. Prior Schick
     testing is not necessary and the material is no longer available.

                        Immunisation against Infectious Disease                 71
             15        Diphtheria
                  s 15.3.3 Children given DTP at monthly intervals without a booster
                  dose at 18 months have been shown to have adequate levels of
                  diphtheria and tetanus antibody at school entry. A booster dose at 18
                  months for such children is therefore not necessary.

                  s 15.3.4 Travel: Primary or reinforcing doses are recommended for
                  travellers to epidemic or endemic areas (see ‘Health Information for
                  Overseas Travel’ for more information).

                  s 15.3.5 Contacts of a diphtheria case, or carriers of a toxigenic strain

                  Individuals exposed to such a risk should be given a complete course or
                  a reinforcing dose according to their age and immunisation history as

                  a. Immunised children up to ten years.
                  One injection of diphtheria vaccine (D).

                  b. Immunised children ten years and over, and adults.
                  One injection of low dose diphtheria vaccine for adults (d or Td).

                  c. Unimmunised children under ten years.
                  Three injections of diphtheria (D) vaccine (or DTP and polio vaccines if
                  appropriate) at monthly intervals.

                  d. Unimmunised children ten years and over, and adults.
                  Three injections of low dose diphtheria vaccine for adults (d) or Td at
                  monthly intervals.

                  Unimmunised contacts of a case of diphtheria should in addition be
                  given a prophylactic course of erythromycin or penicillin. Symptomatic
                  contacts (including close contacts) of cases of sore throat associated with
                  non-toxigenic C. diphtheriae should be swabbed and treated
                  accordingly; asymptomatic contacts do not require swabbing or
                  antibiotic prophylaxis. Contacts of cases of C. ulcerans do not require
                  prophylaxis as human to human transmission does not occur.

                  s 15.3.6 HIV positive individuals may be immunised against
                  diphtheria in the absence of any contraindications.

             72     Immunisation against Infectious Disease
15         Diphtheria
s   15.4 Testing for diphtheria immunity
The material for carrying out the Schick test is no longer available. Individuals
who may be exposed to diphtheria in the course of their work should have
their immunity checked by antibody testing at least three months after
immunisation is completed and boosted at ten year intervals thereafter.

s   15.5 Adverse reactions
     s 15.5.1 Swelling and redness at the injection site are common.
     Malaise, transient fever and headache may also occur. A small painless
     nodule may form at the injection site but usually disappears without
     sequelae. Severe anaphylactic reactions are rare. Neurological reactions
     have been reported occasionally.

     s 15.5.2 Severe reactions should be reported to the Committee on
     Safety of Medicines using the yellow card system.

s   15.6 Contraindications
     s 15.6.1 a. If a child is suffering from any acute illness, immunisation
     should be postponed until the child has fully recovered. Minor
     infections without fever or systemic upset are not reasons to postpone

     b. Immunisation should not proceed in children who have had a severe
     local or general reaction to a preceding dose (see 7.2.2), if it is thought
     that the diphtheria component has caused the preceding reaction.
     Reactions to the pertussis component of DTP are the most likely and
     immunisation should proceed with DT; acellular pertussis vaccine can be
     used if the previous reaction was a local one.

     s 15.6.2 When there is a need to control an outbreak, diphtheria
     vaccine may have to be given to individuals suffering from acute febrile
     illness. Low-dose diphtheria vaccine for adults (d or Td) must be used

     for persons aged ten years and over.

                         Immunisation against Infectious Disease                73
             15           Diphtheria
             s    15.7 Diphtheria antitoxin
             Diphtheria antitoxin is now only used in suspected cases of diphtheria. Tests
             with a trial dose to exclude hypersensitivity should precede its use. It should
             be given without waiting for bacteriological confirmation since its action is
             specific for diphtheria. It may be given intramuscularly or intravenously, the
             dosage depending on the clinical condition of the patient. This is shown in the
             following table. It is no longer used for diphtheria prophylaxis because of the
             risk of provoking a hypersensitivity reaction to the horse serum from which it
             is derived. Unimmunised contacts of a case of diphtheria should be promptly
             investigated, kept under surveillance and given antibiotic prophylaxis and
             vaccine, as in 15.3.5.

                    Table:     Dosage of antitoxin recommended for various types of

              Type of diphtheria         Dosage (units)          Route

              Nasal                      10,000 - 20,000         Intramuscular

              Tonsillar                  15,000 - 25,000         Intramuscular or

              Pharyngeal or laryngeal    20,000 - 40,000         Intramuscular or

              Combined types or          40,000 - 60,000         Intravenous
              delayed diagnosis

              Severe diphtheria          40,000 - 100,000        Intravenous or part
              e.g. with extensive                                intravenous and part
              membrane and/or severe                             intramuscular
              oedema (bull-neck

             If acute anaphylaxis develops, intravenous adrenaline (0.2 to 0.5ml of 1:1000
             solution) should be administered immediately by intravenous injection.

             74       Immunisation against Infectious Disease
15         Diphtheria
Antitoxin is probably of no value for cutaneous disease, although some
authorities use 20,000 to 40,000 units of antitoxin because toxic sequelae
have been reported.

s   15.8 Supplies
     s 15.8.1 Adsorbed diphtheria/tetanus/pertussis (DTP) and adsorbed
     diphtheria/tetanus (DT) vaccines (15.2.2) are manufactured by Evans
     Medical (Tel. 01372 364000) and Pasteur Merieux MSD Ltd (Tel. 01628
     773200). Adsorbed diphtheria vaccine is manufactured by Evans

     s 15.8.2 Low-dose diphtheria vaccine for adults (d) is manufactured
     by Swiss Serum and Vaccine Institute, Berne, and distributed in the UK
     by Farillon (Tel. 01708 379000).

     s 15.8.3 Adsorbed low dose diphtheria vaccine for adults combined
     with tetanus (Td) is manufactured by Pasteur Merieux MSD Ltd (Tel.
     01628 773200).

     s 15.8.4 These vaccines are supplied by Farillon (Tel. 01708 379000)
     as part of the childhood immunisation programme, except for the
     syringe presentation of adsorbed low dose diphtheria vaccine for adults
     combined with tetanus (Td) which is supplied by Pasteur Merieux MSD
     Ltd (Tel. 01628 773200).

     s 15.8.5 In Scotland these vaccines can be obtained through Scottish
     Healthcare Supplies Division of Common Service Agency (Tel. 0131 552

     s 15.8.6 Diphtheria antitoxin is supplied in vials containing 1000 iu
     per ml. Manufactured by Pasteur Merieux MSD Ltd and distributed in
     the UK by the Communicable Disease Surveillance Centre (Tel 0181 200
     6868). In Northern Ireland the source of diphtheria antitoxin is the
     Public Health Laboratory, Belfast City Hospital, Lisburn Road, Belfast
     Tel. 01232 329241.

                         Immunisation against Infectious Disease              75
             15         Diphtheria
             s    15.9 Bibliography
             Immunity of children to diphtheria, tetanus and poliomyelitis.
             Bainton D, Freeman M, Magrath D, Sheffield F W, Smith J G W.
             BMJ 1979; (1), 854-857.

             Advantages of aluminium hydroxide adsorbed combined diphtheria, tetanus
             and pertussis vaccines for the immunisation of infants.
             Butler N R, Voyce M A, Burland W M, Hilton M L.
             BMJ 1959; (1), 663-666.

             Susceptibility to diphtheria.
             Report of Ad Hoc Working Group.
             Lancet 1978; (i), 428-430.

             Immunisation of adults against diphtheria.
             Sheffield F W, Ironside A G, Abbott J D.
             BMJ 1978; (2), 249-250.

             Durability of immunity to diphtheria, tetanus and poliomyelitis after a three
             dose immunisation schedule completed in the first eight months of life.
             Jones E A, Johns A, Magrath D I, Melville-Smith M, Sheffield F.
             Vaccine 1989: 7; 300-2.

             Enhanced surveillance of non-toxigenic C.diphtheriae infections, CDR Weekly
             Report 1996; 6(4);29.

             Manual for the management and control of diphtheria in the European Region
             Begg N
             Copenhagen: The Expanded Programme on Immunisation in the European
             Region of WHO, 1994.

             Diphtheria: Manual for the Laboratory diagnosis of Diphtheria
             Efstratiou A
             Copenhagen : The Expanded Programme on Immunisation in the European
             Region of WHO, 1994.

             Diphtheria Immunity in UK Blood Donors
             Maple P A, Efstratiou A, George R C et al
             Lancet 1995; 345 : 963-65

             76      Immunisation against Infectious Disease

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