Guidance

Diphtheria anti-toxin (DAT): information for healthcare professionals

Published 23 September 2022

Applies to England

Diphtheria anti-toxin (DAT)

Key facts about DAT:

  • DAT treatment should be considered urgently for probable and confirmed cases of diphtheria
  • DAT significantly reduces mortality and morbidity from diphtheria
  • DAT is much more effective if given early before diphtheria toxin has bound to tissues
  • DAT is not usually required for diphtheria cases who only have skin lesions (unless a skin ulcer is sufficiently large (that is greater than 2cm2) and especially if membranous)
  • when DAT use is being considered the case should be discussed with an infectious disease physician, the UK Health Security Agency (UKHSA) Duty Doctor/national experts and the local Health Protection Team (HPT)
  • DAT is issued by UKHSA Colindale
  • when administering DAT, continuous patient monitoring during the infusion is required and supervision by staff prepared to manage any adverse effects including anaphylaxis
  • DAT is made from horse serum and people with a history of a horse allergy should undergo a sensitivity screen prior to DAT treatment

What is DAT?

DAT is an antiserum used for the treatment of:

  • confirmed or probable diphtheria cases [footnote 1]
  • for treatment of confirmed infections, where clinically appropriate, due to toxigenic Corynebacteria ulcerans or C. diphtheriae

DAT is made from equine serum. People with a history of allergy to horses (including asthma, allergic rhinitis, or urticaria or other symptoms of distress when in close proximity to horses) or prior exposure to equine-derived immunoglobulin should undergo sensitivity testing prior to administration of DAT (1,2).

Full details on how to undertake sensitivity testing can be found in the Diphtheria anti-toxin: clinical guidance.

Why DAT is used

Early treatment with DAT, when indicated, is essential to reduce mortality and morbidity of patients with diphtheria. The causative agents of diphtheria are toxigenic C. diphtheriae, C. ulcerans and C. pseudotuberculosis. If left untreated, the bacterial toxin can enter the circulation leading to cardiac and neurologic sequelae (3-5).

Mortality rates for clinical diphtheria frequently exceeded 50% in the pre-antitoxin era. Almost as soon as antitoxin was available, clinical experience showed dramatic declines in mortality in groups of patients treated with antitoxin compared to historical control groups or groups treated at hospitals not using antitoxin. In one controlled trial in which patients at a hospital were allocated to antitoxin treatment or no antitoxin treatment on an alternating day schedule, mortality in treated patients was 3.3% compared to 12.2% in untreated patients (6). Antibiotics may be used in conjunction with DAT to help eliminate the bacteria and toxin production, and to prevent transmission to others (3).

When DAT should be used

DAT should be considered for use in cases of probable or confirmed cases of diphtheria, due to toxigenic C. ulcerans or C. diphtheria. DAT may be used for the following presentations of diphtheria:

  • severe diphtheria, for example, extensive membrane and/or severe oedema (‘bull neck’)
  • any laryngeal or pharyngeal or nasopharyngeal disease
  • cutaneous diphtheria but only when the skin lesion is sufficiently large (greater than 2cm2) and membranous

When DAT is indicated, usually in severely unwell cases or at risk of severe outcomes, prompt treatment of diphtheria is imperative. The risk of complications and fatal outcome increases with each day DAT administration is delayed. This is because DAT is mainly effective against circulating diphtheria toxin and once the toxin is bound to tissues DAT is less effective. When there is an urgent need for consideration of DAT use the case should be discussed with (or cared for by) an infectious disease physician and the UKHSA HPT and UKHSA Duty Doctor who can co-ordinate issuing DAT.

For probable or confirmed cases DAT is administered following on an initial, presumptive clinical diagnosis, and is given as early as possible, even before laboratory results for bacteriological confirmation are obtained (7).

How effective is DAT?

Better outcomes are seen when DAT is given early when indicated. Studies have found increases in severity of morbidity and mortality increases when treatment is delayed. After 3 days since symptom onset, the risk of complications and fatal outcomes increases with each day DAT is delayed (3). A Latvian study found DAT to be ineffective when administered after the second day of symptoms (8).

In a controlled trial where patients were allocated to antitoxin treatment or no antitoxin treatment on alternating days, mortality increased progressively based on the interval from onset of illness to treatment, with a sharp increase from 4% mortality in those treated with antitoxin within 24 to 48 hours to 16.1% in those treated on the third day of illness (5). Mortality rates continued to increase with more prolonged intervals, reaching 29.9% in those treated 7 or more days after onset (6).

How DAT works

Diphtheria toxin typically binds to neural and cardiac tissues, causing irreversible damage. DAT is made up of concentrated proteins (mainly globulins), containing antibodies from the serum of horses that have been immunized against diphtheria. It acts by neutralising the toxins produced by C. diphtheriae, C. ulcerans and C. pseudotuberculosis.

DAT can only neutralise free toxin which has not yet bound to cells (9), which is why early administration is important to optimise outcomes. Current thinking is that toxin fixes to susceptible cells early in disease and fixed toxin is not neutralized by antitoxin (6).

Antibiotics are often used in conjunction with DAT to eradicate the organism. The DAT serves to neutralise circulating toxin, to prevent it binding to tissues and causing irreversible organ damage.

Safety of DAT and precautions for administration

Administration of DAT may cause hypersensitivity reactions including anaphylaxis. Prior to administration, a detailed history should be taken including previous administration of equine-derived anti-toxin or immunoglobulins and regarding any known animal allergy, specifically equine allergy. Diphtheria antitoxin is derived from horse serum and reactions are common (11). People with a history of allergy to horses (including asthma, allergic rhinitis, or urticaria or other symptoms of distress when in close proximity to horses) or prior exposure to equine-derived immunoglobulin should undergo sensitivity testing prior to administration of DAT. Full details on how to undertake sensitivity testing can be found in the Diphtheria anti-toxin: clinical guidance.

Patients with positive sensitivity testing to DAT or with a previous history of adverse reaction to DAT should undergo desensitisation, with full details on how to do this also found in the Diphtheria anti-toxin: clinical guidance.

DAT can be safely administered provided there is continuous patient monitoring during the infusion, staff training on management of adverse effects, and attention to safety precautions (10).

Staff administering DAT should be fully trained in the management of anaphylaxis and administration should take place within facilities able to provide appropriate specialist support. Further information is available from the Resuscitation Council UK’s Emergency treatment of anaphylactic reactions: guidelines for healthcare providers.

Serum sickness can occur in up to 5% of patients according to historic data, usually around 7 to 12 days after the first injection although accelerated reactions have been reported in patients who have previously received equine anti-toxin preparations, with onset within days or even hours. Symptoms include more generalised erythema, urticaria, itching, and occasionally fever, pain and oedema of the joints and lymph nodes.

Treatment is supportive, with anti-inflammatory preparations and antihistamine to provide symptomatic relief although systemic steroids may be needed in more severe cases.

In a recent large outbreak of diphtheria in Bangladesh 25% of patients who received DAT had at least one adverse reaction, however most reactions were mild (cough, rash, itching) and resolved quickly. Three percent had severe hypersensitivity reactions that were consistent with anaphylaxis. Even though most of these patients were not diagnosed as having anaphylaxis at the time, and were not treated as such, all but one of the patients recovered quickly. Five patients died during their DAT infusion or soon afterwards, but no deaths were attributed to DAT (10).

For comparison, in the 1993 to 1996 outbreak in the Republic of Georgia, 2% of DAT-treated patients (8 cases) had anaphylactic shock (12) and in a review of DAT usage in the United States, low rates of DAT associated adverse events were recorded, and deaths in those who received DAT were attributed to other causes (13).

Risk of hypersensitivity increases with additional doses of DAT. The dose of DAT should be determined by the severity and duration of the disease as defined in the Diphtheria anti-toxin: clinical guidance (1). Further doses are not required if the full recommended dose is given. If a sub-optimal dose is administered, the responsible clinician should discuss further treatment with an infectious diseases consultant and in collaboration with specialists at UKHSA. The decision to give additional doses of DAT will depend on severity of diseases and the time delay between doses.

Is there time beyond which DAT is no longer indicated?

Complications from toxin can occur late, after 2 to 6 weeks and may include cranial and peripheral nerve palsies and myocarditis (which may occur both in early as well as later phases of the disease) and are often severe (9).

Using DAT beyond the early stages of toxigenic diphtheria should be discussed with an infectious diseases consultant and specialists at UKHSA, given that the benefit from DAT declines with time since disease onset.

Pregnancy and DAT

DAT (equine) should be used cautiously during pregnancy (1).

There are limited data on the use of DAT in pregnant women however, there have been no reported signals to date to indicate that DAT should not be used in pregnant women if required.

References

  1. UK Health Security Agency (2022). Diphtheria anti-toxin: clinical guidance
  2. Centres for Disease Control and Prevention (2022). Use of Diphtheria Antitoxin (DAT) for Possible Diphtheria Cases: Protocol CDC IRB #4167
  3. The World Health Organization (2018). Diphtheria: Vaccine Preventable Diseases Surveillance Standards
  4. Wagner KS and others (2011). Screening for Corynebacterium diphtheriae and Corynebacterium ulcerans in patients with upper respiratory tract infections 2007-2008: a multicentre European study. Clinical Microbiology and Infectious Diseases: volume 17, issue 4, pages 519 to 525
  5. Both L and others (2014). Access to diphtheria antitoxin for therapy and diagnostics. Eurosurveillance: volume 19, issue 24, page 20830
  6. Centres for Disease Control and Prevention (2020). Expanded Access Investigational New Drug (IND) Application Protocol: Use of Diphtheria Antitoxin (DAT) for Suspected Diphtheria Cases, BB-IND 11184, Protocol CDC IRB # 4167
  7. UK Health Security Agency (2022). Public health control and management of diphtheria in England: 2022 guidelines
  8. Logina I and Donaghy M (1999). Diphtheritic polyneuropathy: a clinical study and comparison with Guillain-Barré syndrome. Journal of Neurology, Neurosurgery & Psychiatry: volume 67, issue 4, pages 433 to 438.
  9. Begg N & The World Health Organization (1994). Diphtheria: Manual for the Management and Control of Diphtheria in the European Region. The Expanded Programme on Immunization in the European Region of WHO
  10. Eisenberg N and others (2021). Diphtheria Antitoxin Administration, Outcomes, and Safety: Response to a Diphtheria Outbreak in Cox’s Bazar, Bangladesh. Clinical Infectious Diseases: volume 73, issue 7, pages e1713-e1718.
  11. Diphtheria antitoxin, National Institute for Health and Care Excellence.
  12. Quick ML and others (2000). Epidemic diphtheria in the Republic of Georgia, 1993-1996: risk factors for fatal outcome among hospitalized patients. Journal of Infectious Diseases: volume 181, Supplementary 1, pages S130 to S137.
  13. Bampoe VD and others (2022). A Review of Adverse Events from the Use of Diphtheria Antitoxin (DAT) in the United States, 2004 to 2019. Clinical Infectious Diseases: volume 74, issue 11, pages 2082 to 3083.
  1. As defined in section 2.2 of the national guidelines