Diphtheria in England: 2021
Updated 25 May 2022
Applies to England
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This report updates Diphtheria in England: 2020, which presented surveillance data for England for that year and reiterates current recommendations on diagnosis and clinical management of diphtheria.
The main points arising from this report are that:
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diphtheria is a life-threatening, but vaccine-preventable infection
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from January to December 2021, toxigenic corynebacteria was isolated from 10 human individuals in England; 3 Corynebacterium diphtheriae cases and 7 Corynebacterium ulcerans cases (including 2 separate episodes in one individual); and one non-toxigenic tox gene-bearing (NTTB) case of C. diphtheriae. There were 2 deaths, both of whom were confirmed with toxigenic C. ulcerans
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two of the toxigenic C. diphtheriae cases presented with cutaneous symptoms while the third was an asymptomatic carrier in the household of one of the cases. Isolates from all 3 cases belonged to the same biovar (gravis) and Sequence Type (ST25) by multi-locus sequence typing (MLST) as a previous cluster in the same geographical area
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three of the 7 toxigenic C. ulcerans cases had cutaneous symptoms and 2 cases had respiratory symptoms; one of whom presented with a membrane. The remaining 2 toxigenic C. ulcerans cases had other symptom presentations; one case had hip pain and the other had ear discharge
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there was one NTTB C. diphtheriae case who presented with cutaneous symptoms, known to be a household contact of a previously confirmed asymptomatic NTTB C. diphtheriae carrier
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all the toxigenic C. ulcerans cases were linked to companion animals
Background
Diphtheria is a very rare infection in England due to the success of the routine immunisation programme that was introduced in 1942, when the average annual number of cases was about 60,000 with 4,000 deaths (1). Over the past decade, the number of diphtheria cases in England has increased from an average of 2 to more than 10 cases per year (with the exception of 2020).
Diphtheria vaccine is made from inactivated diphtheria toxin (only available as combination vaccines) and protects individuals from the effects of toxin-producing corynebacteria.
There are 3 Corynebacterium species that can potentially produce toxin; C. diphtheriae (associated with epidemic person-to-person spread via respiratory droplets and close contact), C. ulcerans and C. pseudotuberculosis (both less common globally and traditionally associated with farm animal contact and dairy products and more recently, for C. ulcerans, with companion animals) (2).
Although there is no direct evidence of person-to-person transmission of C. ulcerans infection, there have been incidents that suggest this mode of transmission is possible (3).
Diphtheria can present with a range of clinical presentations. Classic respiratory diphtheria is characterised by a swollen ‘bull neck’ and strongly adherent pseudomembrane which obstructs the airways; a milder respiratory form of the disease where patients present with sore throat or pharyngitis can occur in immunised or partially immunised individuals (2).
Cutaneous presentations, characterised by ‘rolled edge’ ulcers, are also common, particularly in tropical regions (3). Treatment involves prompt administration of diphtheria anti-toxin (DAT) for severe cases and clearance with appropriate antibiotics. Public health management of clinical cases of diphtheria in England is provided by local Health Protection Teams, including identification, assessment and prophylaxis of close contacts (3).
Laboratory confirmation of diphtheria is usually made by detection of the expression of diphtheria toxin in isolates of C. diphtheriae, C. ulcerans or C. pseudotuberculosis or initially by detection of DNA from these species together with the toxin gene, using PCR.
The determination of toxigenicity in England requires submission of isolates of these three species to UK Health Security Agency’s (UKHSA) Vaccine Preventable Bacteria section (VPBS), Respiratory and Vaccine Preventable Bacteria Reference Unit (RVPBRU), which is the National Reference Laboratory (NRL) for diphtheria. Identification and the presence of the toxin (tox) gene are tested for by real-time PCR. If the tox gene is detected, the isolate is tested for expression of diphtheria toxin using the Elek test (4).
The availability of both PCR and Elek testing has identified a number of C. diphtheriae isolates carrying the tox gene (PCR-positive) but not expressing the toxin (Elek-negative), termed NTTB strains (3). The pathogenesis and clinical significance of isolation of this organism are not yet well understood; NTTB are not thought to cause diphtheria and therefore, as reversion to toxin expression is considered highly unlikely, updated guidelines recommend such cases are managed as non-toxigenic strains with antibiotic therapy only if clinically indicated (3).
Cases of diphtheria in England in 2021
This 2021 review updates a previous annual review of diphtheria cases in England for 2020 (5). Data sources for the enhanced surveillance of diphtheria include notifications, reference and NHS laboratory reports, death registrations, and individual case details such as vaccination history, source of infection, and severity of disease obtained from hospital records and general practitioners.
During 2021, toxigenic strains of corynebacteria were identified from 10 persons (including 2 separate episodes in one person) by the NRL. This compares with one toxigenic strain in 2020 (C. ulcerans), 10 toxigenic strains in 2019 (all C. ulcerans), 11 toxigenic strains in 2018 (3 C. ulcerans; 8 C. diphtheriae) and 5 toxigenic strains in 2017. One NTTB C. diphtheriae strain, was also identified during the 2021 period, 2 in each of the years 2020, 2019 and 2018.
Diphtheria is a notifiable disease in accordance with the amended Public Health (Control of Disease) Act 1984 and accompanying regulations (6). In 2021, there were 3 diphtheria notifications received from NOIDs for England; laboratory investigation identified one as a toxigenic C. diphtheriae infection and one as a non-toxigenic C. diphtheriae infection.
The remaining notification was submitted presumptively prior to local testing and was subsequently found to not be a corynebacterial infection. Of the toxigenic cases, 9 were not formally notified.
During 2021, the NRL received a total of 51 isolates for confirmation and toxigenicity testing from 50 individual cases for investigation (45 human and 5 companion animals) from England. This compares with 29 isolates (25 human and 4 animals) in 2020, and 101 isolates (96 human and 5 animal) in 2019.
Isolates from 3 individuals were identified as toxigenic C. diphtheriae and 8 isolates from 7 individuals as toxigenic C. ulcerans, only one of which was formally notified (Table 1). Toxigenic C. ulcerans strains were confirmed from a further 4 companion animals, 2 of which were not epidemiologically linked to a human case.
Of the remaining isolates, 20 were non-toxigenic C. diphtheriae, 5 were non-toxigenic C. ulcerans and 10 were not C. diphtheriae, C. ulcerans, or C. pseudotuberculosis. One NTTB C. diphtheriae was also isolated.
Table 1: Summary of (a) Diphtheria notifications (NOIDs) (b) Toxigenic corynebacteria by strain and (c) NRL toxigenicity testing, England: 2021
| (a) Total diphtheria notifications in 2021 | |
|---|---|
| Number due to toxigenic C. diphtheriae | 1 |
| Number due to toxigenic C. ulcerans | 0 |
| Number due to non-toxigenic tox gene bearing (NTTB) C. diphtheriae | 0 |
| Number due to non-toxigenic C. diphtheriae | 1 |
| Notified but did not meet possible case classification | 1 |
| (b) All toxigenic corynebacteria isolates from human cases in 2021 | |
|---|---|
| Toxigenic C. diphtheriae | 3 |
| Toxigenic C. ulcerans* | 8 |
| NTTB C. diphtheriae | 1 |
| (c) All toxigenic corynebacteria isolates from human cases in 2021 | |
|---|---|
| Toxigenic C. diphtheriae | 3 |
| NTTB C. diphtheriae | 1 |
| Non-toxigenic C. diphtheriae | 20 |
| Toxigenic C. ulcerans** | 12 |
| Non-toxigenic C. ulcerans*** | 5 |
| Other – Not C. diphtheriae, C. ulcerans, or C. pseudotuberclerosis | 10 |
* Includes 2 episodes in one individual
** Includes 4 isolates from companion animals; 2 not epidemiologically linked to a case
*** Includes 1 isolate from a companion animal
Corynebacterium diphtheriae
In 2021, toxigenic C. diphtheriae strains from 3 individuals were identified with age range 17 to 56 years. One cutaneous case was a 56 year old male identified through a routine clinical appointment for a diabetic skin lesion. He had no history of recent travel and was unvaccinated. Contact tracing identified an asymptomatic case in the same household who was fully vaccinated for age with no history of recent travel.
A third case with cutaneous toxigenic C. diphtheriae was identified in an unrelated unvaccinated individual in the same geographical area. The case was aged 41 years, was not born in the UK and had no history of recent travel. The case was admitted to hospital due to worsening infected leg wounds from a prior injury, discharge and erythema and discharged home after 3 days with the recommended course of antibiotics; no diphtheria anti-toxin was required.
Although no direct epidemiological link to the other two cases was confirmed, all 3 cases were of identical biovar (gravis) and Sequence Type by MLST to previous cases in the area; a cluster of 3 cases in 2018 (7) and one severe respiratory case in 2017 (8), suggesting there may be ongoing onward transmission in this area (9).
In response to this recent cluster of cases, additional local actions are ongoing including increased contact tracing, development of communication materials to raise awareness of diphtheria and the importance of vaccination generally, and liaison with local community networks and GP practices to improve vaccine uptake in the area.
Initial contact tracing for the 3 cases identified 6 close contacts including 5 household contacts and one non-household contact. Due to the ongoing pandemic, all health care workers adhering to coronavirus (COVID-19) protocols, including the use of personal protective equipment (PPE) were deemed sufficiently protected against the transmission of C. diphtheriae and C. ulcerans; no breaches in protocol were reported by the healthcare workers in contact with the cases and therefore they were not considered as close contacts.
One NTTB C. diphtheriae isolate was identified in 2021 from an individual with an inflamed leg wound. The case was a fully vaccinated female in her fifties with no history of recent travel. She is a household contact of an asymptomatic NTTB carrier with an underlying genetic condition that increases their susceptibility to skin infections.
The carrier was identified as a case in 2015 with antibiotics and vaccinations administered to the case and contacts at that time (10); and twice in 2017 where no further treatment was given to the case due to extensive skin damage, nor the contacts due to no evidence of disease (8). The 2021 NTTB case received antibiotics in accordance with national guidelines, but vaccination was deemed unnecessary due to a booster dose administered in 2015.
Corynebacterium ulcerans
There were 8 toxigenic C. ulcerans isolates identified in 7 individuals in 2021, of which 3 had a cutaneous presentation (including one with secondary isolation from a throat swab), 2 had severe respiratory infections, and 2 had non-classical presentations. Of the cases, 5 were women and the age range was 40 to 88 years.
Only 3 cases had a recorded history of receiving diphtheria-containing vaccines. Four cases were hospitalised and 2 died; both cases that died were treated with anti-toxin and were aged in their late eighties. Risk factors for C. ulcerans include consumption of raw milk products and contact with farm and companion animals (3). All cases had contact with domestic pets, and swabs were taken from the animal contacts of 5 cases. In total, swabs were taken from 12 companion animals and 2 of these swabs tested positive for C.ulcerans.
Toxigenic C. ulcerans was isolated from skin swabs on 2 occasions in the same individual in 2021; this individual, a known diabetic, was also identified as a toxigenic C. ulcerans case in 2019 (11). The case was male and aged in his seventies, with incomplete vaccine history and contact with a pet dog.
A second toxigenic C. ulcerans isolate was identified in an unrelated woman in the same geographical area with similar presentation of diabetic skin lesions, however, no direct epidemiological link between the cases has been identified.
The third case of cutaneous C. ulcerans was admitted to hospital in a septic and hypotensive state with infected leg ulcers; a subsequent swab identified toxigenic C. ulcerans was present in the throat also, but no respiratory symptoms were present. The case was aged in her late eighties, with an unknown vaccination history. She responded to antibiotics and anti-toxin treatment initially but then deteriorated. The case had significant underlying health conditions and died after 21 days in hospital. Swabs from the case’s cat were positive for toxigenic C. ulcerans and the cat was euthanised.
A further 2 cases were admitted to hospital with respiratory infections. The first of these was an individual aged 61 with an unknown vaccination history, the case significantly improved after receiving antibiotics (both oral and IV) and no anti-toxin was required. The second respiratory case was in a female in her late eighties with an unknown vaccination history.
She was admitted to hospital with severe respiratory distress, sepsis, and an extremely large membrane from larynx to carina. She was treated with antibiotics and anti-toxin and saw some improvement, however remained weak after tracheostomy and died 2 months after admission.
The remaining 2 cases did not present with classical symptoms. Both cases were aged in their fifties, one had an unknown vaccination history and presented with some swelling in the neck and toxigenic C. ulcerans was isolated from ear discharge following a respiratory tract infection. The other case was fully vaccinated and presented with ongoing hip pain following a number of fractures and surgeries, toxigenic C. ulcerans was isolated from hip joint fluid. The swab from one of the dog contacts of this case tested positive for toxigenic C. ulcerans.
Contact tracing from all toxigenic C.ulcerans cases identified 11 close contacts including 3 household contacts, 4 non-household contacts, and 4 health care workers; no transmission among human contacts was identified. Due to the ongoing pandemic, all health care workers adhering to COVID-19 protocols, including the use of personal protective equipment (PPE), were deemed sufficiently protected against the transmission of C. diphtheriae and C. ulcerans; no breaches in protocol were reported by the other health care workers in contact with the cases and therefore they were not considered as close contacts.
Table 2: Clinical presentation of diphtheria cases and causative organism, England 2021
| Clinical presentation of cases | Toxigenic C. diphtheriae | Toxigenic C. ulcerans | NTTB C. diphtheriae | Total |
|---|---|---|---|---|
| Severe respiratory diphtheria (sore throat with exudate or membrane) | – | 1 | – | 1 |
| Mild respiratory diphtheria (sore throat/pharyngitis) | – | 1 | – | 1 |
| Cutaneous diphtheria | 2 | 3 | 1 | 6 |
| Asymptomatic | 1 | – | – | 1 |
| Other | – | 2 | – | 2 |
Further information
Microbiological laboratories are requested to promptly submit all suspect isolates of C. diphtheriae, C. ulcerans and C. pseudotuberculosis to the NRL at UKHSA, RVPBRU, Colindale, London using the laboratory request form R3 (12).
From 1 April 2014, the test result which helps inform public health actions is a real-time PCR result which confirms the identity of C. diphtheriae, C. ulcerans or C. pseudotuberculosis and determines whether the gene for the diphtheria toxin (tox) is present.
If the tox gene is detected, the isolate goes on to have an Elek test to confirm expression of toxin (4). The NRL also provides advice on all aspects of laboratory testing for diphtheria and related infections. Advice on immunisation against diphtheria, provision of vaccine and provision of diphtheria antitoxin for therapeutic use is available from the UKHSA Colindale Immunisation Department and in the recently published revised guidance for public health control and management of diphtheria (3).
As a disease becomes rare, the completeness and accuracy of surveillance information become more important and each clinical diagnosis (that is notification) needs to be confirmed by laboratory diagnosis. In addition to notifications, enhanced surveillance for diphtheria incorporates data from reference and NHS laboratories, death registration, and individual case details such as vaccination history, source of infection and severity of disease obtained from hospital records, general practitioners and local incident team reports.
Linkage of notified cases of suspected diphtheria and confirmatory laboratory data shows that most notifications are cases of pharyngitis associated with isolation of non-toxigenic strains of C. diphtheriae, and therefore interpretation of notification data should be undertaken with caution.
References
1. UK Health Security Agency. ‘The Green Book, chapter 15: Diphtheria’
2. Wagner KS, White JM, Crowcroft NS, De Martin S, Mann G, Efstratiou A (2010). ‘Diphtheria in the United Kingdom, 1986-2008: the increasing role of Corynebacterium ulcerans’. Epidemiology and Infection: volume 138, issue 11, pages 1519-1530
3. UK Health Security Agency (2022). ‘Public health control and management of diphtheria in England: 2022 guidelines’
4. De Zoysa A, Efstratiou A, Mann G, Harrison TG, Fry NK (2016). ‘Development, validation and implementation of a quadruplex real-time PCR assay for identification of potentially toxigenic corynebacteria’. Journal of Medical Microbiology: volume 65, issue 12, pages 1521-1527
5. PHE (2021). ‘Diphtheria in England: 2020. Health Protection Report: volume 15 number 7’
6. UK Health Security Agency (2021). ‘Notifiable diseases and causative organisms: how to report’
7. PHE (2019). ‘Diphtheria in England: 2018. Health Protection Report: volume 14 number 6’
8. PHE (2018). ‘Diphtheria in England: 2017. Health Protection Report: volume 12 number 18’
9. Edwards D, Kent D, Lester C, Brown CS, Murphy ME, Brown NM and others (2018). ‘Transmission of toxigenic Corynebacterium diphtheriae by a fully immunised resident returning from a visit to West Africa, United Kingdom, 2017’ Eurosurveillance: volume 23, issue 39
10. PHE (2016). ‘Diphtheria in England: 2018. Health Protection Report: volume 11 number 3’
11. PHE (2020). ‘Diphtheria in England: 2018. Health Protection Report: volume 13 number 10’
12. UK Health Security Agency. ‘R3: vaccine preventable bacteria section request form’