Diphtheria

Last updated: January 2021


– Diphtheria is a bacterial infection due to Corynebacterium diphtheriae, spread from person to person through inhalation of infected respiratory droplets of symptomatic or asymptomatic individuals, or direct contact with contaminated objects or diphtheria skin lesions1,21 .
– After infection, C. diphtheriae has an incubation period of 1 to 5 days (max. 10 days)1 during which time it multiplies in the upper respiratory tract. The bacteria secretes a toxin which causes severe local as well as systemic effects. Death can occur from airway obstruction or as a result of systemic complications, including damage to the myocardium and nervous system, caused by the toxin. 
– Cases can remain infectious up to 8 weeks after initial infection2. Antibiotic treatment can reduce infectiousness to 6 days3.
– Vaccination is the key to prevention and control of diphtheria. It protects individuals from severe disease (fewer and less severe symptoms) but does not prevent the spread of C. diphtheriae. Clinical disease does not confer protective immunity and vaccination is an integral part of case management.

Clinical features

– During clinical examination respect standard, contact, and droplet precautions (handwashing, gloves, gown, mask, etc.). Conduct a careful examination of the throat.

– Signs of respiratory diphtheria
1 :
• pharyngitis, rhinopharyngitis, tonsillitis or laryngitis with tough, greyish, firmly adherent pseudo-membranes of the pharynx, nasopharynx, tonsils, or larynx;

• dysphagia and cervical adenitis, at times progressing to massive swelling of the neck;
• airway obstruction and possible suffocation when the infection extends to the nasal passages, larynx, trachea and bronchi;
• fever is generally low-grade2.

– Generalised signs due to effects of the toxin:
• cardiac dysfunction (tachycardia, arrhythmias), severe myocarditis with heart failure and possibly cardiogenic shock (see Shock, Chapter 1) 3 to 7 days or 2 to 3 weeks after onset of the disease;

• neuropathies in 2 to 8 weeks after the onset of disease leading to nasal voice and difficulty with swallowing (paralysis of the soft palate), vision (ocular motor paralysis), breathing (paralysis of respiratory muscles) and ambulation (limb paralysis);
• oliguria, anuria and acute renal failure.

– Differential diagnoses: Epiglottitis and Acute pharyngitis, Chapter 2, Stomatitis, Chapter 3.

Laboratory

– Diagnosis is confirmed by isolation of toxigenic C. diphtheriae by culture (and antibiotic susceptibility test) of swab specimens collected from the affected areas: throat (tonsils, pharyngeal mucosa, soft palate, exudate, ulcer, etc.), nasopharynx.
– The presence of the toxin is confirmed by PCR testing (detection of diphtheria toxin gene).

Treatment

– Isolation of patients; standard, droplet, and contact precautions for medical staff.

Diphtheria antitoxin (DAT)2 derived from horse serum
Administer DAT as soon as possible after disease onset. Do not wait for bacteriological confirmation1; administer DAT under close monitoring in a hospital setting, according to the Besredka method to assess possibility of allergy. Any delay can diminish efficacy.
 There is a risk of anaphylactic reaction, especially in patients with asthma. Close monitoring of the patient is essential, with immediate availability of equipment for manual ventilation (Ambu bag, face mask) and intubation, Ringer lactate and epinephrine (see Shock, Chapter 1).

Besredka method: inject 0.1 ml SC and wait 15 minutes. If there is no allergic reaction (no erythema at the injection site or a flat erythema of less than 0.5 cm in diameter), inject a further 0.25 ml SC. If there is no reaction after 15 minutes, inject the rest of the product IM or IV depending on the volume to be administered.

Doses are given as a function of the severity of illness, and the delay in treatment:

Clinical signs

Dose in units

Administration route

Laryngitis or pharyngitis
or duration < 48 hours

20 to 40 000


IM or IV infusion in 250 ml of 0.9% sodium chloride in 2 to 4 hours for doses of more than 20 000 units.

Rhinopharyngitis

40 to 60 000

Severe disease (respiratory distress, shock), cervical oedema or duration ≥ 48 hours

80 to 100 000

– Antibiotic treatment (as soon as possible without waiting for bacteriological confirmation ) for 14 days or according to length of treatment recommended by the national protocol:
• if the patient can swallow:
azithromycin PO (first-line)
Children: 10 to 12 mg/kg once daily (max. 500 mg daily)
Adults: 500 mg once daily
or
erythromycin PO
Children under 40 kg: 10 to 15 mg/kg (max. 500 mg) 4 times daily
Children 40 kg and over and adults: 500 mg 4 times daily
or
phenoxymethylpenicillin (penicillin V) PO
Children under 40 kg: 10 to 15 mg/kg (max. 500 mg) 4 times daily
Children 40 kg and over and adults: 500 mg 4 times daily

• If the patient cannot swallow, start with one of the treatments below and change as soon as possible to oral route with one of the oral treatments above to complete 14 days of treatment:
procaine benzylpenicillin IM
Children under 25 kg: 50 000 IU/kg (= 50 mg/kg) once daily (max. 1.2 MIU = 1.2 g daily)

Children 25 kg and over and adults: 1.2 MIU (= 1.2 g) once daily
 Never administer procaine benzylpenicillin by IV injection or infusion.
or, if  not available,

benzylpenicillin IM or slow IV (3 minutes)
Children: 50 000 IU/kg (= 30 mg/kg) every 6 hours (max. 4 MIU = 2.4 g daily)
Adults: 1 MIU (= 600 mg) every 6 hours
In penicillin-allergic patients, use erythromycin IV3 .

– Intubation/tracheotomy if necessary (airway obstruction, respiratory failure, etc.).
– If the event of shock, see Shock, Chapter 1, for complementary treatment.
– Update every patient's vaccination status before hospital discharge (or during first visit, if receiving home-based care). If the patient has been administered DAT and can receive adequate home-based follow up after hospital discharge, wait 3 weeks after administration of DAT before vaccination.

Management of close contacts 

Close contacts include household members living under the same roof and people who were directly exposed (less than one metre) to nasopharyngeal secretions of the patient on a regular basis (e.g. family or close friends, children in the same class, medical personnel) during the 5 days or nights prior to onset of symptoms of the case4.

– Collect nasal and pharyngeal swabs for culture before starting antibiotic prophylaxis; temperature and throat examination daily (10 days); exclusion from school or work until 48 hours after starting antibiotic prophylaxis. If symptoms of respiratory infection appear: treat immediately as a case of diphtheria.

– Antibiotic prophylaxis:
benzathine benzylpenicillin IM
Children under 30 kg: 600 000 IU single dose
Children 30 kg and over and adults: 1.2 MIU single dose
 Benzathine benzylpenicillin should never be administered by IV route.
or azithromycin PO or erythromycin PO as above for 7 days.

– Check vaccination status:
• if less than 3 injections received: complete vaccination schedule (see Prevention below);
• if 3 injections received, with the last injection over one year ago: administer a booster dose immediately;
• if 3 injections received, with the last injection less than one year ago: a booster dose is not immediately necessary.

Outbreak surveillance measures

– A suspected case of diphtheria is defined as a person with:
• pharyngitis, rhinopharyngitis, tonsillitis and/or laryngitis
AND
• an adherent pseudo-membrane of the pharynx, nose, tonsils and/or larynx1.

– Isolate and treat suspect cases without delay. Collect swab samples before starting antibiotic treatment. Submit case notification to the public health authorities within 24 hours1.

Prevention 

– Routine vaccination (EPI), for information: 3 doses of conjugate vaccine containing the higher potency (D) formulation of diphtheria toxoid as soon as possible as of 6 weeks of age and at 4 week intervals; D booster between 12 and 23 months, then between 4 and 7 years; booster with a vaccine containing a reduced dose (d) of diphtheria toxoid between 9 and 15 years5.
– Catch-up vaccination (individuals who have not received routine vaccination), for information:
• children 1 to 6 years: 3 doses of conjugate vaccine containing the higher potency (D) formulation of diphtheria toxoid at least 4 weeks apart;
• children 7 years and over and adults (including medical staff): 3 doses of conjugate vaccine containing a reduced dose (d) of diphtheria toxoid. Administer with a minimum interval of 4 weeks between first and second dose and an interval of at least 6 months between second and third dose (in the event of an outbreak this interval may be reduced to 4 weeks to achieve protection quicker).
Administer 2 subsequent booster doses containing d at least 4 weeks apart5.



Footnotes
Ref Notes
1 This guide focuses on respiratory diphtheria and signs due to the toxin. It should be noted that cutaneous diphtheria is still a significant reservoir of C. diphtheriae. [ a b ]
2 DAT reduces mortality and should be given to all diphtheria patients. However, as supply is very limited, it may be necessary to define criteria and reserve DAT for the treatment of patients who will benefit the most from it. DAT can be administered to pregnant women.
3 erythromycin IV infusion (60 minutes)
Children: 12.5 mg/kg every 6 hours (max. 2 g daily); adults: 500 mg every 6 hours
Erythromycin powder (1 g) should be reconstituted in 20 ml of water for injection only. Then, dilute each dose of erythromycin in 10 ml/kg of 0.9% sodium chloride in children less than 20 kg and in a bag of 250 ml of 0.9% sodium chloride in children 20 kg and over and in adults. Do not dilute in glucose.


References

  1. World Health Organization. Diphtheria. Vaccine-Preventable Diseases Surveillance Standards. 2018.
    https://www.who.int/immunization/monitoring_surveillance/burden/vpd/WHO_SurveillanceVaccinePreventable_04_Diphtheria_R2.pdf?ua=1 [Accessed 11 August 2020]

  2. Tiwari TSP, Wharton M. Chapter 19: Diphtheria Toxoid. In: Plotkin SA, Orenstein WA, Offit PA, editors. Vaccines. 7th ed. Philadelphia, PA: Elsevier; 2018. p. 261–275.

  3. Truelove SA, Keegan LT, Moss WJ, Chaisson LH, Macher E, Azman AS, Lessler J. Clinical and Epidemiological Aspects of Diphtheria: A Systematic Review and Pooled Analysis. Clin Infect Dis. 2020 Jun 24;71(1):89-97. 
    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7312233/ [Accessed 24 November 2020]

  4. Pan American Health Organization, World Health Organization. Diphtheria in the Americas - Summary of the situation 2018. Epidemiological Update Diphtheria. 16 April 2018.
    https://www.paho.org/hq/index.php?option=com_docman&view=download&category_slug=diphtheria-%098968&alias=44497-16-april-2018-diphtheria-epidemiological-update-497&Itemid=270&lang=en [Accessed 11 August 2020]

  5. World Health Organization. Diphtheria vaccine: WHO position paper - August 2017. Weekly epidemiological record 2017; 92/(31):417–436.
    https://www.who.int/immunization/policy/position_papers/wer_31_diphtheria_updated_position_paper.pdf?ua=1 [Accessed 11 August 2020]