Diphtheria

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    Last updated: June 2025

     

     

    Diphtheria is a vaccine-preventable bacterial infection caused by Corynebacterium diphtheriae, affecting the respiratory tract and, less commonly, the skinaCitation a.Cutaneous diphtheria presents as a slowly progressing, non-healing ulcer with a greyish pseudomembrane. Pharyngeal manifestation and systemic complications caused by exotoxins are uncommon. Diagnosis and antibiotic management are guided by swab culture..

    The disease is transmitted via respiratory droplets from asymptomatic or symptomatic individuals and through direct contact with contagious cutaneous lesions or contaminated materials[1]Citation 1.Sharma NC, Efstratiou A, Mokrousov I, Mutreja A, Das B, Ramamurthy T. Diphtheria. Nat Rev Dis Primer. 2019;5(1):81. 
    https://doi.org/10.1038/s41572-019-0131-y    , [2]Citation 2.World Health Organization. Diphtheria outbreaks/ Comprehensive guidance for the public health preparedness and response in the WHO African Region | WHO | Regional Office for Africa. December 12, 2024. Accessed December 13, 2024. https://www.afro.who.int/publications/diphtheria-outbreaks-comprehensive-guidance-public-health-preparedness-and-response    . The incubation period ranges from 2 to 5 days[1]Citation 1.Sharma NC, Efstratiou A, Mokrousov I, Mutreja A, Das B, Ramamurthy T. Diphtheria. Nat Rev Dis Primer. 2019;5(1):81. 
    https://doi.org/10.1038/s41572-019-0131-y    , [3]Citation 3.Truelove SA, Keegan LT, Moss WJ, et al. Clinical and Epidemiological Aspects of Diphtheria: A Systematic Review and Pooled Analysis. Clin Infect Dis. 2020;71(1):89-97. 
    https://doi.org/10.1093/cid/ciz808    .

    Respiratory diphtheria is characterised by the formation of a pseudomembrane, which can cause life-threatening airway obstruction. Toxin-producing strains can lead to severe systemic complications, including myocarditis, neuropathy, and acute renal failure[1]Citation 1.Sharma NC, Efstratiou A, Mokrousov I, Mutreja A, Das B, Ramamurthy T. Diphtheria. Nat Rev Dis Primer. 2019;5(1):81. 
    https://doi.org/10.1038/s41572-019-0131-y    , [4]Citation 4.World Health Organization. Clinical management of diphtheria: guideline, 2 February 2024. Accessed December 13, 2024. 
    https://www.who.int/publications/i/item/WHO-DIPH-Clinical-2024.1    . Even with appropriate treatment, the case-fatality rate ranges from 5 to 10%, highlighting the need for early case management and immunisation[2]Citation 2.World Health Organization. Diphtheria outbreaks/ Comprehensive guidance for the public health preparedness and response in the WHO African Region | WHO | Regional Office for Africa. December 12, 2024. Accessed December 13, 2024. https://www.afro.who.int/publications/diphtheria-outbreaks-comprehensive-guidance-public-health-preparedness-and-response, [3]Citation 3.Truelove SA, Keegan LT, Moss WJ, et al. Clinical and Epidemiological Aspects of Diphtheria: A Systematic Review and Pooled Analysis. Clin Infect Dis. 2020;71(1):89-97. 
    https://doi.org/10.1093/cid/ciz808    .

    Diphtheria remains a major concern in overcrowded settings with low vaccination coverage, where outbreaks can occur. Vaccination is essential in preventing severe disease and reducing transmission. 


    Clinical presentation 

    Respiratory diphtheria 

    • Symptoms develop gradually, beginning with mild, non-specific upper respiratory tract symptoms such as sore throat, low-grade fever, and malaise. 
    • Thick, firmly adherent greyish-white pseudomembrane, which bleeds easily when touched, in pharyngeal, tonsillar or nasal passage, potentially extending to larynx, trachea and bronchial tree. 

    Caution: conduct a careful examination and avoid pharyngeal irritation.  

     

    Danger signs[5]Citation 5.Farizo KM, Strebel PM, Chen RT, Kimbler A, Cleary TJ, Cochi SL. Fatal respiratory disease due to Corynebacterium diphtheriae: case report and review of guidelines for management, investigation, and control. Clin Infect Dis Off Publ Infect Dis Soc Am. 1993;16(1):59-68. https://doi.org/10.1093/clinids/16.1.59, [6]Citation 6.Jayashree M, Shruthi N, Singhi S. Predictors of outcome in patients with diphtheria receiving intensive care. Indian Pediatr. 2006;43(2):155-160.

    • Stridor, hoarseness, respiratory distress and airway obstruction 
    • “Bull neck”: fulminant cervical swelling, oedema and lymphadenopathy 

     

    Complications

    Systemic complications result from exotoxin dissemination (with early and late onset):


    Cardiac: Myocarditis with arrhythmias, heart blocks, and heart failure, leading to cardiogenic shock, presenting 3 to 7 days or 2 to 3 weeks after disease onset.

    Neurological: Cranial (e.g. soft palate, oculomotor, respiratory muscles) and peripheral (e.g. limb) neuropathies, presenting 2 to 8 weeks after disease onset.

    Renal: Oliguria, anuria, and acute renal failure

    Differential diagnosis: pharyngitis, oral candidiasis, epiglottitis, croup, stomatitis 
     

    Diagnosis

    Suspected diagnosis
    Upper respiratory tract infection with presence of pseudomembrane
     

    Confirmed diagnosis

    • Isolation of C. diphtheriae by culture from pharyngeal and nasal swab (vigorously rub over and beneath pseudomembranes) with drug susceptibility testing.
    • If positive, specific toxigenicity testing (PCR or Elek test) to confirm toxin production (in specialised laboratories)[2]Citation 2.World Health Organization. Diphtheria outbreaks/ Comprehensive guidance for the public health preparedness and response in the WHO African Region | WHO | Regional Office for Africa. December 12, 2024. Accessed December 13, 2024. https://www.afro.who.int/publications/diphtheria-outbreaks-comprehensive-guidance-public-health-preparedness-and-response
       

    Infection control and prevention 

    • Hospitalisation is required for both suspected and confirmed cases.
    • Healthcare staff: apply standard, contact and droplet precautions (hand hygiene, gloves, gown, mask, face shields).

    Management  

    Start treatment (antibiotics and diphtheria antitoxin simultaneously) as soon as disease is clinically suspected (pseudomembranous pharyngitis). Take swab before initiation of antibiotics (if possible). Do not wait for bacteriological confirmation.  

      Any delay can diminish treatment efficacy and increase mortality due to respiratory and systemic complications[2]Citation 2.World Health Organization. Diphtheria outbreaks/ Comprehensive guidance for the public health preparedness and response in the WHO African Region | WHO | Regional Office for Africa. December 12, 2024. Accessed December 13, 2024. https://www.afro.who.int/publications/diphtheria-outbreaks-comprehensive-guidance-public-health-preparedness-and-response, [4]Citation 4.World Health Organization. Clinical management of diphtheria: guideline, 2 February 2024. Accessed December 13, 2024. 
    https://www.who.int/publications/i/item/WHO-DIPH-Clinical-2024.1

     

    Diphtheria antitoxin (DAT) 

    DAT is an immunoglobulin derived from horse serum that may cause allergic reactions including anaphylaxis. Administer only under close monitoring by trained staff and immediate availability of airway management and treatment (epinephrine, salbutamol, antihistamine, corticosteroid, Ringer lactate). See Anaphylatic shock (Chapter 1)[2]Citation 2.World Health Organization. Diphtheria outbreaks/ Comprehensive guidance for the public health preparedness and response in the WHO African Region | WHO | Regional Office for Africa. December 12, 2024. Accessed December 13, 2024. https://www.afro.who.int/publications/diphtheria-outbreaks-comprehensive-guidance-public-health-preparedness-and-response, [4]Citation 4.World Health Organization. Clinical management of diphtheria: guideline, 2 February 2024. Accessed December 13, 2024. 
    https://www.who.int/publications/i/item/WHO-DIPH-Clinical-2024.1    , [7]Citation 7.Eisenberg N, Panunzi I, Wolz A, et al. Diphtheria Antitoxin Administration, Outcomes, and Safety: Response to a Diphtheria Outbreak in Cox’s Bazar, Bangladesh. Clin Infect Dis. 2021;73(7):e1713-e1718.
    https://doi.org/10.1093/cid/ciaa1718

    DAT is indicated for all suspected cases, including pregnant and breastfeeding women. However, as supply might be limited, it should be prioritised for patients at greater risk of complications. 

    The dose (same for adults and children) depends on the severity and the duration of disease[4]Citation 4.World Health Organization. Clinical management of diphtheria: guideline, 2 February 2024. Accessed December 13, 2024. 
    https://www.who.int/publications/i/item/WHO-DIPH-Clinical-2024.1    . 

     

    Characteristics of diphtheria disease

    Dose of DAT in IU

    Laryngitis or pharyngitis and duration < 48 hours 

    20000

    Pseudomembrane in nasopharynx and duration < 48 hours 

    40000

    Severe disease (respiratory distress, shock) or neck swelling or duration ≥ 48 hours 

    80000 


    DAT is administered as a single dose IM or, preferably, by IV infusion in 0.9% sodium chloride (NaCl)[8]Citation 8.World Health Organization. Preparation and administration of diphtheria antitoxin, 2 February 2024. Accessed December 13, 2024. https://www.who.int/publications/i/item/WHO-Diph-DAT-Poster_B-2024.1:
    Children < 10 kg: individualised scheme to avoid fluid overload (extend duration, decrease volume)
    Children < 10 years: in 250 ml of 0.9% NaCl over 4 hours 
    Children ≥ 10 years and adults: in 250 ml of 0.9% NaCl over 2 hours 


    Antibiotic treatment 

    Antibiotic treatment is given for 14 days. The oral route should be prioritised. The parenteral route should be chosen if the patient is unable to swallow: switch to oral route as soon as possible to complete treatment[4]Citation 4.World Health Organization. Clinical management of diphtheria: guideline, 2 February 2024. Accessed December 13, 2024. 
    https://www.who.int/publications/i/item/WHO-DIPH-Clinical-2024.1    .

    Macrolide antibiotics are the first-line option for empirical treatment due to risk of penicillin resistance. Azithromycin is preferred over erythromycin as it is better tolerated and simpler to administer[4]Citation 4.World Health Organization. Clinical management of diphtheria: guideline, 2 February 2024. Accessed December 13, 2024. 
    https://www.who.int/publications/i/item/WHO-DIPH-Clinical-2024.1    . Antibiotic choice can be adjusted based on drug susceptibility test results.

     

    Macrolide antibiotics (first-line) 

    azithromycin[2]Citation 2.World Health Organization. Diphtheria outbreaks/ Comprehensive guidance for the public health preparedness and response in the WHO African Region | WHO | Regional Office for Africa. December 12, 2024. Accessed December 13, 2024. https://www.afro.who.int/publications/diphtheria-outbreaks-comprehensive-guidance-public-health-preparedness-and-response  

    PO or IV

    Children: 10 to 12 mg/kg (max. 500 mg daily) once daily


    Adults: 500 mg once daily 

    erythromycin  

    PO  

    Children < 40 kg: 10 to 15 mg/kg (max. 500 mg per dose) 4 times daily  


    Children ≥ 40 kg and adults: 500 mg 4 times daily 

    Penicillin antibiotics (if macrolides are not available)bCitation b.Do not confuse short-acting benzylpenicillin (e.g. phenoxymethylpenicillin, benzylpenicillin), administered several times daily by IV route, with long-acting penicillins (benzathine benzylpenicillin and procaine benzylpenicillin) administered by IM route only.

    phenoxymethyl-penicillin (penicillin V)  

    PO

    Children < 40 kg: 10 to 15 mg/kg (max. 500 mg) 4 times daily 


    Children ≥ 40 kg and adults: 500 mg 4 times daily 

    benzylpenicillin (penicillin G)  

    IM or slow IV

    Children < 40 kg: 25 000 IU/kg (15 mg/kg) (max. 1 MIU or 600 mg) every 6 hours
     

    Children ≥ 40 kg and adults: 1 MIU (600 mg) every 6 hours 

    procaine benzylpenicillin (penicillin G procaine)

    IM (never by IV route)

    Children: 50 000 IU/kg (50 mg/kg) once daily (max. 1.2 MIU or 1.2 g daily)

    Adult: 1.2 MIU (1.2 g) once daily

    Airway and circulation

    • Close monitoring of admitted patients (every 2 to 4 hours).

    • In case of stridor, airway oedema, or respiratory distress, see Acute upper airway obstruction, Chapter 2:

      • Dexamethasone IV: 0.6 mg/kg loading dose followed by 0.1 mg/kg every 6 hours (max. 10 mg per dose) and/or

      • Epinephrine (adrenaline) via nebuliser: 0.5 mg/kg (max. 5 mg) in 5 ml of 0.9% NaCl over 10 to 15 minutes.

      • Oxygen if SpO2 < 94% (with target SpO2 94–98%)

    • Intubation, tracheostomy or cricothyroidotomy may become necessary as definitive option, but it should only be considered if the facility can meet all necessary requirements.

    • Renal and cardiac monitoring, including electrocardiography.

    • In the event of cardiac failure and shock, see Shock, Chapter 1.

     

    Immunisation

    Vaccination should be initiated or completed for all individuals (including suspected or confirmed cases and their contacts) without proof of full vaccination (if patient has been administered DAT, wait 3 weeks):

    • If < 3 doses received: administer a dose immediately and complete vaccination schedule (see Prevention).

    • If ≥ 3 doses received, with the last injection over 5 years ago: administer a booster dose immediately.

    Vaccination protects from severe disease but does not prevent transmission. Infection or immunisation does not lead to lasting immunity, making all age-groups susceptible for infection.

     

    Follow up 

    Monitoring for late onset complications (paralysis and myocarditis) for up to 3 months after discharge.

     

    Outbreak management

    Outbreak detection

    • Notify public health authorities immediately of any suspected case.

    • Collect pharyngeal and nasal swabs for laboratory confirmation.

     

    Case definition (once outbreak is declared)[2]Citation 2.World Health Organization. Diphtheria outbreaks/ Comprehensive guidance for the public health preparedness and response in the WHO African Region | WHO | Regional Office for Africa. December 12, 2024. Accessed December 13, 2024. https://www.afro.who.int/publications/diphtheria-outbreaks-comprehensive-guidance-public-health-preparedness-and-response

    A person with pharyngitis, rhinopharyngitis, tonsillitis or laryngitis

    • AND adherent pseudomembrane of the pharyngeal, tonsillar or nasal passage and/or larynx.

    • OR no pseudomembrane but with epidemiological link (e.g. contact) to a suspected/confirmed case.

     

    Management of contacts

    Post-exposure prophylaxis (PEP) and immunisation (see Management and Prevention) are required for all contacts, including home-based isolation, until completion of treatment with regular monitoring of clinical symptoms. If respiratory symptoms appear, contacts should receive immediate treatment for 14 days as per a case of diphtheria.

     

    Contact definition and tracing

    Active contact tracing of individuals who have been exposed to confirmed or suspected cases within 5 days before symptom onset, meeting one of the following criteria:

    • Household or cohort members in school or kindergarten

    • Close exposure of less than one metre for more than one hour

    • Direct exposure to respiratory secretions or mucosal lesion

     

    Post-exposure prophylaxis for contacts[2]Citation 2.World Health Organization. Diphtheria outbreaks/ Comprehensive guidance for the public health preparedness and response in the WHO African Region | WHO | Regional Office for Africa. December 12, 2024. Accessed December 13, 2024. https://www.afro.who.int/publications/diphtheria-outbreaks-comprehensive-guidance-public-health-preparedness-and-response

    Macrolide antibiotics PO (as above) for 7 days or benzathine benzylpenicillin IMbCitation b.Do not confuse short-acting benzylpenicillin (e.g. phenoxymethylpenicillin, benzylpenicillin), administered several times daily by IV route, with long-acting penicillins (benzathine benzylpenicillin and procaine benzylpenicillin) administered by IM route only. single dose (never by IV route):

    • Children < 30 kg: 600 000 IU

    • Children ≥ 30 kg and adults: 1.2 MIU   

     

    Routine vaccination schedule for children < 7 years of age using DTcCitation c.DT vaccines for infants and children up to 6 years of age containing the higher potency (D) formulation of diphtheria toxoid should be distinguished from lower concentrated Td vaccines, which is generally administered for primary vaccination schedule and booster for adolescents and adults. combinations[9]Citation 9.World Health Organization. WHO Position Papers - Recommendations for Routine Immunization. Accessed December 13, 2024. https://www.who.int/publications/m/item/table1-summary-of-who-position-papers-recommendations-for-routine-immunization

    • 3 dose primary vaccination series 4 weeks apart (starting 6 weeks of age), followed by 3 boosters.

    • DT is usually given as polyvalent combination vaccine according to national protocols (e.g. DTP, DTP-HepB, DTP-HepB-Hib-IPV). 

     

    Routine vaccination schedule for children ≥ 7 years of age and adults using TdcCitation c.DT vaccines for infants and children up to 6 years of age containing the higher potency (D) formulation of diphtheria toxoid should be distinguished from lower concentrated Td vaccines, which is generally administered for primary vaccination schedule and booster for adolescents and adults. or Tdap vaccines[9]Citation 9.World Health Organization. WHO Position Papers - Recommendations for Routine Immunization. Accessed December 13, 2024. https://www.who.int/publications/m/item/table1-summary-of-who-position-papers-recommendations-for-routine-immunization

    • 3 dose primary vaccination series (0, 1, 6 months schedule), followed by 2 boosters at least 1 year apart (interval may be reduced to 4 weeks in outbreak situation). 

    • Regular booster between 9 and 15 years of age, after that every 10 years 

     

    Footnotes
    • (a)

      Cutaneous diphtheria presents as a slowly progressing, non-healing ulcer with a greyish pseudomembrane. Pharyngeal manifestation and systemic complications caused by exotoxins are uncommon. Diagnosis and antibiotic management are guided by swab culture.

    • (b)

      Do not confuse short-acting benzylpenicillin (e.g. phenoxymethylpenicillin, benzylpenicillin), administered several times daily by IV route, with long-acting penicillins (benzathine benzylpenicillin and procaine benzylpenicillin) administered by IM route only.

    • (c)

      DT vaccines for infants and children up to 6 years of age containing the higher potency (D) formulation of diphtheria toxoid should be distinguished from lower concentrated Td vaccines, which is generally administered for primary vaccination schedule and booster for adolescents and adults.

    References
    Path