Chapter 1: Diphtheria

Disease Description

Diphtheria is a toxin-mediated disease that is rare in the United States and can manifest as both respiratory and non-respiratory illness. Infection with a toxin-producing strain of the gram-positive bacterium, Corynebacterium diphtheriae, is capable of causing the disease. The bacteria are able to produce this potent exotoxin only after lysogenization by beta-(β) corynebacteriophages that harbor tox, the structural gene for diphtheria toxin.1 Such strains are uncommon in the United States. The majority of C. diphtheriae infections in the U.S. are caused by strains that do not produce diphtheria toxin. Such nontoxin producing strains can cause bacterial infection, but do not cause diphtheria. Additionally, infection with toxigenic strains can occur without development of diphtheria if an infected host possesses sufficient diphtheria antitoxin to neutralize diphtheria toxin (e.g., from vaccination or prior infection).

Sites of C. diphtheriae infection are primarily the respiratory mucosa (respiratory diphtheria) and the skin (cutaneous diphtheria). Rarely, extra-respiratory mucosal sites (e.g., eye, ear, genitals) may be affected. Humans are believed to be the only reservoir of C. diphtheriae, although the bacteria have been occasionally recovered from other animals, including infected horses and companion animals, such as dogs and cats.234 C. diphtheriae infection is transmitted from person to person by respiratory droplets or direct contact with respiratory secretions, discharges from skin lesions, or, rarely, fomites.

The onset of respiratory diphtheria is insidious and begins after an incubation period of 2–5 days (range 1–10 days). Initial symptoms of illness include a sore throat, difficulty in swallowing, malaise, and low-grade fever. The hallmark of respiratory diphtheria is the presence of a tough, grayish-white pseudomembrane over the tonsils, nasopharynx, or larynx. The pseudomembrane is strongly adherent to the underlying tissue and attempts to dislodge it usually result in bleeding. Inflammation of the cervical lymph nodes and swelling of the surrounding soft tissue of the neck can give rise to a "bull-neck" appearance, which is a sign of severe disease. The pseudomembrane may progressively extend into the larynx and trachea and cause airway obstruction, which can be fatal if left untreated. Diphtheria toxin may be absorbed from the site of infection and result in systemic complications, including damage to the myocardium, nervous system, and kidneys. Untreated respiratory diphtheria usually lasts for 1 to 2 weeks, but complications can persist for months. Before treatment was available, the case-fatality rate was approximately 50%; with treatment and vaccination more widely available, the case-fatality rate has declined significantly and remains approximately 10%.5

Cutaneous diphtheria is usually mild, typically consisting of indistinct sores or shallow ulcers. Cutaneous diphtheria may act as a reservoir for transmission and result in respiratory or cutaneous infections in other susceptible hosts.678 Other non-respiratory and non-cutaneous sites (e.g., eye, ear, genital) of infection have been identified and can be present along with respiratory or cutaneous disease.

Two other Corynebacterium species (C. ulcerans and C. pseudotuberculosis) may also produce diphtheria toxin. Both species are zoonotic; such infections have been documented in cats, dogs, goats, pigs, and cattle. Toxin-producing C. ulcerans may cause diphtheria-like respiratory illness or cutaneous disease indistinguishable from that caused by C. diphtheriae, but person-to-person spread has not been well-established.910 C. pseudotuberculosis can cause lymphadenitis in humans.11

In recent years, an increase in nontoxin-producing strains of C. diphtheriae has been detected in the United States [unpublished data]. Infection with this straincan also cause disease. It is generally less severe than diphtheria, with presentations typical of those caused by other nontoxin producing bacteria.

Although invasive disease from these nontoxin producing strains, including bacteremia and endocarditis, has increasingly been identified, these clinical presentations do not constitute diphtheria, which requires the presence of diphtheria toxin.12131415 Disease caused by non–toxigenic tox gene-bearing (NTTB) C. diphtheriae has a similar presentation to that of strains that lack the gene; NTTB strains possess a mutated form of tox,which prevents expression of diphtheria toxin. NTTB strains have been detected in the United States and elsewhere.16

Although vaccination is highly protective against severe effects of diphtheria toxin, it does not prevent the infection with or carriage of C. diphtheriae, regardless of the strain's toxin production status. Some percentage of the population may be carriers of C. diphtheriae, but population carriage rates in the current era of high vaccination coverage are unknown.

Background

Diphtheria is now rarely reported in the United States; however, in the pre-vaccine era, the disease was one of the most common and feared causes of illness and death among children. The United States introduced vaccines containing diphtheria toxoid (formalin-inactivated diphtheria toxin) in the 1920s, and the implementation of universal childhood immunization occurred in the late 1940s. Widespread use of diphtheria toxoid-containing vaccines has contributed to the control of diphtheria in the United States, with the last major outbreak occurring in the 1970s in Seattle, Washington.17

Prior to 2019, an upper respiratory infection caused by any C. diphtheriae, irrespective of toxigenicity, was reportable to CDC's National Notifiable Diseases Surveillance System (NNDSS). Of the 14 cases of diphtheria reported in the U.S. during 1996 – 2018, only one, reported in 1997, was caused by toxigenic C. diphtheriae.

Over the last decade, nonrespiratory (most commonly cutaneous) diphtheria has been increasingly detected in the United States and elsewhere.181920 Given that cutaneous and other forms of nonrespiratory diphtheria can be transmitted and cause respiratory diphtheria, the US case definition was revised in 2019 to include disease caused by toxin-producing C. diphtheriae from any site, including cutaneous sites.2122 Five cases of cutaneous disease caused by toxin-producing C. diphtheriae were reported through NNDSS identified from 2019 to 2023 in the United States, with four of the five cases confirmed to be associated with travel to diphtheria endemic areas.23 One additional case was reported as a bloodstream infection. No respiratory cases were reported.

Diphtheria remains endemic in countries with low routine immunization coverage.24 Displacement of large populations due to political or economic instability and civil conflicts has also resulted in diphtheria outbreaks, largely due to nonhygienic, crowded living conditions coupled with limited access to health care and vaccinations. Most recently, as a result of decline in immunization coverage in the region, a large multi-country outbreak in Western Africa (Nigeria, Niger, Mauritania, Guinea, Cameroon) began in late 2022 and continued into 2024.25 Other outbreaks have occurred in the Americas (Haiti, Brazil, Venezuela, Colombia, Dominican Republic), Asia (Indonesia, Bangladesh [among Rohingya refugees from Myanmar], India, Nepal, Pakistan, Laos, Thailand, Vietnam, Yemen), Africa (South Africa, South Sudan), and Europe (several countries with outbreaks among asylum seekers, Ukraine).262728293031

Among countries that have achieved high childhood vaccination coverage with diphtheria- and tetanus toxoids- and pertussis-containing vaccines (DTP/DTaP), overall incidence is low. However, sporadic cases and outbreaks may still occur among population subgroups. A feature of these outbreaks is that the majority of cases occur among adolescents and adults, many of whom are unvaccinated or incompletely vaccinated against diphtheria.32 Implementation of a recent recommendation by the World Health Organization supporting diphtheria toxoid vaccine booster doses in school-aged children and adolescents may counter this issue.33 Rarely do outbreaks occur in well-vaccinated populations and disease among vaccinated individuals is usually mild, with fewer complications, and no fatalities.34

Importance of Rapid Identification

Prompt recognition and reporting of respiratory diphtheria are important to ensure early, appropriate treatment with diphtheria antitoxin (DAT) and antibiotics. Early clinical recognition of toxin-mediated disease, when possible, is also important to obtain necessary laboratory specimens for initial testing, ideally before initiating antibiotic treatment.

Importance of Surveillance

Data from the National Health and Nutrition Examination Survey (NHANES) III serosurvey (1988–1994) indicated that 60.5% of the US population had protective immunity against diphtheria, but the level of protection declined from about 80% among persons 12–19 years of age to about 30% among persons 60–69 years of age.35 This may be because immunity to diphtheria wanes with time after vaccination, and many older adults may not have received either a primary vaccination series or the recommended decennial tetanus-diphtheria toxoid (Td) booster.

Potential sources of diphtheria include persons traveling to the United States from countries where diphtheria is endemic or epidemic or close contact with a recent traveler from these regions. To ensure timely detection and appropriate management of these cases, clinicians need continued awareness of diphtheria. Surveillance, vaccination, prompt treatment of diphtheria patients, and investigation of close contacts help to halt the spread of diphtheria.

Disease Reduction Goals

Since 1997, no case of culture-confirmed respiratory diphtheria caused by toxin-producing C. diphtheriae has been reported in the United States. Healthy People 2030 does not include specific objectives for diphtheria elimination.36

Case Definition

The Council of State and Territorial Epidemiologists (CSTE) approved the following surveillance case definition for diphtheria at their annual meeting during June 2018, which went into effect on January 1, 2019.22

Suspect: In the absence of a more likely diagnosis, an upper respiratory tract illness with each of the following:

• an adherent membrane of the nose, pharynx, tonsils, or larynx; and
• absence of laboratory confirmation; and
• lack of epidemiologic linkage to a laboratory-confirmed case of diphtheria;

OR

• histopathologic diagnosis.

Confirmed: An upper respiratory tract illness with an adherent membrane of the nose, pharynx, tonsils, or larynx, and any of the following:

• isolation of toxin-producing C. diphtheriae from the nose or throat or
• epidemiologic linkage to a laboratory-confirmed case of diphtheria;

OR

• an infection at a non-respiratory anatomical site (e.g., skin, wound, conjunctiva, ear, genital mucosa) with isolation of toxin-producing C. diphtheriae from that site.

Case classification comments:

• Cases of laboratory-confirmed, nontoxin-producing diphtheriae (respiratory or non-respiratory) should not be reported by state or local health departments to CDC as diphtheria cases.
• Negative laboratory results may be sufficient to rule out a diagnosis of diphtheria; however, clinicians should carefully consider all lab results in the context of the patient's vaccination status, antimicrobial treatment, and other risk factors.
• PCR (polymerase chain reaction) and MALDI-TOF (matrix-assisted laser desorption/ionization-time of flight mass spectrometry) diagnostics for diphtheriae, when used alone, do not confirm toxin production. These tests, when used, should always be combined with a test that confirms toxin production, such as the Elek test.

Laboratory Testing

Refer to Chapter 22, “Laboratory Support for Surveillance of Vaccine-Preventable Diseases” for detailed information on C. diphtheriae specimen collection, laboratory surveillance testing, and specimen shipment to support diphtheria surveillance.

Reporting and Case Notification

Case reporting within a jurisdiction

Each state and territory (jurisdiction) has regulations or laws governing the reporting of diseases and conditions of public health importance. These regulations and laws list the diseases that are to be reported, and describe those persons or groups who are responsible for reporting, such as healthcare providers, hospitals, laboratories, schools, daycare and childcare facilities, and other institutions. Persons reporting these conditions should contact their state/jurisdiction health department for jurisdiction-specific reporting requirements. Detailed information on reportable conditions in each state/jurisdiction is available through CSTE.

The healthcare provider or clinical laboratory that detects C. diphtheriae should first promptly notify the state/jurisdiction health department. The CDC Diphtheria Worksheet is used to collect information about a diphtheria case and is included as Appendix 3 [3 pages], to serve as a guide for data collection during an investigation of reported cases.

Case notification to CDC

The jurisdiction in which the patient resides at the time of diagnosis should submit the case notification to CDC37. State/jurisdiction health departments should send notifications for suspect and confirmed cases of diphtheria to CDC using the event code 10040 in NNDSS via the National Electronic Telecommunications System for Surveillance (NETSS) or National Electronic Disease Surveillance System (NEDSS).

Cases of laboratory-confirmed, nontoxin-producing C. diphtheriae (respiratory or nonrespiratory) do not meet the surveillance case definition requirements and should not be reported to CDC as part of NNDSS.

Rarely, respiratory diphtheria-like illness may result from infection with other Corynebacterium species. While not reportable, if a non-diphtheria Corynebacterium species capable of producing toxin (e.g., C. ulcerans, C. pseudotuberculosis) is identified, jurisdictions are asked to submit available specimens or isolates to the CDC Pertussis and Diphtheria Laboratory for further characterization.

Information to collect

The following data are epidemiologically and clinically important and should be collected during case investigation. Additional information may also be collected at the direction of the state/jurisdiction health department.

• Patient demographic information
  • Name
  • Address
  • Date of birth
  • Age
  • Sex
  • Ethnicity
  • Race
  • Country of birth
• Reporting Source
  • County
  • Earliest date reported
• Clinical
  • Hospitalizations: dates and duration of stay
  • Date of illness onset
  • Site of infection (e.g., nose, throat, larynx, skin, other anatomic site)
  • Symptoms (e.g., fever, sore throat)
  • Signs (e.g., pseudomembrane, neck edema, stridor, tachycardia)
  • Complications (e.g., myocarditis, polyneuropathy)
  • Underlying conditions
  • Outcome (patient survived or died)
  • Date of death
  • Postmortem examination results
  • Death certificate diagnoses
• Treatment
  • Antibiotics given
  • Antibiotic dosage given
  • Duration of antibiotic therapy
• Laboratory
  • Culture
  • Biotype test
  • PCR for diphtheria tox gene
  • Elek test for diphtheria toxin production
• Vaccine information
  • Dates and types of diphtheria vaccination
  • Number of doses of diphtheria toxoid received
  • Manufacturer name
  • Vaccine lot number
  • If not vaccinated, reason
• Epidemiologic
  • Contact with a suspect or confirmed case
  • Local or international travel history: the 6-week period before illness onset or date of presentation
  • Contact with a person who was recently (past 6 weeks) in an endemic-disease area
  • Number of contacts cultured
  • Results of contact cultures
    
  • Contact with domestic pets, horses, or dairy farm animals

Vaccination

For specific information about diphtheria vaccination, refer to CDC's diphtheria vaccine recommendations and the Pink Book, which provides general recommendations, including vaccine scheduling and use, immunization strategies for providers, vaccine contents, adverse events and reactions, vaccine storage and handling, and contraindications and precautions.

Enhancing Surveillance

Because diphtheria is rare in the United States, many clinicians may not include diphtheria in their differential diagnoses. Clinicians are reminded to consider the diagnosis of respiratory diphtheria in patients with membranous pharyngitis who are not up to date with vaccination against diphtheria, especially among those who have recently traveled to areas where the disease remains endemic or epidemic. Clinicians should also be aware that diphtheria could present as a cutaneous infection, also in persons with recent travel to diphtheria-endemic countries. If diphtheria is suspected, clinicians should obtain a pre-antibiotic treatment specimen to increase the probability of isolating the organism. Although appropriate laboratory confirmation may not be feasible locally, state public health laboratories may act as a local reference, and should maintain capacity for isolation of C. diphtheriae, if possible. Reference testing capacity for culture, biotyping, and toxin production testing will remain available at CDC.

Streamlining reporting using electronic methods

Although many surveillance systems still rely on paper and pencil for data collection, the use of data from sources such as electronic medical records, electronic case reporting, and clinical laboratory information systems (LIMS) can significantly improve reporting speed, enhance data quality, and reduce workload.38394041424344

Case and Close Contacts Investigation

Health department officials should initiate a case investigation for all cases (Figure 1; see also Appendix 2) in which there is a high clinical suspicion of respiratory diphtheria. Case investigation should not be delayed pending laboratory confirmation or toxin production results in such cases.

However, because the vast majority of C. diphtheriae infections in the U.S. are nontoxin producing and do not cause diphtheria, laboratory detection of C. diphtheriae alone does not necessitate an immediate full case or contact investigation. In scenarios where C. diphtheriae infections are identified but diphtheria was not initially suspected, health department officials can conduct a preliminary risk stratification to 1) assess whether the patient's clinical findings are consistent with toxin mediated disease (e.g., pseudomembrane, bull neck, cardiomyopathy, neuritis) or 2) if the patient has recently travelled to a country with endemic or epidemic diphtheria. Clinical findings consistent with toxin-mediated disease should prompt an immediate full case and contact investigation, while recent travel history to a country with endemic diphtheria should prompt consideration of a full investigation.

CDC recommends consultation with its diphtheria subject matter experts for all case investigations and investigations of close contacts.

A case investigation for suspected respiratory and non-respiratory diphtheria cases should include the following:

• Obtain nasal and throat cultures,
• Collect preliminary epidemiologic and clinical information, administering antimicrobial treatment,
• Assess diphtheria vaccination status and administering any necessary vaccinations, and
• Identify close contacts.

Diphtheria antitoxin treatment for the patient can be considered; further information is provided below.

Isolation precautions and follow-up testing

Diphtheria cases

Droplet precautions are recommended for respiratory diphtheria cases (meeting the suspect or confirmed case definition) and contact precautions for cutaneous and other non-respiratory cases. If testing reveals that the patient is infected with toxin-producing C. diphtheriae, then elimination of the bacteria should be documented by negative cultures of two consecutive specimens obtained at least 24 hours apart, collected at least 24 hours after completion of antimicrobial treatment. Isolation should remain in place until documentation of these two negative cultures. Persons who continue to harbor the organism after antimicrobial treatment should receive an additional course of antibiotics and should submit specimens again for follow-up testing.

Non-toxigenic or NTTB C. diphtheriae cases

If testing reveals that the patient is infected with nontoxin-producing or NTTB C. diphtheriae, the health department can discontinue the case and contact investigation, and isolation can cease. However, the patient should complete a treatment course of antibiotics. Documentation of negative cultures following antibiotic treatment is not needed for infection with nontoxin-producing or NTTB C. diphtheriae.

Contact investigation

Contact investigations are only necessary for confirmed diphtheria. However, early contact investigation while toxigenicity results are pending should be considered for 1) those with clinical presentation concerning for respiratory diphtheria (e.g., pseudomembrane, bull neck) and 2) those with C. diphtheriae infection who lack clinical signs of respiratory diphtheria but have increased risk of infection with toxigenic strain due to travel history. Close contacts include all household members, persons with a history of habitual, close contact with the suspected diphtheria patient, or persons directly exposed to secretions from the suspected infection site of the patient. Transmission risk is higher with respiratory diphtheria.

Management of close contacts of suspected or confirmed case patients (see Appendix 2) should include:

• Symptom monitoring: monitor for symptoms of respiratory or cutaneous diphtheria for 7-10 days from the time of the last exposure to the suspected or confirmed patient;
• Testing: obtain nasal and throat specimens for cultures and if positive, Elek testing;
• Prophylaxis: administer a course of antimicrobial prophylaxis,
• Vaccination: assess diphtheria vaccination status, and administer any needed diphtheria toxoid-containing vaccine, and
• Contact investigations: begin contact investigations. It is important to determine if diphtheria symptoms are present in each contact to classify the contact as a newly identified case (symptomatic) or carrier (asymptomatic). If the contact is identified as a case, a new case and contact investigation should occur. Diphtheria antitoxin treatment may be considered if the contact has symptomatic respiratory diphtheria. Elimination of toxin-producing C. diphtheriae in this contact should be documented by negative cultures of 2 consecutive specimens obtained at least 24 hours apart and collected at least 24 hours after completion of antimicrobial treatment. If laboratory testing reveals nontoxin-producing or NTTB C. diphtheriae in a contact, then symptom monitoring can be discontinued but the contact should complete a treatment course of antibiotics. If laboratory testing finds that a contact is negative for C. diphtheriae, then diphtheria symptom monitoring and antimicrobial prophylaxis can be discontinued.

Health department officials may use the CDC diphtheria worksheet as a guide for data collection for case investigation for either respiratory or non-respiratory diphtheria (see Appendix 3 [3 pages]).

Figure 1: Schematic of diphtheria case detection, reporting to the state health department, testing, and notification of case to CDC

Diphtheria antitoxin (DAT)

The mainstay of treatment of a case of suspected respiratory diphtheria is prompt administration of DAT. DAT is generally not administered in cases of non-respiratory diphtheria. Clinicians should give DAT early in the course of illness and without waiting for laboratory confirmation of a diagnosis. The recommended dosage and route of administration depend on the extent and duration of disease. While a U.S. Food and Drug Administration-licensed DAT product is no longer available commercially in the United States, it is available from CDC under an Investigational New Drug (IND) protocol.45 When possible, healthcare providers should first notify their respective state/jurisdiction health departments about the suspected diphtheria case before requesting diphtheria antitoxin from CDC.

Contacting CDC for diphtheria antitoxin

After notifying their respective state/jurisdiction health department, healthcare providers should contact the CDC Emergency Operations Center (770-488-7100) if they would like to request DAT. If unable to make contact with the state/jurisdiction health department, healthcare providers may contact the CDC Emergency Operations Center first. Once DAT is requested, additional epidemiologic and clinical data are needed as requirements under the IND. Additional details and documentation related to DAT release can be found on CDC's diphtheria website.

Antibiotics

Persons with infections caused by C. diphtheriae should receive an antimicrobial treatment course, regardless of infection site, presence of symptoms, or toxin-producing status.46A treatment course with erythromycin or penicillin is administered over 14 days.47Close contacts of diphtheria patients should receive a course of antimicrobial prophylaxis: a 7- or 10-day course of erythromycin or a single intramuscular injection of penicillin G benzathine. Providers may need to consider the increasing penicillin resistance that has been identified globally.48

Vaccination

Because diphtheria does not always confer immunity, an age-appropriate vaccine containing diphtheria toxoid should be administered during convalescence (time period during symptom resolution). The vaccine does not protect against infection itself, only against local and systemic effects of diphtheria toxin; therefore, patients can present with infection or asymptomatic carriage following vaccination.

Resources

• Webcast related to this manual

• Diphtheria vaccination

• Treatment: Diphtheria Antitoxin (DAT)

• Diphtheria disease timeline

Authors and Suggested Citation

Farrell A. Tobolowsky, DO, MS, Lucia C. Pawlowski, PhD, Erin Tromble, MD

Suggested citation: Given the variations in the timing for when chapter updates are made, a Manual edition number is no longer used. Therefore, it is recommended that the date at the top right of the web page be used in references/citations.

Content source:
National Center for Immunization and Respiratory Diseases