Chapter 1: Diphtheria

Author: Anna M. Acosta, MD; Valerie D. Bampoe, DrPH

Key points

This chapter provides general guidance for vaccine-preventable disease surveillance, describing the disease background/epidemiology, case investigation and reporting/notification, disease case definitions, and activities for enhancing surveillance, case investigation, and outbreak control for diphtheria.

Disease Description

Diphtheria is a rare disease in the United States. Infection with toxin-producing strains of a gram-positive bacterium, Corynebacterium diphtheriae, causes the disease. The bacteria are able to produce this potent exotoxin after lysogenization by beta-(β) corynebacteriophages that harbor tox, the structural gene for diphtheria toxin1. Sites of 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 The disease 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 infections caused by toxin-producing strains of C. diphtheriae are usually mild, typically consisting of indistinct sores or shallow ulcers. While rarely developing into invasive or systemic disease, cutaneous diphtheria may act as a reservoir for transmission and result in respiratory or cutaneous infections in other susceptible hosts.678

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

Non–toxin-producing strains of C. diphtheriae can also cause disease. It is generally less severe, potentially causing a mild sore throat and, rarely, membranous pharyngitis, although invasive disease, including bacteremia and endocarditis, has increasingly been identified.12131415 Disease caused by non–toxigenic tox gene-bearing (NTTB) C. diphtheriae has a similar presentation to that of non–toxin-producing strains; while rare, NTTB strains have been detected in the United States and elsewhere.1617 Although vaccination is highly protective against disease caused by toxin-producing strains it does not prevent the carriage of C. diphtheriae, regardless of the strain's toxin production status. A small percentage of the population may be carriers of non–toxin-producing or toxin-producing strains of C. diphtheriae, but population carriage rates in the current era of high vaccine 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.18 From 1996 through 2018, 14 cases of respiratory diphtheria were reported to CDC's National Notifiable Diseases Surveillance System (NNDSS), with only 2 cases reported since 2012, in 2014 and 2018. In both instances, disease was caused by non-toxin-producing C. diphtheriae. The last case of respiratory disease caused by toxin-producing C. diphtheriae was reported in 1997. Recently, cutaneous disease caused by toxin-producing C. diphtheriae has been increasingly detected in the United States and elsewhere.1920 Four cases of cutaneous disease caused by toxin-producing C. diphtheriae were identified from 2014 to 2018 in the United States, associated with travel to diphtheria endemic areas.21 Given that cutaneous disease can be transmitted and cause respiratory disease, the US reporting case definition was revised in 2019 to include disease caused by toxin-producing C. diphtheriae from any site.22 Two cases caused by toxin-producing C. diphtheriae were reported in 2019: both were associated with non-respiratory infections (cutaneous infection, bloodstream infection) and travel to diphtheria-endemic areas.23

Diphtheria remains endemic in countries with low routine immunization coverage.24 In the 1990s, a large epidemic of diphtheria occurred in the former Soviet Union where diphtheria had previously been well controlled; multiple factors, including insufficient population immunity, weakened socioeconomic infrastructure, and delayed public health response, contributed to this epidemic.2526 Displacement of large populations due to political or economic instability and civil conflicts has also resulted in diphtheria outbreaks, largely due to non-hygienic, crowded living conditions coupled with limited access to healthcare and vaccinations. Recent outbreaks have occurred in the Americas (Haiti, Brazil, Venezuela, Colombia), Asia (Indonesia, Bangladesh [among Rohingya refugees from Myanmar], India, Nepal, Pakistan, Laos), Africa (South Africa, Nigeria), and Europe (Yemen, Ukraine).27282930

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.31 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.32 Rarely do outbreaks occur in well-vaccinated populations with intense exposure to toxin-producing C. diphtheriae, but disease among vaccinated individuals is usually mild, with fewer complications, and no fatalities.33

Importance of Rapid Identification

Prompt recognition and reporting of the disease are important to ensure early, appropriate treatment with diphtheria antitoxin (DAT) and antibiotics when indicated. Early recognition is also important to obtain necessary laboratory specimens for confirmatory testing, ideally before initiating antibiotic treatment. Timely identification of close contacts is critical to monitor for development of respiratory or cutaneous disease; assess bacterial carriage through nasal and oropharyngeal swabs; assess vaccination status and offer age-appropriate diphtheria toxoid-containing vaccines; and provide post-exposure antimicrobial prophylaxis.

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.34 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 infection include persons traveling to the United States from countries where diphtheria is endemic and from asymptomatic carriers (persons with C. diphtheriae bacteria present in the nose and/or throat who do not have disease symptoms). Persons with cutaneous diphtheria infection may also transmit the bacteria to others, resulting in skin or respiratory infection. To ensure timely detection and appropriate management of these cases, clinicians need continued awareness of diphtheria. Surveillance, prompt treatment of diphtheria patients and investigation of close contacts help to halt the spread of disease. Public health officials use information obtained through surveillance to characterize infected persons so that additional intervention efforts can be focused to reduce disease incidence.

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 2020 does not include specific objectives for diphtheria elimination.35

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, non-toxin-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

Early laboratory testing is critical for confirmation of diagnosis and prompt implementation of appropriate prevention and control measures. All isolates of C. diphtheriae, C. ulcerans, or C. pseudotuberculosis from any anatomical site should be sent to the CDC's Pertussis and Diphtheria Laboratory for reference testing. If diagnosis or case classification is not straightforward based on available laboratory testing, CDC recommends consultation with its diphtheria subject matter experts for further discussion. Refer to the CDC web page Diphtheria/Laboratory and Chapter 22, "Laboratory Support for the Surveillance of Vaccine-Preventable Diseases" for detailed information on laboratory testing for diphtheria.

Specimen collection and shipment

Specimen collection and shipping are important steps in obtaining laboratory diagnosis or confirmation for vaccine-preventable diseases. Guidelines have been published for specimen collection and handling of microbiologic agents. 36Information is also available on using CDC laboratories as support for reference and disease surveillance;3738 this includes:

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.39 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, 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 CDC. 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, non–toxin-producing C. diphtheriae (respiratory or non-respiratory) do not meet the surveillance case definition requirements and should not be reported to CDC as part of NNDSS. In addition, individuals that do not meet the clinical criteria as described by the diphtheria surveillance case definition but for whom toxin-producing Corynebacterium diphtheriae is confirmed via laboratory testing should not be classified as cases. These individuals are considered carriers of the bacteria and are not reportable.

Rarely, respiratory diphtheria-like illness may result from infection with other Corynebacterium species (e.g., C. ulcerans, C. pseudotuberculosis). While not reportable, if a non-diphtheria Corynebacterium species 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 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)
    • Outcome (patient survived or died)
    • Date of death
    • Postmortem examination results
    • Death certificate diagnoses
  • Treatment
    • Date of administration of antitoxin
    • Number of units of antitoxin given
    • 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
    • Contact with a person who was recently (past 6 weeks) in an endemic-disease area
    • Number of contacts cultured
    • Results of contact cultures
    • Local or international travel history: the 6-week period before illness onset or date of presentation
    • Contact with domestic pets, horses, or dairy farm animals

Vaccination

For specific information about diphtheria vaccination, refer to 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. 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.40414243444546

Case and Close Contacts Investigation

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

Non-respiratory diphtheria, such as cutaneous disease, may not be clinically suspected and may only be detected through incidental laboratory testing; thus, a non-respiratory case investigation can be initiated upon notification from a clinical laboratory of the detection of C. diphtheriae. If during a case investigation, a patient with a non-respiratory C. diphtheriae infection reports recent travel history to a country with endemic diphtheria, an investigation of close contacts should then be initiated while awaiting testing results regarding toxin production. 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 obtaining nasal and throat cultures, collecting preliminary epidemiologic and clinical information, administering antimicrobial treatment, assessing diphtheria vaccination status and administering any necessary vaccinations, and identifying close contacts. Diphtheria antitoxin treatment for the patient can be considered; further information is provided below. In addition, isolation should be instituted until proven that the patient is not infected with toxin-producing C. diphtheriae; droplet precautions are recommended for suspected respiratory cases and contact precautions for cutaneous 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 2 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 2 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. If testing reveals that the patient is infected with non–toxin-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 non–toxin-producing or NTTB C. diphtheriae.

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. Management of close contacts of suspected or confirmed case patients (see Appendix 2) should include monitoring for symptoms of respiratory or cutaneous diphtheria for 7-10 days from the time of the last exposure to the suspected patient; obtaining nasal and throat specimens for cultures and Eltek testing; administering a course of antimicrobial prophylaxis, assessing diphtheria vaccination status, and administering any needed diphtheria toxoid-containing vaccine; and beginning contact investigations. 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. In addition, it is important to determine if diphtheria symptoms are present in this contact to classify the contact as a newly identified case (symptomatic) or carrier (asymptomatic). Diphtheria antitoxin treatment may be considered if this contact is symptomatic. If laboratory testing reveals non-toxin-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).

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

Provider

  • Sees patient with possible diphtheria
  • Notifies state health department of suspected diphtheria case
  • Ships specimen to appropriate laboratory for testing

arrow pointing down

Clinical laboratory

  • Detects C. diphtheriae from a clinical specimen
  • Notifies state health department of a positive laboratory test
  • Ships specimen to appropriate laboratory for testing

arrow pointing down

State health department

  • For possible respiratory cases: initiate case and contact investigations; investigations of patients with high clinical suspicion and investigations of close contacts should not be delayed pending laboratory confirmation or toxin-production results
  • For non-respiratory cases: case investigation can be initiated while awaiting toxin-production results; however, initiate investigation of close contacts if patient had recent travel history to country with endemic diphtheria

arrow pointing down

State public health laboratory

  • Once specimen is received, perform culture. If culture is positive for diphtheriae, ship to CDC’s Pertussis and Diphtheria Laboratory for confirmation of toxin-production
  • If culture cannot be performed at local laboratory or state public health laboratory, ship specimen to CDC’s Pertussis and Diphtheria Laboratory following guidance found in the CDC Test Directory.

arrow pointing down

CDC Pertussis and Diphtheria laboratory

  • Tests for presence of C. diphtheriae and toxin production; reports results to state health department

arrow pointing down

State health department

  • Report all diphtheria meeting the CSTE case definition criteria for Suspect and Confirmed cases to CDC
  • If toxin-producing C. diphtheriae at any anatomic site: case should be reported as “Confirmed”, and investigation of close contacts should be continued
  • If non-toxin-producing C. diphtheriae: case is not reported, and investigation of close contacts should be discontinued

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.47 Healthcare providers should first discuss the suspected diphtheria case with their respective state/jurisdiction health departments before requesting diphtheria antitoxin from CDC.

Contacting CDC for diphtheria antitoxin

After consultation with their respective state/jurisdiction health department, healthcare providers should contact the CDC Emergency Operations Center (770-488-7100) to request DAT and assistance for its transport. 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.48 A treatment course with erythromycin or penicillin is administered over 14-days.49 Close 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.49

Vaccination

Because diphtheria disease does not always confer immunity, an age-appropriate vaccine containing diphtheria toxoid should be administered during convalescence.

  1. Holmes RK, Barksdale L. Genetic analysis of tox+ and tox- bacteriophages of Corynebacterium diphtheriae. J Virol 1969;3(6):586–98. doi: 10.1128/JVI.3.6.586-598.1969
  2. Kraszewska A, Anusz Z. [Appearance in domestic animals of Corynebacterium diphtheriae and other Corynebacterium strains pathogenic for man]. Przegl Epidemiol 1979;33(2):269–76.
  3. Henricson B, Segarra M, Garvin J, et al. Toxigenic Corynebacterium diphtheriae associated with an equine wound infection. J Vet Diagn Invest 2000;12(3):253–7. doi: 10.1177/104063870001200309
  4. Leggett BA, De Zoysa A, Abbott YE, Leonard N, Markey B, Efstratiou A. Toxigenic Corynebacterium diphtheriae isolated from a wound in a horse. Vet Rec 2010;166(21):656–7. doi: 10.1136/vr.b4846
  5. Tiwari TSP, Wharton M. Diphtheria toxoid. In: Plotkin S, Orenstein W, Offit P, editors. Vaccines. 7th ed. Philadelphia: Saunders, 2018:259–73.
  6. Harnisch JP, Tronca E, Nolan CM, Turck M, Holmes KK. Diphtheria among alcoholic urban adults. A decade of experience in Seattle. Ann Intern Med 1989;111(1):71–82. doi: 10.7326/0003-4819-111-1-71
  7. Belsey MA. Isolation of Corynebacterium diphtheriae in the environment of skin carriers. Am J Epidemiol 1970;91(3):294–9. doi: 10.1093/oxfordjournals.aje.a121139.
  8. Koopman JS, Campbell J. The role of cutaneous diphtheria infections in a diphtheria epidemic. J Infect Dis 1975;131(3):239–44. doi: 10.1093/infdis/131.3.239
  9. Hacker E, Antunes CA, Mattos-Guaraldi AL, Burkovski A, Tauch A. Corynebacterium ulcerans, an emerging human pathogen. Future Microbiol 2016;11:1191–208. doi: 10.2217/fmb-2016-0085
  10. Otshudiema JO, Acosta AM, Cassiday PK, Hadler SC, Hariri S, Tiwari TSP. Respiratory illness caused by Corynebacterium diphtheriae and C. ulcerans, and use of diphtheria anti-toxin in the United States, 1996–2018. Clin Infect Dis 2021;73(9):e2799–806. doi 10.1093/cid/ciaa1218
  11. Peel MM, Palmer GG, Stacpoole AM, Kerr TG. Human lymphadenitis due to Corynebacterium pseudotuberculosis: report of ten cases from Australia and review. Clin Infect Dis 1997;24(2):185–91. doi: 10.1093/clinids/24.2.185
  12. Gubler J, Huber-Schneider C, Gruner E, Altwegg M. An outbreak of nontoxigenic Corynebacterium diphtheriae infection: single bacterial clone causing invasive infection among Swiss drug users. Clin Infect Dis 1998;27(5):1295–8. doi: 10.1086/514997
  13. Fricchione MJ, Deyro HJ, Jensen CY, Hoffman JF, Singh K, Logan LK. Non-toxigenic penicillin and cephalosporin-resistant Corynebacterium diphtheriae endocarditis in a child: a case report and review of the literature. J Pediatric Infect Dis Soc 2014;3(3):251–4. doi: 10.1093/jpids/pit022
  14. Damade R, Pouchot J, Delacroix I, Boussougant Y, Vinceneux P. Septic arhritis due to Corynebacterium diphtheriae. Clin Infect Dis 1993;16(3):446–7. doi: 10.1093/clind/16.3.446
  15. Dewinter LM, Bernard KA, Romney MG. Human clinical isolates of Corynebacterium diphtheriae and Corynebacterium ulcerans collected in Canada from 1999 to 2003 but not fitting reporting criteria for cases of diphtheria. J Clin Microbiol 2005;43(7):3447–9. doi: 10.1128/JCM.43.7.3447-3449.2005
  16. Hall AJ, Cassiday PK, Bernard KA, et al. Novel Corynebacterium diphtheriae in domestic cats. Emerg Infect Dis 2010;16(4):688–91. doi: 10.3201/eid1604.091107
  17. Zakikhany K, Neal S, Efstratiou A. Emergence and molecular characterisation of non-toxigenic tox gene-bearing Corynebacterium diphtheriae biovar mitis in the United Kingdom, 2003–2012. Euro Surveill 2014;19(22):20819. doi: 10.2807/1560-7917.es2014.19.22.20819
  18. Chen RT, Broome CV, Weinstein RA, Weaver R, Tsai TF. Diphtheria in the United States, 1971–81. AJPH 1985;75(12):1393–7. doi: 10.2105/ajph.75.12.1393
  19. Gower CM, Scobie A, Fry NK, et al. The changing epidemiology of diphtheria in the United Kingdom, 2009 to 2017. Euro Surveill 2020;25(11).
  20. European Centre for Disease Prevention and Control. Diphtheria. In: ECDC. Annual epidemiological report for 2018. Stockholm: ECDC, 2021.
  21. Griffith J, Bozio CH, Poel AJ, et al. Imported toxin-producing cutaneous diphtheria – Minnesota, Washington, and New Mexico, 2015–2018. MMWR Morb Mortal Wkly Rep 2019;68(12):281–4.
  22. Council of State and Territorial Epidemiologists. CSTE Position Statement 18-ID-03: Revision to the Case Definition for National Diphtheria Surveillance [8 pages]. Accessed July 1.
  23. Centers for Disease Control and Prevention. National Notifiable Diseases Surveillance System, 2019 Annual Tables of Infectious Disease Data.
  24. World Health Organization. Immunization, Vaccines and Biologics. Diphyheria. Accessed November 1, 2022. https://www.who.int/immunization-vaccines-and-biologics/diseases/diphtheria
  25. Galazka AM, Robertson teams/SE, Oblapenko GP. Resurgence of diphtheria. Eur J Epidemiol 1995;11(1):95–105. doi: 10.1007/BF01719954. doi: 10.1007/BF01719954
  26. Galazka A. Implications of the diphtheria epidemic in the gormer Soviet Union for immunization programs. J Infect Dis 2000;181 Suppl 1:S244–8. doi: 10.1086/315570
  27. Pan American Health Organization and World Health Organization. Diphtheria. Washington, D.C.:2004-2010 NATIONAL ASSESSMENTS OF ELECTRONIC LABORATORY REPORTING IN HEALTH DEPARTMENTS SUMMARY (studylib.net).
  28. Finger F, Funk S, White K, Siddiqui MR, Edmunds WJ, Kucharski AJ. Real-time analysis of the diphtheria outbreak in forcibly displaced Myanmar nationals in Bangladesh. BMC Med 2019;17(1):58. doi: 10.1186/s12916-019-1288-7
  29. Mahomed S, Archary M, Mutevedzi P, et al. An isolated outbreak of diphtheria in South Africa, 2015. Epidemiol Infect 2017;145(10):2100–8. doi: 10.1017/S0950268817000851
  30. Murhekar M. Epidemiology of diphtheria in India, 1996–2016: Implications for prevention and control. Am J Trop Med Hyg 2017;97(2):313–8. doi: 10.4269/ajtmh.17-0047
  31. Clarke KEN, MacNeil A, Hadler S, Scott C, Tiwari TSP, Cherian T. Global epidemiology of diphtheria, 2000–2017. Emerg Infect Dis 2019;25(10):1834–42. doi: 10.3201/eid2510.190271
  32. World Health Organization. Diphtheria vaccine: WHO position paper-August 2017. Wkly Epidemiol Rec 2017;92(31):417–36. https://www.who.int/publications/journals/weekly-epidemiological-record
  33. Ohuabunwo C, Perevoscikovs J, Griskevica A, et al. Respiratory diphtheria among highly vaccinated military trainees in Latvia: improved protection from DT compared with Td booster vaccination. Scand J Infect Dis 2005;37(11–12):813–20. doi: 10.1080/00365540500262658
  34. McQuillan GM, Kruszon-Moran D, Deforest A, Chu SY, Wharton M. Serologic immunity to diphtheria and tetanus in the United States. Ann Intern Med 2002;136(9):660–6. doi: 10.7326/0003-4819-136-9-200205070-00008
  35. U.S. Department of Health and Human Services. Healthy People 2020. Washington, DC: Department of Health and Human Services, Office of Disease Prevention and Health Promotion, 2020.
  36. Centers for Disease Control and Prevention. Handbook of specimen collection and handling in microbiology.
  37. Centers for Disease Control and Prevention. Infectious diseases laboratories: submitting specimens to CDC. [updated 2022 September 16].
  38. Centers for Disease Control and Prevention. Division of Scientific Resources: specimen management branch.
  39. Roush S, Birkhead G, Koo D, Cobb A, Fleming D. Mandatory reporting of diseases and conditions by health care professionals and laboratories. JAMA 1999;282(2):164–70. doi: 10.1001/jama.282.2.164
  40. Centers for Disease Control and Prevention. Progress in improving state and local disease surveillance–United States, 2000-2005. MMWR Morb Mortal Wkly Rep 2005;54(33):822–5.
  41. Council of State and Territorial Epidemiologists. CSTE position statement 13-SI-03: Improving public health practice by enhancing the public health community's capability for electronic information exchange using HL7 CDA [5 pages].
  42. Council of State and Territorial Epidemiologists. CSTE position statement 15-EB-01: Common data structure for national notifiable diseases [6 pages].
  43. Smith PF, Hadler JL, Stanbury M, Rolfs RT, Hopkins RS, Group CSS. "Blueprint version 2.0": updating public health surveillance for the 21st century. J Public Health Manag Pract 2013;19(3):231–9. doi: 10.1097/PHH.0b013e318262906e
  44. Council of State and Territorial Epidemiologists. Review of and recommendations for the National Notifiable Disease Surveillance System: a state and local health department perspective [49 pages]. Atlanta, GA, 2013.
  45. Council of State and Territorial Epidemiologists. 2004—2010 national assessments of electronic laboratory reporting in health departments: findings and recommendations.
  46. Mac Kenzie WR, Davidson AJ, Wiesenthal A, et al. The pomise of electronic case reporting. Public Health Rep 2016;131(6):742–6. doi: 10.1177/0033354916670871
  47. Centers for Disease Control and Prevention. Expanded access investigational new drug (IND) application protocol: use of diphtheria antitoxin (DAT) for suspected diphtheria Cases [19 pages].
  48. 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 1993;16(1):59–68. doi: 10.1093/clinids/16.1.59
  49. American Academy of Pediatrics. Diphtheria. In: Kimberlin DW, Brady MT, Jackson MA, Long SS, editors. Red Book: report of the Committee on Infectious Diseases, 31st ed. Elk Grove, IL: American Academy of Pediatrics; 2018:319–23.