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Chapter 1: Diphtheria
Manual for the Surveillance of Vaccine-Preventable Diseases (4th Edition, 2008)
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Tejpratap S.P. Tiwari, M.D.
Disease Description
Diphtheria is an uncommon disease in the United States. It is caused by infection with toxigenic strains of gram-positive Corynebacterium diphtheriae. Important sites of infection are the respiratory mucosa (respiratory diphtheria) and the skin (cutaneous diphtheria). Rarely, extra-respiratory mucosal sites, e.g., the eye, ear, or genitals, may be affected. Humans are the only known reservoir of C. diphtheriae. 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. 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 an exudate that organizes into a tough, grayish-white pseudomembrane over the tonsils, the pharynx, or larynx. The pseudomembrane is strongly adherent to the underlying tissue, and attempts to dislodge it usually result in bleeding. Accompanying inflammation of the cervical lymph nodes and surrounding soft-tissue swelling of the neck give rise to a “bull-neck” appearance and are a sign of moderate to severe disease. The membrane may progressively extend into the larynx and trachea and cause airway obstruction, which, if left untreated, can be fatal. Absorption of diphtheria toxin from the site of infection can cause systemic complications, including damage to the myocardium, nervous system and kidneys. Respiratory diphtheria usually lasts several days, but complications can persist for months. The case-fatality rate is about 10%.
Nontoxigenic strains of C. diphtheriae may cause a mild sore throat and, rarely, a membranous pharyngitis, but these strains also may be invasive and cause bacteremia and endocarditis.1 Isolation of nontoxigenic strains of C. diphtheriae from the throat does not necessarily indicate a pathogenic role in the illness. A small percentage of the population may carry nontoxigenic or toxigenic strains of C. diphtheriae without disease symptoms, but the frequency at which this occurs is unknown.
Cutaneous diphtheria, caused by either toxigenic or nontoxigenic strains of C. diphtheriae, is usually mild, typically consisting of nondistinctive sores or shallow ulcers, and rarely causes toxic complications (1%–2% of infections with toxigenic strains). Since 1980, cutaneous diphtheria has not been a nationally reportable disease.
Rarely, other Corynebacterium species (C. ulcerans or C. pseudotuberculosis) may produce diphtheria toxin and lead to classic respiratory diphtheria-like illness.2, 3 Both species cause disease in animals.
Background
Although diphtheria is now reported only infrequently in the United States, in the prevaccine era, the disease was one of the most common causes of illness and death among children. Since the introduction and widespread use of vaccines containing diphtheria toxoid (formalin-inactivated diphtheria toxin) beginning in the 1920s and 1930s and universal childhood immunization in the late 1940s, diphtheria has been well controlled in the United States. In the 1970s, diphtheria was endemic in the Southwest, the Northern Plains, and the Pacific Northwest. The last major outbreak was in Seattle, Washington, in the 1970s.4 In recent years, some cases in the United States have been related to importation.5–7 From 1980 to 2005, 55 cases of diphtheria were reported to CDC’s National Notifiable Diseases Surveillance System. The majority of cases (77%) were among persons 15 years of age or older. Four of the five fatal cases occurred among unvaccinated children, and the fifth fatal case was in a 75-year-old male returning to the United States from a country with endemic disease.5, 6 Although few cases of respiratory diphtheria have been reported in the United States in recent years, enhanced surveillance in a previously endemic-disease area—a Northern Plains Indian community—has shown ongoing circulation of toxigenic C. diphtheriae.8 Similarly, endemic circulation of toxigenic C. diphtheriae strains has also persisted in some communities in Canada.9
Diphtheria remains endemic in many parts of the developing world, including some countries of the Caribbean and Latin America, Eastern Europe, Southeast Asia, and the sub-Saharan belt in Africa. In the 1990s, a large epidemic of diphtheria occurred in the former Soviet Union, where diphtheria had previously been well controlled, and renewed interest in the factors associated with persistent circulation of toxigenic C. diphtheriae.10, 11 During the past decade, many developing countries have achieved marked reduction in diphtheria incidence with high childhood immunization coverage.12 However, sporadic cases and outbreaks still occur among population subgroups.10–12 A feature of these outbreaks is that the majority of cases have occurred among adolescents and adults instead of children. Many of these adolescents and adults did not routinely or recently receive diphtheria toxoid booster vaccinations. Rarely, outbreaks occur in well-vaccinated populations with intense exposure to toxigenic C. diphtheriae, but disease is usually mild, with fewer complications and no fatalities.13
Importance of Rapid Case Identification
Prompt recognition and reporting of the disease is important to ensure early, appropriate treatment with diphtheria antitoxin; to obtain necessary laboratory specimens before antibiotic or antitoxin treatment; to identify and evaluate contacts; and to provide necessary antimicrobial prophylaxis to prevent further spread. The outcome of diphtheria infection improves with early, appropriate treatment.
Importance of Surveillance
About half of U.S. adults are estimated to have levels of diphtheria toxin antibodies below the lower limit of protection (0.01 IU/ml). This is because immunity to diphtheria wanes with time after vaccination, and many older adults did not receive either a primary vaccination series or a recommended tetanus-diphtheria toxoid (Td) booster every 10 years. In 1996, endemic transmission of C. diphtheriae was documented in a Northern Plains state. Persons traveling to the United States from countries where diphtheria is endemic may import the disease. Therefore, continued awareness of diphtheria is needed and enhanced surveillance is particularly important in areas in which diphtheria was endemic in the 1970s.8
Contacts of persons with diphtheria may be asymptomatic carriers (persons infected with C. diphtheriae bacteria in the nose and/or throat but who do not have disease symptoms). Carriers often augment the spread of the bacteria to other persons. Surveillance, prompt investigation, and treatment of case-patients and contacts help to halt the spread of disease.
Information obtained through surveillance is used to assess progress towards the year 2010 disease elimination goals. This information is used to characterize infected persons or areas so that additional intervention efforts can be focused to reduce disease incidence.
Disease Reduction Goals
A Healthy People 2010 goal is the elimination of indigenous diphtheria among persons younger than 35 years of age in the United States.14
Case Definition
The following case definition for diphtheria was revised in 1995 by the Council of State and Territorial Epidemiologists (CSTE) and published in 1997.15
Clinical description
An upper-respiratory tract illness characterized by sore throat, low-grade fever, and an adherent membrane of the tonsil(s), pharynx, and/or nose.
Laboratory criteria for diagnosis
- Isolation of C. diphtheriae from a clinical specimen, or
- Histopathologic diagnosis of diphtheria
Case classification
Probable: A clinically compatible case that is not laboratory confirmed and is not epidemiologically linked to a laboratory-confirmed case.
Confirmed: A clinically compatible case that is either laboratory confirmed or epidemiologically linked to a laboratory-confirmed case.
Comment: Cutaneous diphtheria should not be reported. Respiratory disease caused by nontoxigenic C. diphtheriae should be reported as diphtheria. All diphtheria isolates, regardless of association with disease, should be sent to the Diphtheria Laboratory, National Center for Immunization and Respiratory Diseases (NCIRD), CDC. Rarely, respiratory diphtheria may result from infection with other Corynebacterium species (C. ulcerans or C. pseudotuberculosis). These isolates should also be forwarded to CDC.
An epidemiologically linked case is one in which the patient has had contact with one or more persons who have or had the disease, and transmission of the agent by the usual modes of transmission is plausible. A case may be considered epidemiologically linked to a laboratory-confirmed case if at least one case in the chain of transmission is laboratory confirmed.
Laboratory Testing
Diagnostic tests used to confirm infection include isolation of C. diphtheriae on culture and toxigenicity testing. Although no other tests for diagnosing diphtheria are commercially available, CDC can perform a polymerase chain reaction (PCR) test on clinical specimens to confirm infection with a toxigenic strain. The PCR assay allows for detection of the regulatory gene for toxin production (dtxR) and the diphtheria toxin gene (tox).16 PCR is useful if nonviable C. diphtheriae organisms are present in clinical specimens that are obtained after antibiotic therapy has been initiated. The state health department should be contacted to report a suspected case and to arrange for laboratory testing.
Although, as performed by the CDC Diphtheria Laboratory, PCR provides supportive evidence for the diagnosis, data are not yet sufficient for PCR to be accepted as a criterion for laboratory confirmation. At present, a case that is PCR positive without isolation of the organism or histopathologic diagnosis and without epidemiologic linkage to a laboratory-confirmed case should be classified as a probable case.
For additional information on laboratory testing for confirmation of diphtheria, see Chapter 22, “Laboratory Support for the Surveillance of Vaccine-Preventable Diseases.”
Note: Other pathogens can cause a membrane of the throat and tonsils, including Streptococcus spp., Epstein-Barr virus and cytomegalovirus (both of which cause infectious mononucleosis syndrome), Arcanobacter hemolyticum, Candida albicans; anaerobic organisms (Vincent’s angina), and some viruses. The patient’s healthcare provider should be encouraged to perform appropriate laboratory tests to rule out these conditions.
Isolation of C. diphtheriae by culture
Isolation of C. diphtheriae by culture is essential for confirming diphtheria. However, even if the patient’s culture is negative, isolation of C. diphtheriae from close contacts may confirm the diagnosis of the case. Clinical specimens for culture should be taken from the nose or nasopharynx, and throat from all persons with suspected cases and their close contacts. If possible, swabs also should be taken from beneath the membrane, or a piece of the membrane be obtained. Specimens for culture should be obtained as soon as diphtheria (involving any site) is suspected, even if treatment with antibiotics has already begun. For more information on collection of clinical specimens, see Appendix 1. The laboratory should be alerted to the suspicion of diphtheria because isolation of C. diphtheriae requires special culture media containing tellurite.
Toxigenicity testing and biotyping
After C. diphtheriae has been isolated, biotyping should be performed to determine the biotype (intermedius, belfanti, mitis, or gravis), and toxigenicity testing using the Elek test should be done to determine whether the organisms produce diphtheria toxin. Demonstration of toxin production is required to classify a case as confirmed diphtheria. Note that PCR does not demonstrate production of diphtheria toxin but only detection of the diphtheria toxin gene. A positive PCR test in the absence of a positive culture does not meet the laboratory requirement for classifying a case as confirmed diphtheria. Elek and PCR tests are not readily available in many clinical microbiology laboratories; isolates should be sent to a reference laboratory proficient in performing the tests.
Polymerase chain reaction (PCR) testing
Isolation of C. diphtheriae may not always be possible because many patients will have received antibiotics before a diagnosis of diphtheria is considered. PCR allows for detection of the regulatory gene for toxin production (dtxR) and the diphtheria toxin gene (tox) on nonviable organisms. Additional clinical specimens for PCR testing at CDC should be collected when specimens are being collected for culture. Clinical specimens (nasal and throat swabs, pieces of membrane, biopsy tissue) can be transported to CDC with cold packs in a sterile empty container or in silica gel sachets. For detailed information on specimen collection and shipping, and to arrange for PCR testing, the state health department may contact the CDC Diphtheria Laboratory at 404-639-1231.
Serologic testing
Measurement of the patient’s serum antibodies to diphtheria toxin before administration of antitoxin may help in assessing the probability of the diagnosis of diphtheria. The state health department or CDC can provide information on laboratories that offer this test (few laboratories have the capability to accurately test antibody levels). If antibody levels are less than 0.01 IU/ml, immunity is likely to be absent, but a level of greater than 0.1 IU/ml is considered protective and diphtheria is unlikely to be the cause of the patient’s illness. Diphtheria antibody levels between 0.01 IU/ml and 0.09 IU/ml indicate the presence of basic immunity.
Submission of C. diphtheriae isolates
All isolates of C. diphtheriae, whether toxigenic or nontoxigenic, regardless of association with disease, and from any body site (respiratory or cutaneous, other) should be sent to the CDC Diphtheria Laboratory, NCIRD, CDC, for reference testing. To arrange specimen shipping, contact the state health department.
Submission of isolates of other Corynebacterium species
Infrequently, other diphtheria toxin-producing Corynebacterium species (e.g., C. ulcerans or C. pseudotuberculosis) may be isolated from patients. Such isolates should also be sent to the CDC laboratory (Phone: 404-639-1231) to arrange specimen shipping.
Reporting
Each state and territory has regulations or laws governing the reporting of diseases and conditions of public health importance.17 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 health-care providers, hospitals, laboratories, schools, daycare and childcare facilities, and other institutions. Persons reporting these conditions should contact their state health department for state-specific reporting requirements.
Reporting to CDC
Suspected diphtheria cases should be reported promptly by telephone to CDC so that diphtheria antitoxin can be obtained for the patient; an FDA-licensed diphtheria antitoxin product is no longer available commercially in the United States. Because in the United States diphtheria antitoxin is only available from CDC as an Investigational New Drug (IND)18 (See Section X, “Treatment,” for contact information), additional epidemiologic and clinical data are needed.
The healthcare provider should notify the state health department promptly so that an epidemiologic investigation can be initiated. Reports of probable and confirmed cases should be forwarded by the state health department to the National Notifiable Disease Surveillance System (NNDSS) via the National Electronic Telecommunications System for Surveillance (NETSS) or National Electronic Disease Surveillance System (NEDSS). Reporting should not be delayed because of incomplete information or lack of laboratory confirmation.
Respiratory disease caused by nontoxigenic C. diphtheriae should be reported as diphtheria. Rarely, respiratory diphtheria-like illness may result from infection with other Corynebacterium species (e.g., C. ulcerans, C. pseudotuberculosis, or C. pseudodiphtheriticum). Such cases should also be reported to CDC.
Cutaneous diphtheria is no longer reportable, and these cases should not be reported to NNDSS.
Information to collect
The following data are epidemiologically important and should be collected in the course of case investigation. Additional information may also be collected at the direction of the state health department.
- Demographic information
- Name
- Address
- Date of birth
- Age
- Sex
- Ethnicity
- Race
- Country of birth
- Length of time in United States
- 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)
- Symptoms (e.g., fever, sore throat)
- Signs (e.g., neck edema, stridor, tachycardia)
- Complications (e.g., myocarditis, neuritis)
- 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 therapy
- Laboratory
- Culture
- Biotype and toxigenicity test
- PCR
- Molecular typing
- 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 probable or confirmed case
- Contact with immigrants or returning travelers from endemic-disease areas
- Number of contacts cultured
- Results of contact cultures
- Local or international travel history: 6-week period before illness onset or date of presentation
- Contact with domestic pets, horses, or dairy farm animals
Vaccination
Primary diphtheria immunization with diphtheria-tetanus toxoids-acellular pertussis vaccine (DTaP) is recommended for all persons at least 6 weeks old but less than 7 years of age and without a history of contraindications. DTaP is the preferred vaccine for all doses in the infant and childhood vaccination series (including completion of the series for children who have received one or more doses of whole-cell DTP). The primary vaccination with DTaP series consists of a three-dose series, administered at ages 2, 4, and 6 months, with a minimum interval of 4 weeks between the first three doses. The fourth (first booster) dose is recommended at 15–18 months of age to maintain adequate immunity during preschool years. The fourth dose should be administered at least 6 months after the third. If the interval between the third and fourth doses is 6 months or greater and the child is unlikely to return for a visit at the recommended age, the fourth dose of DTaP may be administered as early as age 12 months. The fifth (second booster) dose is recommended for children aged 4–6 years to confer continued protection against disease during the early years of schooling. A fifth dose is not necessary if the fourth dose in the series is administered on or after the fourth birthday.19
Adolescents 11–18 years of age should receive a single dose of Tdap instead of Td for booster immunization against tetanus, diphtheria, and pertussis if they have completed the recommended childhood DTP/DTaP vaccination series. Thereafter, routine booster doses of Td vaccine should be given at 10-year intervals. Adolescents and adults who have never been vaccinated against diphtheria should receive a primary series of three doses of Td. The first two doses should be administered at least 4 weeks apart, and the third dose 6–12 months after the second dose. For added protection against pertussis, Tdap can substitute for any one dose in the 3-dose primary series. Td is preferred to TT for adults as part of wound management if the last dose of Td was received 5 or more years earlier. Up-to-date vaccination against diphtheria is especially important for travelers who will be living or working with local populations in countries where diphtheria is endemic.20
For added protection against pertussis, adults 19–64 years of age should receive a single dose of Tdap (ADACEL®) to replace a single dose of Td for active booster immunization against tetanus, diphtheria and pertussis, if they received their last dose of Td 10 or more years earlier and have not previously received a dose of Tdap.21 Tdap is not licensed or recommended for adults 65 years of age or older; these persons should receive Td instead.
Healthcare providers should ensure that travelers to all countries with endemic or epidemic diphtheria are up-to-date with diphtheria vaccination. Information on countries with diphtheria is summarized in a recent publication by the World Health Organization22 and updates can be found on the CDC website for travelers at http://www.cdc.gov/travel. Vaccine providers should carefully review the vaccine history of all travelers to areas with endemic and epidemic diphtheria to ensure that they are optimally protected according to the recommendations of the Advisory Committee on Immunization Practices.19–22
Treatment
Diphtheria antitoxin
The mainstay of treatment of a case of suspected diphtheria is prompt administration of diphtheria antitoxin. This should be given without waiting for laboratory confirmation of a diagnosis. The recommended dosage and route of administration depend on the extent and duration of disease. Detailed recommendations can be obtained from the state health department and CDC. Diphtheria antitoxin is currently available for treatment of clinical cases of respiratory diphtheria in the United States only through CDC under an FDA-approved Investigational New Drug protocol. The healthcare provider should contact CDC to obtain antitoxin and assistance with arrangements for its transport, and should also contact the local and state health departments.
Antibiotics
Persons with suspected diphtheria should also receive antibiotics to eradicate carriage of C. diphtheriae, to limit transmission, and to prevent further production of diphtheria toxin.23 Treatment with erythromycin or penicillin is administered as a 14-day course.
Vaccination
Because diphtheria disease does not always confer immunity, an age-appropriate vaccine containing diphtheria toxoid should be administered during convalescence.
Contacting CDC
During office hours, 8:00 a.m.–4:30 p.m. Eastern time, contact staff at the Meningitis and Vaccine-Preventable Diseases Branch, NCIRD, CDC, at 404-639-3158 or the DEOC at 404-639-7100 for diphtheria antitoxin at any time.
Enhancing Surveillance
Because diphtheria has occurred only rarely in the United States in recent years, many clinicians may not consider the diagnosis. Clinicians are reminded to consider the diagnosis of respiratory diphtheria in patients with membranous pharyngitis and who are not up-to-date with vaccination against diphtheria. Even if diphtheria is suspected, appropriate laboratory confirmation may not be feasible locally because isolation of the organism requires selective media. Treatment with antibiotics before specimen collection may further decrease the probability of isolating the organism. Local health departments should assure the availability of laboratory capacity for isolation of C. diphtheriae, and at the state level, reference capacity for biotyping, and toxigenicity testing should be available. Laboratories should maintain proficiency in the necessary laboratory procedures.
In areas that were endemic for C. diphtheriae in the 1970s, public health officials should consider recommending routine screening for C. diphtheriae of clinical specimens obtained from patients in high-risk populations who have pharyngitis or ear drainage. High-risk populations are defined according to the epidemiology of diphtheria in the area. For consultation and assistance in deciding which populations may be at increased risk for C. diphtheriae infection, contact the state health department. See Chapter 19, “Enhancing Surveillance,” for additional recommendations for enhancing surveillance of vaccine-preventable diseases.
Case Investigation
Guidelines for investigating a suspected case and for managing contacts are published and are included in Appendix 2, Figure 1.23
Management of contacts of persons with suspected cases should include screening for possible respiratory or cutaneous diphtheria, obtaining nasopharyngeal cultures for C. diphtheriae, administering prophylactic antibiotics, assessing diphtheria vaccination status, and administering any necessary vaccinations. The CDC Diphtheria Worksheet may be used for guidelines in conducting a case investigation (see Appendix 3).
References
- 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;27:1295–8.
- CDC. Respiratory diphtheria caused by Corynebacterium ulcerans—Terre Haute, Indiana, 1996. MMWR. 1997;46:330–2.
- Wong TP, Groman N. Production of diphtheria toxin by selected isolates of Corynebacterium ulcerans and Corynebacterium pseudotuberculosis. Infect Immun 1984;43:1114–6.
- Chen RT, Broome CV, Weinstein RA, Weaver R, Tsai TF. Diphtheria in the United States, 1971–81. Am J Public Health 1985;75:1393–7.
- Bisgard KM, Hardy IR, Popovic T, Strebel PM, Wharton M, Chen RT, Hadler SC. Respiratory diphtheria in the United States, 1980 through 1995. Am J Public Health 1998;88:787–91.
- CDC. Summary of notifiable diseases–United States, 2003. MMWR 2003;52:71–5.
- CDC. Fatal respiratory diphtheria in a U.S. traveler to Haiti—2003. MMWR 2003;52:1285–6.
- CDC. Toxigenic Corynebacterium diphtheriae—Northern Plains Indian Community, August-October 1996. MMWR 1997;46:506–10.
- Marston CK, Jamieson F, Cahoon F, Lesiak G, Golaz A, Reeves M, et al. Persistence of a distinct Corynebacterium diphtheriae clonal group within two communities in the United States and Canada where diphtheria is endemic. J Clin Microbiol 2001;39:1586–90.
- Galazka AM, Robertson SE, Oblapenko GP. Resurgence of diphtheria. Eur J Epidemiol 1995;11:95–105.
- Galazka A. Implications of the diphtheria epidemic in the former Soviet Union for immunization programs. J Infect Dis 2000;181 [Suppl 1]:S244–8.
- Tharmaphornpilas P, Yoocharoan P, Prempree P, Youngpairoj S, Sriprasert P, Vitek CR. Diphtheria in Thailand in the 1990s. J Infect Dis 2001;184:1035–40.
- Ohuabunwo CJ, Perevoscikovs J, Griskevica A, Gargiullo P, Brilla A, Viksna L, 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;37:813–20.
- US Department of Health and Human Services. Healthy People 2010. 2nd. ed. With understanding and improving health and objectives for improving health (2 vols.). Washington DC: US Department of Health and Human Services, 2000.
- CDC. Case definitions for infectious conditions under public health surveillance. MMWR 1997;46 (No. RR-10):1–55.
- Nakao H, Popovic T. Development of a direct PCR assay for detection of the diphtheria toxin gene. J Clin Microbiol 1997;35:1651–5.
- Roush S, Birkhead G, Koo D, Cobb A, Fleming D. Mandatory reporting of diseases and conditions by health care professionals and laboratories. JAMA 1999;282:164–70.
- CDC. Availability of diphtheria antitoxin through an investigational new drug protocol. MMWR 2004;53:413.
- CDC. General recommendations on immunization: recommendations of the Advisory Committee on Immunization Practices. MMWR 2006;55(No. RR-15):1–49.
- CDC. Preventing tetanus, diphtheria, and pertussis among adolescents: use of tetanus toxoid, reduced diphtheria toxoid and acellular pertussis vaccines: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR 2006;55(No. RR-3):1–34.
- CDC. Preventing tetanus, diphtheria, and pertussis among adults: use of tetanus toxoid, reduced diphtheria toxoid and acellular pertussis vaccine: recommendations of the Advisory Committee on Immunization Practices (ACIP) and recommendation of ACIP, supported by the Healthcare Infection Control Practices Advisory Committee (HICPAC), for use of Tdap among health-care personnel. MMWR 2006;55(No. RR-17):1–35.
- World Health Organization. WHO vaccine-preventable diseases monitoring system: 2006 global summary. Geneva, Switzerland: World Health Organization, 2006. Available at http://www.who.int/vaccines-documents/GlobalSummary/GlobalSummary.pdf (exit site)
- 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;16:59–68.
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Content last reviewed on August 20, 2008
Content Source: National Center for Immunization and Respiratory Diseases