Respiratory Diphtheria Caused by Corynebacterium ulcerans -- Terre Haute, Indiana, 1996

Diphtheria is a potentially severe illness; among unvaccinated persons, the case- fatality rate may be 5%-10%, even with appropriate treatment. During 1990-1995, approximately 4000 deaths resulted from the ongoing diphtheria epidemic in the former Soviet Union (1). In the United States, respiratory diphtheria is rare: during 1980-1995, only 41 cases were reported. Serologic studies in the 1970s and 1980s indicated that 20%-60% of U.S. adults aged greater than or equal to 20 years lacked immunity to diphtheria (2,3). This report describes a recent case of respiratory diphtheria caused by a toxin-producing strain of Corynebacterium ulcerans. The case occurred in a resident of Indiana, and an investigation by public health authorities indicated that acquisition of the organism occurred locally in the state.

On October 24, 1996, a 54-year-old woman residing in Terre Haute, Indiana, had onset of fever, sore throat, and difficulty swallowing. On October 26, she was examined in an outpatient clinic and reported a gradual increase in symptoms and onset of neck swelling. Inflammation of the uvula and pharynx was noted, and acute pharyngitis was diagnosed. A rapid screening test for B-hemolytic streptococcal infection was negative. The patient was administered 1 g of cefotaxime intramuscularly and was prescribed 300 mg of clindamycin orally three times a day.

On the morning of October 27, she was hospitalized with vomiting, inability to swallow, and difficulty breathing. On physical examination, her temperature was normal, but she had mild tachycardia, marked swelling of the uvula with a membranous exudate covering the uvula and both tonsils, bilateral cervical lymphadenopathy, and soft-tissue swelling. Both the patient and her mother reported that the patient had never received any vaccinations. Based on the history and physical findings, a preliminary diagnosis of acute membranous pharyngitis consistent with respiratory diphtheria was made, and 40,000 international units (IU) of equine diphtheria antitoxin was administered on the evening of October 27. The patient also received one dose of ceftriaxone intramuscularly, and therapy was initiated with 2 g of erythromycin intravenously per day. On October 28, her symptoms began to improve, and by October 29, the membrane and neck swelling had begun to recede. She was discharged November 1 on oral erythromycin. An electrocardiogram, echocardiogram, and neurologic examination performed during hospitalization were normal. In addition, during hospitalization, she was vaccinated with one dose of adult formulation tetanus and diphtheria toxoid (Td); she was to complete a three-dose primary series of Td as an out- patient.

The patient worked as a telephone sales operator, had not traveled outside the state during the previous month, and had no known contact with any international travelers. Although she had attended a large rural folk arts festival on October 20, she denied consumption of any unpasteurized milk products or exposure to farm animals. Close contacts in the household and in the hospital (n=18) were administered prophylactic antibiotics and were vaccinated with additional doses of diphtheria toxoid vaccine as indicated.

Initial specimens for diphtheria culture (throat swabs and fragments of membrane) were sent to a private laboratory and to CDC's Diphtheria Laboratory. The cultures at the private laboratory were reported as negative; however, a polymerase chain reaction (PCR) assay for the toxin gene performed directly on the clinical specimens at CDC on October 31 was positive. A strain of Corynebacterium ulcerans was subsequently isolated from the culture specimen at CDC, and toxin production by this strain was confirmed by a toxin-antitoxin precipitation assay (Elek test) and by PCR assay on the isolate.

Reported by: S McDonald, MD, D Cox, MD, Terre Haute; R Allen, W Staggs, MS, D Bixler, MD, G Steele, PhD, State Epidemiologist, Indiana State Health Dept. Childhood and Respiratory Diseases Br, Div of Bacterial and Mycotic Diseases, National Center for Infectious Diseases; Child Vaccine Preventable Disease Br, Epidemiology and Surveillance Div, National Immunization Program, CDC.

Editorial Note

Editorial Note: Most cases of diphtheria result from infection with toxin-producing strains of C. diphtheriae; however C. ulcerans, a related species found more commonly in cattle than other animals, can carry the same bacteriophage that codes for the toxin elaborated by toxigenic strains of C. diphtheriae. Sporadic cases of diphtheria caused by C. ulcerans have been reported in humans, and at least two of these cases have been fatal. C. ulcerans infection in humans frequently has been associated with antecedent contact with farm animals or with consumption of unpasteurized dairy products; human-to-human transmission has not been documented (4). However, because of limited information about human-to-human transmission, cultures should be obtained from persons who have had close contact with cases of diphtheria caused by toxigenic C. ulcerans; in addition, such contacts should receive prophylactic antibiotics and diphtheria toxoid vaccinations as recommended for persons exposed to cases of diphtheria caused by C. diphtheriae (5).

The clinical presentation of the patient described in this report was characteristic of severe diphtheria; classic features include an extensive membrane, diffuse cervical lymphadenopathy and soft-tissue swelling ("bull-neck" appearance). Patients with severe diphtheria are at high risk for complications or death; therefore, to reduce morbidity and mortality, diphtheria antitoxin should be administered promptly based on the clinical presentation and presumptive diagnosis. Diphtheria antitoxin is the treatment of choice, and prompt administration is the most important factor in reducing morbidity and mortality associated with mild or severe diphtheria cases. Antibiotics are useful in eradicating the organism and thereby limiting both toxin production and transmissibility. Because clinical diphtheria may not confer protective immunity, patients with diphtheria must receive the complete series of diphtheria toxoid as appropriate for their age.

Most U.S. clinical laboratories lack the expertise and materials to reliably identify toxigenic C. diphtheriae. In the case described in this report, efforts to culture-confirm the diagnosis of diphtheria were complicated by the initiation of antibiotic treatment before the culture specimen had been obtained. However, the diagnosis was confirmed by PCR, demonstrating the usefulness of this method for rapid laboratory confirmation despite previous antibiotic treatment. This assay is available at CDC through state health departments.

This case and two cases of diphtheria in U.S. citizens infected in the New Independent States of the former Soviet Union (6) underscore the need for U.S. clinicians to consider diphtheria in the differential diagnosis of cases of membranous pharyngitis. Suspected cases should be reported to local public health authorities; diphtheria antitoxin is available from CDC's Child Vaccine Preventable Disease Branch, Epidemiology and Surveillance Division, National Immunization Program, telephone (404) 639-8255, Monday-Friday, 8:00 a.m.-4:30 p.m. Eastern time, or (404) 639-2889 at other times.

The identification of toxigenic strains of C. ulcerans in the United States and the continued risk for importation of toxigenic C. diphtheriae emphasize the need for achieving and maintaining high levels of diphtheria immunity among children and adults in the United States. The Advisory Committee on Immunization Practices recommends that all children receive a routine series of five doses of diphtheria toxoid-containing vaccine at ages 2, 4, 6, and 12-18 months and at age 4-6 years; booster doses of diphtheria and tetanus toxoids should then be administered beginning at age 11-12 years (provided at least 5 years have passed since the last dose of diphtheria toxoid-containing vaccine) and every 10 years thereafter (7-9). Td is the preferred preparation for active tetanus vaccination in the management of wounds among adults; wider use of Td could decrease the proportion of adults susceptible to diphtheria. Persons planning travel to areas where diphtheria has been identified should review their vaccination status with a health-care provider and receive age-appropriate vaccinations.

References

1. CDC. Update: diphtheria epidemic -- New Independent States of the former Soviet Union, January 1995-March 1996. MMWR 1996;45:693-7.

2. Crossley K, Irvine P, Warren JB, Lee BK, Mead K. Tetanus and diphtheria immunity in urban Minnesota adults. JAMA 1979;242:2298-300.

3. Koblin BA, Townsend TR. Immunity to diphtheria and tetanus in inner-city women of child-bearing age. Am J Public Health 1989;79:1297-8.

4. Kisely SR, Price S, Ward T. `Corynebacterium ulcerans': a potential cause of diphtheria. Commun Dis Rep Rev 1994;4:R63-R64.

5. Farizo KM, Strebel PM, Chen RT, Kimbler A, Cleary TJ, Cochi SL. Fatal respiratory disease due to Corynebacterium diphtheriae: case report and review of guidelines for management, investigation, and control. Clin Infect Dis 1993;16:59-68.

6. CDC. Diphtheria acquired by U.S. citizens in the Russian Federation and Ukraine, 1994. MMWR 1995;44:237,243-4.

7. CDC. Diphtheria, tetanus, and pertussis: recommendations for vaccine use and other preventive measures: recommendations of the Immunization Practices Advisory Committee (ACIP). MMWR 1991;40(no. RR-10).

8. CDC. Recommended childhood immunization schedule -- United States, July-December 1996. MMWR 1996;45:635-8.

9. CDC. Food and Drug Administration approval of an acellular pertussis vaccine for the initial four doses of the diphtheria, tetanus, and pertussis vaccination series. MMWR 1996;45:676-7.

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