Diphtheria

Diphtheria

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Diphtheria T S P Tiwari, Centers for Disease Control and Prevention, Atlanta, GA, USA Published by Elsevier Inc.

History Although diphtheria was described by Hippocrates in 500 BC, the causative agent, Corynebacterium diphtheriae, was not isolated until 1883 by Edwin Klebs. In 1888, Roux and Yersin demonstrated the presence of diphtheria toxin from sterile broth filtrate of cultures of the organism, and in 1901, Behring received a Nobel Prize for production of an equine diphtheria antitoxin. In 1920, Ramon demonstrated the protective efficacy of serologic immunity by induced diphtheria toxoid prepared by inactivation of diphtheria toxin with heat and formalin (Wharton and Vitek, 2004).

Disease Burden Diphtheria was one of the most devastating childhood diseases during the eighteenth and nineteenth centuries, causing large numbers of childhood deaths in Europe with case-fatality rates reaching 50%. In 1943, diphtheria caused an estimated 1 million cases and 50 000 deaths. Improvement of vaccination coverage (Figure 1) by national programs of childhood immunization has reduced the global burden of diphtheria from almost 100 000 cases in 1980 to 8229 cases in 2005 (WHO, 2006a). Diphtheria in Europe declined to 623 cases in 1980 after implementation of widespread vaccination programs in the mid-1940s.

In developed countries, diphtheria evolved from a major childhood killer in the early twentieth century to a clinical curiosity after the mid 1940s because of widespread vaccination with diphtheria toxoid and improvements in living standards. The reported number of cases of diphtheria in the United States declined from over 200 000 cases in 1921 to an annual average of 2 reported cases from 1990 through 2006. Serologic surveys during the 1980s and 1990s in the United States indicated that protective levels of antibodies against diphtheria decreased with increasing age; less than 40% of adults had sero-protective levels by age 60 years. A similar serologic trend has been seen in other developed countries in Europe where high childhood vaccine coverage drastically reduced the circulation of toxigenic Corynebacterium diphtheriae. In developing countries, it is estimated that 1 million cases with a case-fatality rate of 5 to 6% occurred annually before diphtheria toxoid became easily accessible in the 1980s. A steady decrease in diphtheria occurred after the introduction of the WHO Expanded Program of Immunization in the late 1970s and the implementation of supplemental childhood vaccination campaigns. However, the disease remains endemic in developing countries, particularly in Asia and sub-Saharan Africa where childhood vaccine coverage is inadequate and living conditions are suboptimal. In 2005, developing countries of the South-East Asian and European regions of WHO contributed more than 87% of 8229 cases reported

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WHO/UNICEF estimated coverage Figure 1 Diphtheria global reported incidence and DTP3 coverage, 1980–2005. Reproduced from World Health Organization (2006) WHO Vaccine-Preventable Diseases Monitoring System: 2006 Global Summary. Geneva: WHO.

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globally. Reporting of diphtheria to WHO depends on functional national surveillance systems, and the lack of surveillance infrastructure may explain the low reported incidence in the African region. Resurgence of diphtheria can occur if high vaccination coverage is not maintained, even in countries where the disease had been controlled. A recent example is a large diphtheria outbreak that spread rapidly to involve all 15 newly independent states (NIS) of the former Soviet Union and the Baltic states. Between 1990 and 2001 over 160 000 cases with over 4000 deaths were reported in these countries and accounted for more than 80% of reported cases worldwide. The vast majority of cases occurred among the adult population. Additional factors that may have contributed to the resurgence include lowered childhood vaccination coverage due to misperceptions about the relative risks and benefits of vaccination by the population and by physicians; deteriorating health infrastructure; increased population movement due to the breakup of the Soviet Union; and socioeconomic hardships (Hardy et al., 1996). The outbreak was controlled by raising childhood and adult vaccination coverage through routine and mass vaccination campaigns for children and adults. In 2005, about 99% of 500 cases from the European region were reported from the NIS. The epidemic in the NIS emphasizes the importance of maintaining high vaccination coverage among children and adults in order to provide both individual protection and optimal population herd immunity.

Infectious Agent Diphtheria is caused by toxin-producing strains of C. diphtheriae. The organism is a slender, nonencapsulated, nonmotile, club-shaped, Gram-positive bacillus. C. diphtheriae exists in four biotypes – gravis, mitis, belfanti, and intermedius. Some strains produce a potent exotoxin that causes classic local diphtheria and systemic complications, whereas non-toxin-producing strains of C. diphtheriae generally cause a mild sore throat. Toxin-producing strains of all biotypes produce an identical exotoxin, and cause similar pathogenicity or severity of disease. Before C. diphtheriae becomes toxigenic, it must be infected by a corynebacteriophage. The process is called lysogenic conversion. The bacteriophage carries the structural gene (tox). Expression of the tox gene is regulated by an iron-dependent repressor gene (dtxR) in the bacterial host. In the presence of low concentrations of iron, the gene regulator is inhibited, resulting in increased toxin production (Funke et al., 1997). Diphtheria toxin is a heat-labile polypeptide composed of two segments (A and B) which are linked by a disulfide bond. The B-segment binds to a receptor on a susceptible cell, undergoes proteolytic cleavage, and

facilitates the entry of segment A that causes inhibition of protein synthesis and cell death. Diphtheria toxin is very potent (lethal dose, approximately 0.1 mg/kg of body weight) and a single molecule can cause cell death.

Epidemiology Humans are the only natural hosts for C. diphtheriae. In areas with endemic disease, 3 to 5% of healthy individuals may harbor the organism in their throats. Asymptomatic carriage is important for perpetuating both endemic and epidemic diphtheria. Immunization reduces an individual’s likelihood of being a carrier. In developed countries with high vaccination coverage, isolation of the organism from the throats of healthy individuals is rare. Carriage of C. diphtheriae in skin lesions can act as a silent reservoir for the organism. Skin infection is the primary source of infection in tropical countries, but has been associated with diphtheria outbreaks in Europe and North America, particularly among alcoholic and other disadvantaged groups. Transmission occurs via respiratory droplets and/or direct contact with either respiratory secretions of cases or exudate from infected skin lesions. Person-toperson spread from infected skin sites is more efficient than spread from the respiratory tract. Indirect transmission by airborne droplet nuclei or dust is not established, although the organism can survive freezing and desiccation in the external environment for months. Milk has been the vehicle of transmission in some outbreaks. Rarely, fomites can play a role in transmission. Overcrowding and substandard living conditions, poor skin hygiene, inadequate health infrastructure, and lack of awareness among providers all may facilitate the spread of the disease. In temperate climates, most disease occurs in the colder months and is associated with crowded indoor living conditions and hot, dry air.

Clinical Manifestations Transmission of C. diphtheriae to a susceptible host more often results in transient carriage or mild disease in previously vaccinated persons. C. diphtheriae commonly affect the mucosa of the upper respiratory tract and the skin and, rarely, other mucosal sites, for example, the conjunctiva, external auditory canal, or vulvovaginal area. Diphtheria is classified according to the anatomic site of infection as respiratory (e.g., nasal, pharyngeal, nasopharyngeal, tonsillar, laryngeal, tonsillopharyngeal, laryngotracheal), cutaneous, or other (conjunctival, genital, auditory). After an average incubation period of 2 to 5 days (range 1–10 days), local signs and symptoms of inflammation develop. The primary site of respiratory infection is

Diphtheria

usually the tonsils or pharynx. The disease has a gradual onset and is characterized by an exudative pharyngitis, a mild fever which rarely exceeds 39  C but with a disproportionately rapid pulse, difficulty in swallowing, a change in voice, and the formation of a dense, gray, adherent pseudomembrane composed of a mixture of dead epithelial cells, fibrin, leukocytes, and erythrocytes. The pseudomembrane may be localized in the tonsils, pharynx, nasal mucosa, larynx, or any combination of these sites. Removal of the pseudomembrane results in bleeding. Patients with pharyngeal or tonsillar diphtheria usually present with sore throat, difficulty swallowing, and lowgrade fever. Examination of the throat may show erythema, localized exudate, or a pseudomembrane that may be localized to the posterior pharynx or tonsil, and the soft and hard palates. The course of the illness is variable. In mild cases, the membrane sloughs off between the 7th and 10th day and the patient has an uneventful recovery. In moderate cases, the course is frequently complicated by myocarditis and neuritis, and convalescence is slow. Severe cases are characterized by severe prostration, pallor, rapid thready pulse, stupor, and coma. Soft tissue swelling in the submandibular area and neck and cervical lymphadenitis imparts a ‘bull neck’ appearance. Extension of the pseudomembrane into the nasal cavity or larynx may cause acute airway obstruction, or partial dislodgement can lead to aspiration. Nasal diphtheria generally is the mildest form of respiratory diphtheria. Poor absorption of toxin from this site accounts for the mildness of the disease and the lack of other systemic symptoms. It is characterized by a nasal discharge which is serous or serosanguinous. The discharge may become mucopurulent and obscure the presence of a membrane on the nasal septum or turbinates. The membrane occasionally extends into the pharynx. In untreated patients, the nasal discharge may persist for many days or weeks and is often indistinguishable from a common cold. The discharge is a rich source of diphtheria bacilli and poses a risk to all exposed and susceptible contacts. Laryngeal and laryngotracheal diphtheria are the most severe forms of respiratory diphtheria and are usually associated with hoarseness and a croupy cough. The pseudomembrane may cause acute airway obstruction. Signs of toxemia are minimal in primary laryngeal involvement because toxin is poorly absorbed from the larynx. However, laryngeal involvement is frequently preceded by pharyngotonsillar disease. Cutaneous diphtheria is more common in tropical regions and is a reservoir for infection. In colder climates, cutaneous diphtheria occurs infrequently except in association with poor hygiene or among poor inner-city dwellers and alcoholics. Cutaneous diphtheria often results from a secondary infection of a skin abrasion and it is characterized by an indolent, nonhealing ulcer covered

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with a gray membrane. The ulcer is often co-infected with Staphylococcus aureus and group A streptococci and may be confused with streptococcal impetigo. Severe diphtheria rarely results from isolated cutaneous infections, even in inadequately immunized individuals. C. diphtheriae infections can occur, rarely, at mucosal sites other than the respiratory tract or the skin. In conjunctival infection, the palpebral surface is red, swollen, and membranous. Infection of the external auditory canal is usually characterized by a persistent purulent discharge. Vulvovaginal infection results in an ulcerative lesion. Local effects of the toxin include paralysis of the palate and hypopharynx. Systemic complications may result from absorption of the toxin into the blood circulation. Diphtheriae toxin exhibits a predilection for the myocardium and the cells of the peripheral nervous system leading to myocarditis and neural demyelination. Myocarditis begins in the 1st through the 6th week of clinical illness. Abnormal electrocardiographic changes include flattening and inversion of T waves, elevation of the ST segment, and conduction abnormalities, including complete heart block. Myocarditis may be followed by cardiac failure. Recovery is usually complete in survivors, but cardiac abnormalities can persist for years following illness. Neurological complications may occur in about 15 to 20% of cases and may manifest 2 to 10 weeks after disease onset. Neurologic complications may result from cranial nerve involvement and can manifest as loss of visual accommodation, diplopia, palatal paralysis with a nasal voice, and difficulty in swallowing. Peripheral nerve involvement frequently results in symmetric peripheral neuritis of the lower extremities. Rarely, diaphragmatic paralysis can occur. Complete recovery of neurologic impairment is the rule. Necrosis of kidney tubules, thrombocytopenia, or shock with disseminated intravascular coagulation can also occur. Death from complications may occur within 6 to 10 days of disease onset. Even with treatment, the casefatality rate of respiratory diphtheria is about 5 to 10%. Other conditions can present with pseudomembranes. They include streptococcal pharyngitis, infectious mononucleosis, viral pharyngitis, oral candidiasis, and prolonged use of drugs, for example, corticosteroids and methotrexate.

Laboratory Diagnosis Diphtheria is confirmed by isolating toxigenic C. diphtheriae from throat specimens or cutaneous lesions. Isolation of C. diphtheriae requires culture of specimens on telluritecontaining medium (e.g., Tinsdale medium) for optimal growth. C. diphtheriae and its biotypes can be identified from colony morphology (black colonies with a surrounding halo) and from biochemical tests.

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Diphtheria

Toxin-producing C. diphtheriae can be identified by in vivo (guinea pig) or in vitro (modified Elek) testing. Conventional polymerase chain reaction (PCR) tests for gene coding for the A and B fragments of the exotoxin can confirm the presence of toxigenic organisms but not toxin production. PCR testing is useful for specimens taken from patients after administration of antibiotics. However, this test is currently available only at some reference laboratories. Molecular subtyping methods of C. diphtheriae strains show considerable promise in aiding epidemiologic studies, but these approaches (ribotyping, pulsed-field gel electrophoresis, multilocus enzyme electrophoresis, DNA-sequencing, random amplified polymorphic DNA) are only available at a few research laboratories.

Treatment Patients should be isolated and health-care personnel should observe respiratory droplet precautions. The mainstay of treatment of respiratory diphtheria is equine diphtheria antitoxin (DAT). Because DAT only neutralizes unbound circulating toxin, it is important to administer it as early in the course of illness as possible. Delays in administration of DAT and extensive membrane formation are associated with increased risk of complications and a fatal outcome. Antitoxin should be administered without waiting for laboratory confirmation of the diagnosis. Patients who report previous hypersensitivity reactions to horse serum should be desensitized before DAT is administered. The dose of DAT depends on the site and extent of local membrane as well as the duration and severity of illness. The recommended dose ranges from 10 000 to 120 000 IU and is administered preferably as an intravenous drip in 500 mL saline for rapid action. Alternatively, undiluted DAT may be injected intramuscularly in the gluteal muscles. The patient should be monitored during DAT administration for signs of shock. Patients often require bed rest, nursing care, and monitoring for respiratory, cardiac, or other complications (American Academy of Pediatrics, 2006). Antimicrobial therapy plays a secondary role in the treatment of diphtheria and is not a substitute for antitoxin treatment. Treatment with appropriate antimicrobial agents usually renders patients noninfectious within 24 hours, halts toxin production, and prevents transmission to close contacts. Untreated patients are infectious for 2 to 3 weeks. Penicillin and erythromycin are highly effective and are the antimicrobial agents of choice. Penicillin may be given as aqueous procaine penicillin (25 000 to 50 000 units per kilogram of body weight per day for children, with a maximum dosage of 1.2 million units per day, in two divided doses). Patients who are sensitive to penicillin should be given erythromycin in a daily dosage

of 40 to 50 mg per kilogram, with a maximum dosage of 2 g per day. Parenteral therapy is recommended initially until the patient can swallow. When the patient can swallow comfortably, oral penicillin V (125 to 250 mg 4 times daily) or oral erythromycin in four divided doses may be substituted for a recommended total treatment period of 14 days. Eradication of the organism at the end of treatment should be confirmed by follow-up cultures obtained at least 2 weeks apart after the completion of therapy. Persons who continue to harbor the organism after treatment with either penicillin or erythromycin should receive an additional 10-day course of erythromycin. As diphtheria may not confer immunity, a dose of an age-appropriate formulation of diphtheria toxoid should be given during the convalescent period (Farizo et al., 1993). Close contacts of the patient should be identified, evaluated, and maintained under surveillance for 7 days for the occurrence of symptoms. Close contacts include household members, medical staff exposed to oral or respiratory secretions of the case-patient, and other persons having direct contact with a case or respiratory secretions. Regardless of vaccination status, both nasal and pharyngeal swabs should be obtained for culture. Postexposure prophylaxis with an antimicrobial agent should be given as soon as specimens are obtained. The recommended antimicrobial agents include either a single dose of intramuscular penicillin (600 000 units for children under 6 years of age and 1.2 million units for those 6 years of age or older) or a 7- to 10-day course of oral erythromycin (40 mg/kg/day for children, 1 g/day for adults). Contacts who have not received a dose of a diphtheria toxoid within the last 5 years should receive a booster dose. Contacts who were never vaccinated should receive an immediate dose of diphtheria toxoid and complete a primary series in accordance with the recommended schedule for vaccination (Farizo et al., 1993).

Outbreak Prevention and Control Immunity to diphtheria can be acquired after recovery from disease or subclinical infection or by active immunization with diphtheria toxoid. Immunization of at least 75% of the population is required to prevent outbreaks of diphtheria. Diphtheria toxoid is a safe and effective vaccine and anaphylaxis is rare. However, local reaction rates at the site of injection, such as redness, mild swelling, and tenderness, range from 10 to 50%. Adverse reactions occur more frequently with increasing number of doses, high pre-vaccination titers of diphtheria antitoxin, higher antigenic content of diphtheria toxoid, and when combined with tetanus and pertussis vaccines. The World Health Organization (WHO) recommends a 3-dose primary series with a high antigenic-content

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diphtheria toxoid preparation during infancy starting as early as 6 weeks of age and given at least 4 weeks apart. Whenever possible, boosters should be given at age 12 months, and at school entry. Because immunity wanes over time, decennial boosters are advocated. Diphtheria toxoid is available in combination with tetanus toxoid (DT) and whole-cell pertussis (DTwP) or acellular pertussis antigens (DTaP) for use in children under 7 years of age; the antigenic content of diphtheria toxoid in these preparations ranges from 6.7 to 15 limit of flocculation (Lf ) units. Newer combinations of DTaP or DTwP with inactivated poliomyelitis vaccine, hepatitis B vaccine, or Haemophilus influenzae type b vaccine are available. Because the frequency and severity of local reactions from diphtheria toxoid increases with age, a vaccine (Td) with lower antigenic content (2 Lf units) is used in children 7 years of age or older and in adults. Vaccination strategies vary by country depending on the capacity of immunization services, vaccine resources, and the epidemiologic pattern of diphtheria. Few developing countries provide routine diphtheria toxoid boosters to older children or adults (WHO, 2006b). In the United States, the childhood and adolescent schedule recommends three doses of diphtheria-toxoidcontaining vaccine (DTaP, DTwP, or DT) at 4- to 8-week intervals beginning at 2 months of age, a fourth dose at 15 to 18 months, and a fifth dose at 4 to 6 years of age. For children under 7 years of age in whom pertussis vaccine is contraindicated, DT should be used instead of DTaP/DTwP. An adolescent booster dose with Tdap is recommended at 11 to 12 years of age and a Td dose every 10 years thereafter for maintaining immunity throughout life. Unvaccinated individuals who are 7 years of age or older should receive a 3-dose primary series with Td with the first two doses given at 4 to 8 weeks intervals and the third dose 6 to 12 months later. Booster doses are recommended at 10-year intervals (CDC, 2006). For improving coverage in adults, health-care providers should be encouraged to administer Td, whenever tetanus toxoid is indicated.

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See also: Bacterial Infections: Overview; Respiratory Infections, Acute; Social Dimensions of Infectious Diseases; Vaccines, Historical.

Citations American Academy of Pediatrics (2006) Diphtheria. In: Pickering LK, Baker CJ, Long SS and McMillan JA (eds.). Red Book: 2006 Report of the Committee on Infectious Diseases, 27th edn., pp. 277–281. Elk Grove Village, IL: American Academy of Pediatrics. CDC (2006) 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 Morbidity and Mortality Weekly Report 55(RR-3): 1–50. Farizo KM, Strebel PM, Chen RT, et al. (1993) Fatal respiratory disease due to Corynebacterium diphtheriae: Case report and review of guidelines for management, investigation, and control. Clinical Infectious Diseases 16: 59–68. Funke F, von Graevenitz A, Clarridge JE, and Bernard KA (1997) Clinical microbiology of coryneform bacteria. Clinical Microbiology Reviews 10: 125–159. Hardy IR, Dittmann S, and Sutter RW (1996) Current situation and control strategies for resurgence of diphtheria in newly independent states of the former Soviet Union. The Lancet 347: 1739–1744. Wharton M and Vitek CR (2004) Diphtheria toxoid. In: Plotkin SA and Orenstein WA (eds.) Vaccines, 4th edn., pp. 211–228. Philadelphia, PA: W. B. Saunders. World Health Organization (2006a) WHO Vaccine-Preventable Diseases Monitoring System: 2006 Global Summary. Geneva, Switzerland: WHO. World Health Organization (2006b) Diphtheria vaccine: WHO position paper. Weekly Epidemiological Record 81: 24–32.

Further Reading Funke G and Bernard KA (2003) Coryneform gram-positive rods. In: Murray PR, Baron JE, Pfaller MA, Tenover FC and Yolken RH (eds.) Manual of Clinical Microbiology, 8th edn., vol. 1, pp. 472–501. Washington, DC: ASM Press. Galazka A (2000) The changing epidemiology of diphtheria in the vaccine era. Journal of Infectious Diseases 181(supplement 1): S2–S9. Galazka AM (1993) The immunologic basis for immunization: Diphtheria. Geneva, Switzerland: World Health Organization.

Disability and Rehabilitation N E Groce, Yale School of Public Health, New Haven, CT, USA ã 2008 Elsevier Inc. All rights reserved.

Globally, 600 million individuals, or roughly 10% of the world’s population, live with a physical, sensory (blindness, deafness), intellectual, or mental health disability that has a profound effect on their day-to-day lives, as

well as their long-term health and well-being; 80% of these people live in low-income countries, where they face significant barriers to accessing health and rehabilitative services (WHO, 2007). Because of stigma, prejudice,