Diphtheria

Clinical Description

Identification

An acute bacterial disease primarily involving the mucous membrane of the upper respiratory tract (nose, tonsils, pharynx, larynx), skin, or rarely other mucous membranes e.g. conjunctivae, vagina, or ear. Inapparent infections (colonization) outnumber clinical cases. The characteristic lesion, caused by reaction to a potent exotoxin, is an asymmetrical adherent greyish white membrane with surrounding inflammation. In moderate to severe cases of respiratory diphtheria, the throat may be moderately to severely sore with enlarged and tender cervical lymph nodes, and, together with marked swelling of the neck, can give rise to a “bull neck” appearance. Pharyngeal membranes may extend into the trachea or progress to cause airway obstruction. Nasal diphtheria can be mild and chronic with one-sided serosanguinous nasal discharge and excoriations. The lesions of cutaneous diphtheria are variable and may be indistinguishable from impetigo. Absorption of diphtheria toxin can lead to myocarditis, with heart block and progressive congestive failure beginning about 1 week after onset. Neurologic complications may occur about 2 weeks after onset of illness and include polyneuropathies that can mimic Guillain-Barré syndrome. The case-fatality rate is 5%–10% for respiratory diphtheria even with treatment, and has changed little in the past 50 years.

Infectious Agent

Toxin-producing strains of Corynebacterium diphtheriae. There are four biotypes: gravis, mitis, intermedius, and belfanti. Toxin production results when bacteria are infected by corynebacteriophage containing the diphtheria toxin gene tox. Nontoxigenic strains may cause sore throat, but rarely produce membranous lesions; however, they are increasingly associated with infective endocarditis.


Diagnosis

Respiratory diphtheria should be suspected in the differential diagnosis of membranous pharyngitis that includes streptococcal pharyngitis, Vincent angina, infectious mononucleosis, oral syphilis, oral candidiasis and adenoviruses.

Presumptive diagnosis is based on observation of an asymmetrical, adherent grayish membrane associated with tonsillitis, pharyngitis, or a serosanguinous nasal discharge. Bacteriological examination of lesions confirms the diagnosis. If respiratory diphtheria is strongly suspected, specific treatment with antitoxin and antibiotics should be initiated without awaiting laboratory confirmation by culture, and continued even if the laboratory report is negative. Delay in starting treatment is associated with increased risk for complications and death.


Epidemiology

Mode of transmission

Contact with a patient or carrier; more rarely, contact with articles soiled with discharges from lesions of infected people. Raw milk has served as a vehicle.

Incubation period

Usually 2–5 days, occasionally longer.

Period of communicability

Variable, until virulent bacilli have disappeared from discharges and lesions; usually 2 weeks or less, seldom more than 4 weeks for respiratory diphtheria. The rare chronic carrier may shed organisms for 6 months or more. Effective antibiotic therapy promptly terminates shedding.

Reservoir

Humans.

Susceptibility

Infants born to immune mothers have passive protection, which is usually lost before the 6th month. Disease or inapparent infection may induce long-lasting or lifelong immunity, but does not always do so. Immunization with diphtheria toxoid produces prolonged but not lifelong immunity. Immunity wanes with increasing age. Serosurveys in the USA indicate that more than 40% of adults lack protective levels of circulating antibodies; decreasing antibody levels have also been found in Australia, Canada and several European countries. Older adults may have immunological memory and may be protected against disease after exposure. Immunity induced by diphtheria toxoid protects against toxin-mediated systemic disease but not against colonization in the nasopharynx.

Occurrence

A disease of colder months in temperate zones, primarily involving nonimmunized or underimmunized children below 15 years of age, but which may be found among adult population groups with low vaccination coverage. In the tropics, seasonal trends are less distinct; inapparent, cutaneous and wound diphtheria cases are much more common.

Diphtheria epidemics can occur in susceptible populations. In 1990, for example, a massive outbreak began in the Russia and spread to all countries of the former Soviet Union and Mongolia. Contributing factors included increased susceptibility among adults due to waning of vaccine-induced immunity; and failure fully to immunize children because of unwarranted contraindications, antivaccine movements, and declining socioeconomic conditions. After peaking in 1995, the epidemic declined. It was responsible for more than 150 000 reported cases and 5 000 deaths between 1990 and 1997.

In Ecuador, an outbreak of about 200 cases occurred in 1993–94; about 50% cases occurred in persons aged 15 years or older. In both epidemics, control was achieved through mass immunization campaigns.


Prevention and Control

1)    Preventive measures:

a)    Educational measures are important: inform the public, particularly parents of young children, of the hazards of diphtheria and the need for active immunization.

b)    The only effective control is widespread active immunization with diphtheria toxoid. Immunization should be initiated in infancy with a formulation containing diphtheria toxoid, tetanus toxoid and either acellular pertussis antigens (DTaP, preferred in the USA) or whole cell pertussis vaccine (DTP). Some currently available formulations combine DTP or DTaP with one or more of the following: Hemophilus influenzae type B vaccine, inactivated poliomyelitis vaccine, or hepatitis B vaccine.

c)    The schedule recommended in developing countries is at least 3 primary doses IM at 6, 10 and 14 weeks of age; and a DTP booster at 18 months to 4 years.
The following schedules are recommended for use in industrialized countries (some countries may recommend different ages or dosages):

i)    Recommended immunization schedule for persons aged 0–18 Years—
Vaccination is recommended with a primary series of diphtheria toxoid combined with other antigens, such as DTaP, or DTP-Hib, DTaP-HepB-Inactivated Polio vaccine. The first 3 doses are given at 4- to 8-week intervals beginning when the infant is 6 to 8 weeks of age; a fourth dose is given 6–12 months after the third dose. This schedule should not entail restarting immunizations because of delays in administering scheduled doses. A fifth dose is given at 4–6 years, prior to school entry; this dose is not necessary if the fourth dose was given after the fourth birthday. If the pertussis component of DTP is contraindicated, diphtheria and tetanus toxoids for children (DT) should be substituted. A booster dose with an adult formulation, Tdap (or Td if Tdap is unavailable), is recommended at 11–18 years of age.

ii)    Previously unvaccinated persons aged >7 years—
Because adverse reactions may increase with age, a preparation with a reduced concentration of diphtheria toxoid (adult Td) is usually given after the seventh birthday for booster doses. For a previously unimmunized person, a primary 3-dose series of adsorbed tetanus and diphtheria toxoids (Td) is advised. Two doses are given at 4- to 8-week intervals, and the third dose is given 6 months to 1 year after the second dose. If the person is aged 10 years or older, a dose of Tdap may be substituted for a single Td dose in the series. Limited data from Sweden suggest that the 3-dose Td regimen may not induce protective diphtheria antibody levels in most adults, and additional doses may be needed.

iii)    Active protection should be maintained by administering a dose of Td every 10 years thereafter. A one-time dose of Tdap may be substituted for the next Td dose in persons ages 19–64 years, for added protection against pertussis.

d)    Special efforts should be made to ensure that those who are at higher risk of patient exposure, such as health workers, are fully immunized and receive a booster dose of Td every 10 years.

e)    For those who are severely immunocompromised or infected with HIV, diphtheria immunization is indicated, with the same schedule and dose as for immunocompetent persons, even though immune response may be suboptimal.

2)    Control of patient, contacts and the immediate environment:

a)    Report to local health authority: Case report obligatory in most countries, Class 2 (See Annex: Reporting of Communicable Diseases).

b)    Isolation: Strict isolation for pharyngeal diphtheria and contact isolation for cutaneous diphtheria, until 2 cultures from both throat and nose (and skin lesions in cutaneous diphtheria), taken at least 24 hours apart and at least 24 hours after cessation of antibiotic therapy, fail to grow C. diphtheriae. Where culture is impractical, isolation may end after 14 days of appropriate antibiotic therapy.

c)    Concurrent disinfection: Of all articles in contact with patient and all articles soiled by discharges of patient. Terminal cleaning.

d)    Quarantine: Adult contacts whose occupations involve handling food (especially milk) or close association with nonimmunized children should be excluded from that work until treated as described below, and until bacteriological examination proves them not to be carriers.

e)    Management of contacts: All close contacts should have swabs taken from nose and throat for culture of C. diphtheriae, and should be kept under surveillance for 7 days. A single dose of benzathine penicillin (IM), or a 7–10 day course of erythromycin (PO, 40 mg/kg/day for children and 1 gram/day for adults), is recommended for all persons with household exposure to diphtheria, regardless of immunization status. Those who handle food or work with school children should be excluded from work or school until proven not to be carriers. Previously immunized contacts should receive a booster dose of diphtheria toxoid if more than 5 years have elapsed since their last dose, and in nonimmunized contacts, a primary series should be initiated; use Td, DT, DTP, DTaP or DTP-Hib, DTP-HepB-IPV, or Tdap combination vaccine, depending on the contact's age and indication for other components.

f)    Investigation of contacts and source of infection: Searching for carriers by culture of nasal and throat specimens, other than among close contacts, is neither useful nor indicated.

g)    Specific treatment: Diphtheria antitoxin is the specific treatment for respiratory diphtheria. Sensitivity testing (skin or eye testing) should be undertaken before giving antitoxin—only antitoxin of equine origin is available. After completion of tests to rule out hypersensitivity, if diphtheria is strongly suspected on the basis of clinical findings, a single dose of antitoxin (in the range of 20 000 units for anterior nasal diphtheria to 100 000 units for extensive disease of 3 days duration) should be given daily intramuscularly for 14 days immediately after bacteriological specimens are taken, without waiting for results (to obtain diphtheria antitoxin in the USA, contact Centers for Disease Control and Prevention, Tel: 1-770-488-7100). Antibiotics are not a substitute for antitoxin but will eliminate C. diphtheriae and halt toxin production, and reduce communicability. Procaine penicillin G (IM) (25 000 to 50 000 units/kg/day for children and 1.2 million units/kg/day for adults, in 2 divided doses) or parenteral erythromycin (40–50 mg/kg/day, with a maximum of 2 grams/day in divided doses), is recommended until the patient can swallow comfortably. Erythromycin PO in 4 divided doses or penicillin V PO (125–250 mg 4 times daily) may be substituted for a recommended total treatment period of 14 days. Erythromycin-resistant strains are uncommon and have not been a public health problem.

Prophylactic treatment of carriers: A single dose of benzathine penicillin G (IM) (600 000 units for persons under 6 years and 1.2 million units for persons 6 or older) or a 7–10 day course of erythromycin (PO, 40 mg/kg/day for children and 1 gram/day for adults) has been recommended. If culture is positive, treat as for patients.


3)    Epidemic measures:

a)    Immunize the largest possible proportion of the population group involved, especially infants and preschool children. In an epidemic involving adults, immunize groups that are most affected or at high risk. Repeat immunization procedures 1 month later to provide at least 2 doses to recipients.

b)    Identify close contacts and define population groups at special risk. In areas with appropriate facilities, carry out a prompt field investigation of reported cases to verify the diagnosis and to determine the biotype and toxigenicity of C. diphtheriae.

4)    Disaster implications:

Outbreaks can occur when social or natural conditions lead to crowding of susceptible groups, especially infants and children. This frequently occurs when there are large-scale movements of susceptible populations.

5)    International measures:

People traveling to or through countries where either respiratory or cutaneous diphtheria is common should receive primary immunization if necessary, or a booster dose of Td for those previously immunized.

Source: Heymann (Ed.). (2008). Control of Communicable Diseases Manual, 19th edition. Washington, DC: American Public Health Association.
 


Available Vaccines

WHO-Prequalified diphtheria vaccines

 

Common Disease Taxonomy: