BASICS
DESCRIPTION
- Acute respiratory tract infection typically causing a membranous pharyngitis by gram-positive facultative anaerobic bacterium Corynebacterium diphtheriae
- Incubation period 2 to 5 days (range 1 to 10 days)
- Infection peaks in fall and winter in temperate regions:
- Seasonal trends are less distinct in the tropics.
- Cutaneous form peaks in August to October in Southern United States
- Transmission by respiratory spread from infected person or carrier
- Humans are the only reservoir.
- Rarely transmitted directly from skin lesions or contaminated fomites
- Several forms occur:
- Membranous pharyngotonsillar diphtheria
- Nasal diphtheria
- Obstructive laryngotracheitis
- Cutaneous diphtheria
- System(s) affected: cardiovascular, nervous, skin/exocrine, respiratory
EPIDEMIOLOGY
- Predominant age: children <15 years and poorly immunized adults
- Predominant sex: male = female
Incidence
- United States: noncutaneous form, 1.6 in 100 million
- Diphtheria remains rare in the United States today.
- Worldwide in 2011: 4,887 cases reported to the World Health Organization (WHO)
- Recent outbreaks have occurred in Brazil, West-Africa, Ukraine, Poland, India, New Zealand, and the tropical Polynesian Islands.
ETIOLOGY AND PATHOPHYSIOLOGY
Toxigenic strains of C. diphtheriae produce an exotoxin that inhibits protein synthesis in all cell types. Toxin causes local damage and necrosis of the pharyngeal membranes, leading to the Greek name "diphtheria," translated as "leather hide." Toxin is absorbed and disseminated hematogenously and can lead to myocarditis and neuritis.
RISK FACTORS
- Crowded living conditions
- Inadequate immunization
- Lower socioeconomic status
- Native American ethnicity
- Alcoholism
- Travelers: Outbreaks have occurred in various countries; see CDC travel Web site.
GENERAL PREVENTION
Immunization: diphtheria toxoid (inactivated toxin)
- Primary series of five immunizations. Children should receive doses at 2, 4, 6, 15 to 18 months and 4 to 6 years of age with 0.5 mL of DTaP vaccine IM. If the pertussis component is contraindicated, then pediatric diphtheria tetanus (DT) should be used. A booster dose of adult Tdap should be given at 11 to 12 years.
- Due to the rise in pertussis, new Advisory Committee on Immunization Practices recommendations include a Tdap dose during each pregnancy (regardless of prior immunizations), ideally given between 27 and 36 weeks' gestation is now recommended.
- Unimmunized persons ≥7 years should receive 2 doses of adult Td 4 to 8 weeks apart, with a 3rd dose 6 to 12 months later. 0.5 mL of Td should be given. Subsequently, booster doses with Td should be given every 10 years to all individuals without a contraindication. CDC currently recommends that Tdap substitute for one of the recommended decennial Td boosters.
- Immunized individuals may develop a milder course of diphtheria; immunization protects against the toxin, not infection or microbial carriage in the nose, pharynx, or skin.
- Close contacts should be cultured and given antibiotic prophylaxis, regardless of immunization status.
- Contacts should receive a diphtheria toxoid-containing vaccine unless vaccinated within the past 5 years.
DIAGNOSIS
HISTORY
- Membranous pharyngotonsillar diphtheria
- Sore throat
- Malaise, fever, and prostration
- Nasal diphtheria
- Rhinorrhea (often unilateral)
- Often chronic, mild course
- Obstructive laryngotracheitis
- Hoarseness
- Cough progressing to dyspnea
- Labored breathing
- Cutaneous diphtheria
- Initially tender pustule on skin, conjunctiva, vulva, vagina, and penis
PHYSICAL EXAM
- Membranous pharyngotonsillar diphtheria
- Low-grade fever of 37.8-38.8 °C (100-100.9 °F)
- Initially bluish white membrane, which is easily removed. Can progress to
- Adherent, whitish gray, leathery membrane on tonsils or pharynx which may turn gray-green or black (hemorrhage) and bleed if removed
- Injected pharynx
- Cervical adenopathy, may progress to edematous, swollen neck (bull neck)
- Paralysis of soft palate
- Purpura
- Nasal diphtheria
- Serosanguineous or seropurulent discharge and excoriations
- Obstructive laryngotracheitis
- Croupy cough
- Stridor
- Labored breathing
- Thick speech
- Cutaneous diphtheria
- Primary cutaneous diphtheria: starts as tender lower extremity pustule transforming to deep, round, punched out ulcer covered by grayish membrane
- Secondary infection of preexisting wound, purulent exudate, and partial membrane
DIFFERENTIAL DIAGNOSIS
- Bacterial pharyngitis including group A Streptococcus
- Viral pharyngitis
- Mononucleosis
- Oral syphilis
- Candidiasis
- Vincent angina
- Acute epiglottitis
DIAGNOSTIC TESTS & INTERPRETATION
Initial Tests (lab, imaging)
- Definitive diagnosis (confirmed case): clinically compatible history and exam with laboratory confirmation by culture, Gram stain, or Albert stain
- Gram-positive rods in pathognomonic "Chinese character" configuration
- In experienced hands, methylene blue stains satisfactory for presumptive diagnosis.
- Obtain culture from nose and throat beneath membrane and plate on special media (tellurite plate ± blood agar); inform lab that diphtheria is suspected (1)[A].
- Positive toxin assays. Test for toxigenicity of strain by Elek, polymerase chain reaction (PCR), or enzyme immunoassays (EIA) (1)[A].
- Culture on special media (cystine-tellurite blood agar or modified Tinsdale agar) is typically positive in 8 to 12 hours if not previously treated with an antibiotic.
- Laboratory must be alerted to use special media
- Moderate leukocytosis, thrombocytopenia
- Transient albuminuria
- Serial ECGs and cardiac enzymes (myocarditis)
- Delayed peripheral nerve conduction velocities in cases of neuritis, peripheral neuropathy
- Drugs that may alter lab results:
- If an antibiotic was used, then ≥5 days may be required for the culture to grow on medium.
Test Interpretation
- Pleomorphic gram-positive rods
- Necrotic epithelium
- Hyaline degeneration
TREATMENT
GENERAL MEASURES
- Appropriate health care generally entails:
- Inpatient, initial hospitalization in unit to monitor cardiac and respiratory status (must act on presumptive diagnosis because therapy cannot wait for culture confirmation)
- Droplet isolation for pharyngeal diphtheria until cultures are negative on 2 consecutive days. The first culture must be taken at least 24 hours after the cessation of antibiotic therapy.
- Contact precautions for cutaneous diphtheria
- Have airway support readily available. For laryngeal disease, laryngoscopy is desirable. Early intubation or tracheostomy may be necessary.
- Avoid hypnotics and sedatives while monitoring respiratory status.
MEDICATION
First Line
- Antitoxins and antibiotics are both needed for noncutaneous diphtheria.
- Diphtheria antitoxin (DAT) equine: Use 20,000 to 40,000 U of DAT for laryngeal or pharyngeal disease of <48-hour duration; 40,000 to 60,000 U for nasopharyngeal lesions; and 80,000 to 120,000 U for extensive disease ≥3 days or swelling of the neck (bull neck) (2)[B]
- Mix DAT in 250 to 500 mL of normal saline and infuse by IV over 2 to 4 hours (2).
- Some experts recommend treating cutaneous disease with 20,000 to 40,000 U of antitoxin, whereas others doubt its value when there are no signs of systemic disease.
- Antitoxin is obtained in the United States from the CDC's Emergency Operations Center (770-488-7100; www.cdc.gov/diphtheria/dat.html#requesting) under Investigational New Drug protocol, which should be followed exactly (2):
- Equine antitoxin: 7% of patients are sensitive to equine antitoxin and need desensitization. Test for hypersensitivity to antitoxin prior to administration:
- A drop of 1:100 dilution of antitoxin is placed on a scratch/prick/puncture on the forearm with negative (saline) and positive (histamine) controls; read at 15 to 20 minutes.
- If scratch test is negative, an intradermal skin test is done with 1:1,000 dilution.
- If no reaction to first intradermal, then repeat test with a 1:100 dilution.
- Erythromycin IV or PO, 40 to 50 mg/kg/day; maximum of 2 g/day for 14 days, OR penicillin G 300,000 IU daily IM (under 10 kg) or 600,000 IU daily IM (over 10 kg) for 14 days, OR penicillin G 50,000 units/kg IV q12h, switching to oral Pen VK 250 mg QID when able and treating for 14 days (3)[B]. For cutaneous diphtheria, 10 days of any one of these antibiotics.
Second Line
DL-carnitine 100 mg/kg/day by mouth BID for 4 days in children with myocarditis (experimental)
ADDITIONAL THERAPIES
- Antibiotics are recommended for close contacts: penicillin G (600,000 units IM for age â€6 years or 1.2 million units IM for individuals >6 years of age) or erythromycin (500 mg PO 4 times daily for 7 to 10 days).
- Administer age-appropriate diphtheria toxoid-containing vaccine to contacts unless they have been given a booster within the past 5 years.
- Contacts, <7 years and lacking 4th dose of DTaP should be vaccinated.
- Antibiotics are recommended for carriers.
ONGOING CARE
FOLLOW-UP RECOMMENDATIONS
Rest for at least 3 weeks until risk of developing myocarditis has passed.
Patient Monitoring
- ECG, cardiac enzymes, neurologic status, and respiratory status. Serial ECG 2 to 3 times per week for 4 to 6 weeks to detect myocarditis
- Document elimination of the organism by two negative cultures 24 hours apart. The first culture should be 24 hours after the completion of antimicrobial therapy.
- During convalescence, immunize patients against diphtheria because infection does not necessarily confer lifelong immunity.
DIET
Liquid to soft as tolerated
PATIENT EDUCATION
Materials for patient education available at:
- www.cdc.gov/vaccines/vpd-vac/diphtheria/fs-parents.html
PROGNOSIS
- <5% mortality for cutaneous form and 5-10% mortality for respiratory form of diphtheria
- Prognosis guarded until recovery is complete
- In convalescing patients, there is a 5-10% persistence rate in the nasopharynx.
- Worse prognosis if myocarditis
COMPLICATIONS
- Myocarditis (10-25%)
- Cranial and peripheral neuropathy (2 to 6 weeks after onset)
- ECG abnormalities in 2/3 of patients, including extrasystoles, bundle branch block, tachycardia, atrial or ventricular fibrillation
- Right-sided heart failure
- Local paralysis of soft palate and posterior pharynx can lead to regurgitation of fluids through the nares.
- Peripheral and cranial neuropathy affect primarily motor nerve functions. Motor dysfunction starts proximally and extends distally. It resolves slowly. This syndrome resembles Guillain-Barr © syndrome.
REFERENCES
11 Efstratiou A, Engler KH, Mazurova IK, et al. Current approaches to the laboratory diagnosis of diphtheria. J Infect Dis. 2000;181(Suppl 1):S138-S145.22 Tiwari T, Clark T. Use of Diphtheria Antitoxin (DAT) for Suspected Diphtheria Cases. Atlanta, GA: Centers for Disease Control and Prevention; 2008.www.cdc.gov/diphheria/downloads/protocol.pdf. Accessed 2014.33 Kneen R, Pham NG, Solomon T, et al. Penicillin vs. erythromycin in the treatment of diphtheria. Clin Infect Dis. 1998;27(4):845-850.
ADDITIONAL READING
- ACOG Committee Opinion No. 566: update on immunization and pregnancy: tetanus, diphtheria, and pertussis vaccination. Obstet Gynecol. 2013;121(6):1411-1144.
- American Academy of Pediatrics. Diphtheria. In Pickering LK, Baker CJ, Kimberlin DW, et al, eds. Red Book: 2009 Report of the Committee on Infectious Diseases. 28th ed. Elk Grove Village, IL: American Academy of Pediatrics; 2009:280-283.
- Bar-On ES, Goldberg E, Hellmann S, et al. Combined DTP-HBV-HIB vaccine versus separately administered DTP-HBV and HIB vaccines for primary prevention of diphtheria, tetanus, pertussis, hepatitis B and Haemophilus influenzae B (HIB). Cochrane Database Syst Rev. 2012;(4):CD005530.
- Centers for Disease Control and Prevention. Diphtheria Infection: Clinical Features. Atlanta, GA: Centers for Disease Control and Prevention. www.cdc.gov/diphtheria/clinicians.html. AccessedJune 26, 2015.
- Cherry JD, Karam AG. Hypotonic and hyporesponsive episodes after diptheria-tetanus-acellular pertussis vaccination. Pediatr Infect Dis J. 2007;26(10):966-967.
- Rosenblum E, McBane S, Wang W, et al. Protecting newborns by immunizing family members in a hospital-based vaccine clinic: a successful Tdap cocooning program during the 2010 California pertussis epidemic. Public Health Rep. 2014;129(3):245-251.
CODES
ICD10
- A36.9 Diphtheria, unspecified
- A36.0 Pharyngeal diphtheria
- A36.1 Nasopharyngeal diphtheria
- A36.3 Cutaneous diphtheria
- A36.84 Diphtheritic tubulo-interstitial nephropathy
- A36.89 Other diphtheritic complications
- A36.85 Diphtheritic cystitis
- A36.83 Diphtheritic polyneuritis
- A36.82 Diphtheritic radiculomyelitis
- A36.81 Diphtheritic cardiomyopathy
- A36.2 Laryngeal diphtheria
- A36.86 Diphtheritic conjunctivitis
ICD9
- 032.9 Diphtheria, unspecified
- 032.3 Laryngeal diphtheria
- 032.2 Anterior nasal diphtheria
- 032.85 Cutaneous diphtheria
- 032.89 Other specified diphtheria
- 032.83 Diphtheritic peritonitis
- 032.0 Faucial diphtheria
- 032.1 Nasopharyngeal diphtheria
- 032.82 Diphtheritic myocarditis
- 032.84 Diphtheritic cystitis
- 032.81 Conjunctival diphtheria
SNOMED
- Diphtheria (disorder)
- Laryngeal diphtheria
- Nasopharyngeal diphtheria
- Cutaneous diphtheria
- Diphtheritic myocarditis (disorder)
- Faucial diphtheria
- Diphtheritic cystitis
- Anterior nasal diphtheria
- Diphtheritic peritonitis
- Conjunctival diphtheria
CLINICAL PEARLS
- Close contacts of known cases of C. diphtheriae should be cultured, checked for immunization status, and considered for antimicrobial prophylaxis (penicillin or erythromycin).
- Tdap is recommended between 27 and 36 weeks of pregnancy.
- Past infection does not necessarily confer immunity.
- C. diphtheriae requires special culture media-alert laboratories before sending specimens.