Pink Book "Diphtheria" - Centers for Disease Control and Prevention

DiphtheriaDiphtheriaDiphtheria is an acute, toxin-mediated disease caused bythe bacterium Corynebacterium diphtheriae. The name ofthe disease is derived from the Greek diphthera, meaningleather hide. The disease was described in the 5th centuryBCE by Hippocrates, and epidemics were described in the6th century AD by Aetius. The bacterium was first observedin diphtheritic membranes by Klebs in 1883 and cultivatedby Löffler in 1884. Antitoxin was invented in the late 19thcentury, and toxoid was developed in the 1920s.6Corynebacterium diphtheriaeC. diphtheriae is an aerobic gram-positive bacillus. Toxinproduction (toxigenicity) occurs only when the bacillus isitself infected (lysogenized) by a specific virus (bacteriophage)carrying the genetic information for the toxin (tox gene).Only toxigenic strains can cause severe disease.Culture of the organism requires selective media containingtellurite. If isolated, the organism must be distinguishedin the laboratory from other Corynebacterium species thatnormally inhabit the nasopharynx and skin (e.g., diphtheroids).C. diphtheriae has three biotypes—gravis, intermedius, andmitis. The most severe disease is associated with the gravisbiotype, but any strain may produce toxin. All isolates of C.diphtheriae should be tested by the laboratory for toxigenicity.PathogenesisSusceptible persons may acquire toxigenic diphtheria bacilli inthe nasopharynx. The organism produces a toxin that inhibitscellular protein synthesis and is responsible for local tissuedestruction and membrane formation. The toxin produced atthe site of the membrane is absorbed into the bloodstreamand then distributed to the tissues of the body. The toxin isresponsible for the major complications of myocarditis andneuritis and can also cause low platelet counts (thrombocytopenia)and protein in the urine (proteinuria).Clinical disease associated with non-toxin-producing strainsis generally milder. While rare severe cases have beenreported, these may actually have been caused by toxigenicstrains that were not detected because of inadequate culturesampling.Clinical FeaturesThe incubation period of diphtheria is 2–5 days (range, 1–10days).Disease can involve almost any mucous membrane. Forclinical purposes, it is convenient to classify diphtheria into anumber of manifestations, depending on the site of disease.75

Diphtheria6Anterior Nasal DiphtheriaThe onset of anterior nasal diphtheria is indistinguishablefrom that of the common cold and is usually characterizedby a mucopurulent nasal discharge (containing both mucusand pus) which may become blood-tinged. A white membraneusually forms on the nasal septum. The disease is usuallyfairly mild because of apparent poor systemic absorption oftoxin in this location, and it can be terminated rapidly byantitoxin and antibiotic therapy.Pharyngeal and Tonsillar DiphtheriaThe most common sites of diphtheria infection are thepharynx and the tonsils. Infection at these sites is usuallyassociated with substantial systemic absorption of toxin. Theonset of pharyngitis is insidious. Early symptoms includemalaise, sore throat, anorexia, and low-grade fever. Within2–3 days, a bluish-white membrane forms and extends,varying in size from covering a small patch on the tonsilsto covering most of the soft palate. Often by the time aphysician is contacted, the membrane is greyish-green, orblack if bleeding has occurred. There is a minimal amountof mucosal erythema surrounding the membrane. Themembrane is adherent to the tissue, and forcible attemptsto remove it cause bleeding. Extensive membrane formationmay result in respiratory obstruction.The patient may recover at this point; or if enough toxin isabsorbed, develop severe prostration, striking pallor, rapidpulse, stupor, and coma, and may even die within 6 to 10days. Fever is usually not high, even though the patient mayappear quite toxic. Patients with severe disease may developmarked edema of the submandibular areas and the anteriorneck along with lymphadenopathy, giving a characteristic“bullneck” appearance.Laryngeal DiphtheriaLaryngeal diphtheria can be either an extension of thepharyngeal form or can only involve this site. Symptomsinclude fever, hoarseness, and a barking cough. The membranecan lead to airway obstruction, coma, and death.Cutaneous (Skin) DiphtheriaIn the United States, cutaneous diphtheria has been mostoften associated with homeless persons. Skin infections arequite common in the tropics and are probably responsiblefor the high levels of natural immunity found in these populations.Skin infections may be manifested by a scaling rashor by ulcers with clearly demarcated edges and membrane,but any chronic skin lesion may harbor C. diphtheriae alongwith other organisms. Generally, the organisms isolated76

Diphtheriafrom recent cases in the United States were nontoxigenic.The severity of the skin disease with toxigenic strainsappears to be less than in other forms of infection withtoxigenic strains. Skin diseases associated with nontoxigenicstrains are no longer reported to the National NotifiableDiseases Surveillance System in the United States.Other sites of involvement include the mucous membranesof the conjunctiva and vulvovaginal area, as well as theexternal auditory canal.6ComplicationsMost complications of diphtheria, including death, areattributable to effects of the toxin. The severity of thedisease and complications are generally related to the extentof local disease. The toxin, when absorbed, affects organsand tissues distant from the site of invasion. The mostfrequent complications of diphtheria are myocarditis andneuritis.Myocarditis may present as abnormal cardiac rhythms andcan occur early in the course of the illness or weeks later,and can lead to heart failure. If myocarditis occurs early, itis often fatal.Neuritis most often affects motor nerves and usuallyresolves completely. Paralysis of the soft palate is mostfrequent during the third week of illness. Paralysis of eyemuscles, limbs, and diaphragm can occur after the fifthweek. Secondary pneumonia and respiratory failure mayresult from diaphragmatic paralysis.Other complications include otitis media and respiratoryinsufficiency due to airway obstruction, especially in infants.DeathThe overall case-fatality rate for diphtheria is 5%–10%, withhigher death rates (up to 20%) among persons younger than5 and older than 40 years of age. The case-fatality rate fordiphtheria has changed very little during the last 50 years.Laboratory DiagnosisDiagnosis of diphtheria is usually made on the basis ofclinical presentation since it is imperative to begin presumptivetherapy quickly.Culture of the lesion is done to confirm the diagnosis. It iscritical to take a swab of the pharyngeal area, especially anydiscolored areas, ulcerations, and tonsillar crypts. Culturemedium containing tellurite is preferred because it providesa selective advantage for the growth of this organism.77

DiphtheriaA blood agar plate is also inoculated for detection of hemolyticstreptococcus. If diphtheria bacilli are isolated, theymust be tested for toxin production.6Gram stain and Kenyon stain of material from themembrane itself can be helpful when trying to confirmthe clinical diagnosis. The Gram stain may show multipleclub-shaped forms that look like Chinese characters. OtherCorynebacterium species (diphtheroids) that can normallyinhabit the throat may confuse the interpretation of directstain. However, treatment should be started if clinicaldiphtheria is suggested, even in the absence of a diagnosticGram stain.In the event that prior antibiotic therapy may have impededa positive culture in a suspect diphtheria case, two sourcesof evidence can aid in presumptive diagnosis: 1) isolationof C. diphtheriae from cultures of specimens from closecontacts, or 2) a low nonprotective diphtheria antibodytiter (less than 0.1 IU) in serum obtained prior to antitoxinadministration. This is done by commercial laboratories andrequires several days. To isolate C. diphtheriae from carriers,it is best to inoculate a Löffler or Pai slant with the throatswab. After an incubation period of 18–24 hours, growthfrom the slant is used to inoculate a medium containingtellurite.Medical ManagementDiphtheria AntitoxinDiphtheria antitoxin, produced in horses, was first usedin the United States in 1891. It is no longer indicated forprophylaxis of contacts of diphtheria patients, only for thetreatment of diphtheria. Since 1997, diphtheria antitoxinhas been available only from CDC, and only through anInvestigational New Drug (IND) protocol.Antitoxin will not neutralize toxin that is already fixed totissues, but it will neutralize circulating (unbound) toxin andwill prevent progression of disease. The patient must betested for sensitivity before antitoxin is given. Consultationon the use of diphtheria antitoxin is available through theduty officer at the CDC through CDC's Emergency OperationsCenter at 770-488-7100.Persons with suspected diphtheria should be given antibioticsand antitoxin in adequate dosage and placed inisolation after the provisional clinical diagnosis is made andappropriate cultures are obtained. Respiratory support andairway maintenance should also be administered as needed.78

DiphtheriaAntibioticsTreatment with erythromycin orally or by injection (40mg/kg/day; maximum, 2 gm/day) for 14 days, or procainepenicillin G daily, intramuscularly (300,000 U/day forthose weighing 10 kg or less, and 600,000 U/day for thoseweighing more than 10 kg) for 14 days. The disease isusually not contagious 48 hours after antibiotics are instituted.Elimination of the organism should be documentedby two consecutive negative cultures after therapy iscompleted.6Preventive MeasuresFor close contacts, especially household contacts, adiphtheria booster, appropriate for age, should be given.Contacts should also receive antibiotics—benzathinepenicillin G (600,000 units for persons younger than 6 yearsold and 1,200,000 units for those 6 years old and older) or a7- to 10-day course of oral erythromycin, (40 mg/kg/day forchildren and 1 g/day for adults). For compliance reasons, ifsurveillance of contacts cannot be maintained, they shouldreceive benzathine penicillin G. Identified carriers in thecommunity should also receive antibiotics. Maintain closesurveillance and begin antitoxin at the first signs of illness.Contacts of cutaneous diphtheria should be treated asdescribed above; however, if the strain is shown to benontoxigenic, investigation of contacts can be discontinued.EpidemiologyOccurrenceDiphtheria occurs worldwide, but clinical cases are moreprevalent in temperate zones. In the United States duringthe pretoxoid era, the highest incidence was in theSoutheast during the winter. More recently, highest incidencerates have been in states with significant populationsof Native Americans. No geographic concentration of casesis currently observed in the United States.ReservoirHuman carriers are the reservoir for C. diphtheriae and areusually asymptomatic. In outbreaks, high percentages ofchildren are found to be transient carriers.TransmissionTransmission is most often person-to-person spread fromthe respiratory tract. Rarely, transmission may occur fromskin lesions or articles soiled with discharges from lesions ofinfected persons (fomites).79

DiphtheriaTemporal PatternIn temperate areas, diphtheria most frequently occursduring winter and spring.6CommunicabilityTransmission may occur as long as virulent bacilli arepresent in discharges and lesions. The time is variable, butorganisms usually persist 2 weeks or less, and seldom morethan 4 weeks, without antibiotics. Chronic carriers may shedorganisms for 6 months or more. Effective antibiotic therapypromptly terminates shedding.Secular Trends in the United StatesDiphtheria was once a major cause of morbidity andmortality among children. In England and Wales during the1930s, diphtheria was among the top three causes of deathfor children younger than 15 years of age.In the 1920s in the United States, 100,000–200,000 casesof diphtheria (140–150 cases per 100,000 population) and13,000–15,000 deaths were reported each year. In 1921, atotal of 206,000 cases and 15,520 deaths were reported. Thenumber of cases gradually declined to about 19,000 casesin 1945 (15 per 100,000 population). A more rapid decreasebegan with the widespread use of toxoid in the late 1940s.From 1970 to 1979, an average of 196 cases per year werereported. This included a high proportion of cutaneouscases from an outbreak in Washington State. Beginningin 1980, all cases with nontoxigenic cutaneous isolateswere excluded from reporting. Diphtheria was seen mostfrequently in Native Americans and persons in lower socioeconomicstrata.From 1980 through 2004, 57 cases of diphtheria were reportedin the United States, an average of 2 or 3 per year (range, 0–5cases per year). Only 5 cases have been reported since 2000.Of 53 reported cases with known patient age since 1980, 31(58%) were in persons 20 years of age or older; 44% of caseswere among persons 40 years of age or older. Most caseshave occurred in unimmunized or inadequately immunizedpersons. The current age distribution of cases corroboratesthe finding of inadequate levels of circulating antitoxin inmany adults (up to 60% with less than protective levels).Although diphtheria disease is rare in the United States,it appears that Corynebacterium diphtheriae continues tocirculate in areas of the country with previously endemicdiphtheria. In 1996, 10 isolates of C. diphtheriae wereobtained from persons in an Native American community inSouth Dakota. Eight of these isolates were toxigenic.80

DiphtheriaNone of the infected persons had classic diphtheria disease,although five had either pharyngitis or tonsillitis. Thepresence of toxigenic C. diphtheriae in this community isa good reminder for providers not to let down their guardagainst this organism.Diphtheria continues to occur in other parts of the world.A major epidemic of diphtheria occurred in countries ofthe former Soviet Union beginning in 1990. By 1994, theepidemic had affected all 15 Newly Independent States(NIS). More than 157,000 cases and more than 5,000 deathswere reported. In the 6 years from 1990 through 1995, theNIS accounted for more than 90% of all diphtheria casesreported to the World Health Organization (WHO) fromthe entire world. In some NIS countries, up to 80% of theepidemic diphtheria cases have been among adults. Theoutbreak and the age distribution of cases are believed tobe due to several factors, including a lack of routine immunizationof adults in these countries. A total of 7,088 casesof diphtheria was reported to WHO in 2008.6Diphtheria ToxoidCharacteristicsBeginning in the early 1900s, prophylaxis was attemptedwith toxin–antitoxin mixtures. Toxoid was developedaround 1921 but was not widely used until the early 1930s.It was incorporated with tetanus toxoid and pertussisvaccine and became routinely used in the 1940s.Diphtheria toxoid is produced by growing toxigenic C.diphtheriae in liquid medium. The filtrate is incubatedwith formaldehyde to convert toxin to toxoid and is thenadsorbed onto an aluminum salt.Single-antigen diphtheria toxoid is not available.Diphtheria toxoid is available combined with tetanustoxoid as pediatric diphtheria-tetanus toxoid (DT) or adulttetanus-diphtheria (Td), and with both tetanus toxoid andacellular pertussis vaccine as DTaP and Tdap. Diphtheriatoxoid is also available as combined DTaP-HepB-IPV(Pediarix) and DTaP-IPV/Hib (Pentacel)—see Pertussischapter for more information. Pediatric formulations (DTand DTaP) contain a similar amount of tetanus toxoid asadult Td, but contain 3 to 4 times as much diphtheriatoxoid. Children younger than 7 years of age should receiveeither DTaP or pediatric DT. Persons 7 years of age or oldershould receive the adult formulation (adult Td), even ifthey have not completed a series of DTaP or pediatric DT.Two brands of Tdap are available—Boostrix (approved forpersons 10 through 64 years of age) and Adacel (approvedfor persons 11 through 64 years of age). DTaP and Tdapvaccines do not contain thimerosal as a preservative.81

Diphtheria6Immunogenicity and Vaccine EfficacyAfter a primary series of three properly spaced diphtheriatoxoid doses in adults or four doses in infants, a protectivelevel of antitoxin (defined as greater than 0.1 IU of antitoxin/mL) is reached in more than 95%. Diphtheria toxoid hasbeen estimated to have a clinical efficacy of 97%.Vaccination Schedule and UseDTaP (diphtheria and tetanus toxoids and acellular pertussisvaccine) is the vaccine of choice for children 6 weeks through6 years of age. The usual schedule is a primary series of 4doses at 2,4,6, and 15–18 months of age. The first, second,and third doses of DTaP should be separated by a minimumof 4 weeks. The fourth dose should follow the third doseby no less than 6 months, and should not be administeredbefore 12 months of age.If a child has a valid contraindication to pertussis vaccine,pediatric DT should be used to complete the vaccinationseries. If the child was younger than 12 months old whenthe first dose of DT was administered (as DTP, DTaP, or DT),the child should receive a total of four primary DT doses. Ifthe child was 12 months of age or older at the time the firstdose of DT was administered, three doses (third dose 6–12months after the second) completes the primary DT series.If the fourth dose of DT, DTP or DTaP is administeredbefore the fourth birthday, a booster (fifth) dose is recommendedat 4 through 6 years of age. The fifth dose is notrequired if the fourth dose was given on or after the fourthbirthday.Because of waning antitoxin titers, most persons haveantitoxin levels below the optimal level 10 years after thelast dose. Tetanus toxoid should be given with diphtheriatoxoid as Td every 10 years. The first booster dose may begiven at 11 or 12 years of age. ACIP recommends this dosebe administered as Tdap. If a dose is given sooner as partof wound management, the next booster is not neededfor 10 years thereafter. More frequent boosters are notindicated and have been reported to result in an increasedincidence and severity of local adverse reactions.Td is the vaccine of choice for children 7 years and olderand for adults. A primary series is three or four doses,depending on whether the person has received prior dosesof diphtheria-containing vaccine and the age these doseswere administered. The number of doses recommended forchildren who received one or more doses of DTP, DTaP, orDT before age 7 years is discussed above. For unvaccinatedpersons 7 years and older (including persons who cannot82

Diphtheriadocument prior vaccination), the primary series is threedoses. The first two doses should be separated by at least4 weeks, and the third dose given 6 to 12 months after thesecond. ACIP recommends that one of these doses (preferablythe first) be administered as Tdap. A booster dose ofTd should be given every 10 years. Tdap is approved for asingle dose at this time (i.e., it should not be used for all thedoses of Td in a previously unvaccinated person 7 years orolder). Refer to the pertussis chapter for more informationabout Tdap.6Interruption of the recommended schedule or delay ofsubsequent doses does not reduce the response to thevaccine when the series is finally completed. There is noneed to restart a series regardless of the time elapsedbetween doses.Diphtheria disease might not confer immunity. Personsrecovering from diphtheria should begin or complete activeimmunization with diphtheria toxoid during convalescence.Contraindications and Precautions toVaccinationPersons with a history of a severe allergic reaction (anaphylaxis)to a vaccine component or following a prior doseshould not receive additional doses of diphtheria toxoid.Diphtheria toxoid should be deferred for those persons whohave moderate or severe acute illness, but persons withminor illness may be vaccinated. Immunosuppression andpregnancy are not contraindications to receiving diphtheriatoxoid. See pertussis chapter for additional information oncontraindications and precautions to Tdap.Adverse Reactions FollowingVaccinationLocal reactions, generally erythema and induration with orwithout tenderness, are common after the administrationof vaccines containing diphtheria toxoid. Local reactionsare usually self-limited and require no therapy. A nodulemay be palpable at the injection site for several weeks.Abscess at the site of injection has been reported. Feverand other systemic symptoms are not common.Exaggerated local (Arthus-type) reactions are occasionallyreported following receipt of a diphtheria- ortetanus-containing vaccine. These reactions present asextensive painful swelling, often from shoulder to elbow.They generally begin 2–8 hours after injections and arereported most often in adults, particularly those who havereceived frequent doses of diphtheria or tetanus toxoid.Persons experiencing these severe reactions usually havevery high serum antitoxin levels; they should not be given83

Diphtheriafurther routine or emergency booster doses of Td morefrequently than every 10 years. Less severe local reactionsmay occur in persons who have multiple prior boosters.6Rarely, severe systemic reactions such as generalized urticaria,anaphylaxis, or neurologic complications have beenreported following administration of diphtheria toxoid.Vaccine Storage and HandlingAll diphtheria-toxoid-containing vaccines should be storedcontinuously at 35°–46°F (2°–8°C). Freezing reduces thepotency of the tetanus component. Vaccine exposed tofreezing temperature should never be administered.Suspect Case Investigation and ControlImmediate action on all highly suspect cases (including cutaneous)is warranted until they are shown not to be causedby toxigenic C. diphtheriae. The following action should alsobe taken for any toxigenic C. diphtheriae carriers who aredetected.1. Contact state health department or CDC.2. Obtain appropriate cultures and preliminary clinical andepidemiologic information (including vaccine history).3. Begin early presumptive treatment with antibiotics andantitoxin. Impose strict isolation until at least two culturesare negative 24 hours after antibiotics were discontinued.4. Identify close contacts, especially household membersand other persons directly exposed to oral secretions ofthe patient. Culture all close contacts, regardless of theirimmunization status. Ideally, culture should be fromboth throat and nasal swabs. After culture, all contactsshould receive antibiotic prophylaxis. Inadequatelyimmunized contacts should receive DTaP/DT/Td/Tdapboosters. If fewer than three doses of diphtheria toxoidhave been given, or vaccination history is unknown, animmediate dose of diphtheria toxoid should be givenand the primary series completed according to thecurrent schedule. If more than 5 years have elapsed sinceadministration of diphtheria toxoid-containing vaccine, abooster dose should be given. If the most recent dose waswithin 5 years, no booster is required (see the ACIP's 1991Diphtheria, Tetanus, and Pertussis: Recommendations forVaccine Use and Other Preventive Measures for schedulefor children younger than 7 years of age). Unimmunizedcontacts should start a course of DTaP/DT/Td vaccine andbe monitored closely for symptoms of diphtheria for 7 days.845. Treat any confirmed carrier with an adequate course ofantibiotic, and repeat cultures at a minimum of 2 weeks

Diphtheriato ensure eradication of the organism. Persons whocontinue to harbor the organism after treatment witheither penicillin or erythromycin should receive an additional10-day course of erythromycin and should submitsamples for follow-up cultures.6. Treat any contact with antitoxin at the first sign of illness.6Selected ReferencesCDC. Diphtheria, tetanus, and pertussis: Recommendationsfor vaccine use and other preventive measures. MMWR1991;40 (No. RR-10):1–28.CDC. Pertussis vaccination: use of acellular pertussis vaccinesamong infants and young children. Recommendations ofthe Advisory Committee on Immunization Practices (ACIP).MMWR 1997;46 (No. RR-7):1–25.CDC. Preventing tetanus, diphtheria, and pertussis amongadolescents: use of tetanus toxoid, reduced diphtheriatoxoid and acellular pertussis vaccines. Recommendations ofthe Advisory Committee on Immunization Practices (ACIP).MMWR 2006;55(No. RR-3):1–34.CDC. Preventing tetanus, diphtheria, and pertussis amongadults: use of tetanus toxoid, reduced diphtheria toxoidand acellular pertussis vaccines. Recommendations of theAdvisory Committee on Immunization Practices (ACIP) andRecommendation of ACIP, supported by the HealthcareInfection Control Practices Advisory Committee (HICPAC),for Use of Tdap Among Health-Care Personnel. MMWR2006;55(No. RR-17):1–33.Farizo KM, Strebel PM, Chen RT, Kimbler A, Cleary TJ, CochiSL. 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.Vitek CR, Wharton M. Diphtheria in the former SovietUnion: reemergence of a pandemic disease. Emerg Infect Dis1998;4:539–50.Vitek CR, Wharton M, Diphtheria toxoid. In Plotkin SA,Orenstein WA, Offit PA, eds. Vaccines. 5th ed. China:Saunders, 2008:139–56.85

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