Corynebacterium diphtheriae

• Aerobic gram-positive bacillus

• Toxin production occurs onlywhen C. diphtheriae infected byvirus (phage) carrying tox gene

• If isolated, must be distinguishedfrom normal diphtheroid

• Toxoid developed in 1920s

Diphtheria Clinical Features

• Incubation period 2-5 days(range, 1-10 days)

• May involve any mucous membrane

• Classified based on site of infection–anterior nasal

–pharyngeal and tonsillar

–laryngeal

–cutaneous

–ocular

–genital

Pharyngeal and Tonsillar Diphtheria

• Insidious onset

• Exudate spreads within 2-3 daysand may form adherent membrane

• Membrane may cause respiratoryobstruction

• Pseudomembrane: fibrin, bacteria,and inflammatory cells, no lipid

• Fever usually not high but patientappears toxic

Diphtheria Complications

• Most attributable to toxin

• Severity generally related toextent of local disease

• Most common complicationsare myocarditis and neuritis

• Death occurs in 5%-10% forrespiratory disease

Diphtheria Antitoxin

• Produced in horses

• First used in the U.S. in 1891

• Used only for treatment ofdiphtheria

• Neutralizes only unbound toxin

• Lifetime of Ab: 15 days – 3weeks, wait 3-4 weeks beforegiving toxoid. Only given once.

Diphtheria Epidemiology

• Reservoir Human carriers Usually asymptomatic

• Transmission Respiratory, aerosols Skin lesions

• Temporal pattern Winter and spring

• Communicability Up to several weekswithout antibiotics

0

2000

4000

6000

8000

10000

12000

14000

16000

18000

20000

1940 1950 1960 1970 1980 1990 2000

Cases

Diphtheria - United States,1940-2005

Year

0

1

2

3

4

5

6

1980 1985 1990 1995 2000 2005

Cases

Diphtheria - United States,1980-2005

Year

0

5

10

15

20

25

<5 5-14 15-24 25-39 40-64 65+

Age group (yrs)

Cases

Diphtheria – United States, 1980-2004Age Distribution of Reported Cases

N=53

Diphtheria Toxoid

• Formalin-inactivated diphtheria toxin

• Schedule Three or four doses + booster Booster every 10 years

• Efficacy Approximately 95%

• Duration Approximately 10 years

• Should be administered with tetanustoxoid as DTaP, DT, Td, or Tdap

Dose

Primary 1

Primary 2

Primary 3

Primary 4

Age

2 months

4 months

6 months

15-18 months

Routine DTaP PrimaryVaccination Schedule

4-6 yrs

11-12 yrs

Every 10 yrs

Diphtheria and Tetanus ToxoidsAdverse Reactions

• Local reactions (erythema,induration)

• Exaggerated local reactions(Arthus-type)

• Fever and systemic symptomsnot common

• Severe systemic reactions rare

Diphtheria and Tetanus ToxoidsContraindications and Precautions

• Severe allergic reaction tovaccine component or followinga prior dose

• Moderate or severe acute illness

Tetanus

• First described by Hippocrates

• Etiology discovered in 1884 byCarle and Rattone

• Passive immunization used fortreatment and prophylaxisduring World War I

• Tetanus toxoid first widely usedduring World War II

Clostridium tetani

• Anaerobic gram-positive, spore-forming bacteria

• Spores found in soil, animalfeces; may persist for months toyears

• Multiple toxins produced withgrowth of bacteria

• Tetanospasmin estimatedhuman lethal dose = 2.5 ng/kg

Tetanus Pathogenesis

• Anaerobic conditions allowgermination of spores andproduction of toxins

• Toxin binds in central nervoussystem

• Interferes with neurotransmitterrelease to block inhibitor impulses

• Leads to unopposed musclecontraction and spasm

Tetanus Clinical Features

• Incubation period; 8 days(range, 3-21 days)

• Generalized tetanus: descendingsymptoms of trismus (lockjaw),difficulty swallowing, muscle rigidity,spasms

• Spasms continue for 3-4 weeks;complete recovery may take months

• Fatality rate ~90% w/o treatment

~30% w/ treatment

Neonatal Tetanus

• Generalized tetanus in newborninfant

• Infant born without protectivepassive immunity

• Estimated >215,000 deathsworldwide in 1998

>270,000 cases worldwide per year

Tetanus Complications

• Laryngospasm

• Fractures

• Hypertension

• Nosocomial infections

• Pulmonary embolism

• Aspiration pneumonia

• Death

Tetanus Wound Management

Vaccination History

Unknown or <3 doses

3+ doses

Td TIG

Yes No

No* No

Td TIG

Yes Yes

No** No

Clean, minor

wounds

All other

wounds

* Yes, if >10 years since last dose

** Yes, if >5 years since last dose

Tetanus Epidemiology

• Reservoir Soil and intestine of animals and humans

• Transmission Contaminated wounds Tissue injury

• Temporal pattern Peak in summer orwet season

• Communicability Not contagious

0

100

200

300

400

500

600

700

1950 1960 1970 1980 1990 2000

Cases

Tetanus—United States, 1947-2005

Year

0

10

20

30

40

50

60

70

80

90

100

1980 1985 1990 1995 2000

Cases

Tetanus—United States, 1980-2005

Year

0

100

200

300

400

500

600

700

800

900

1000

<5 5-14 15-24 25-39 40+

Age group (yrs)

Ca

se

s

Tetanus—United States, 1980-2003Age Distribution

N=1,277

28

72

42

58

0

10

20

30

40

50

60

70

80

<40 40+

Age group (yrs)

Pe

rce

nt

of

Ca

se

s

1991-1995 1996-2000

Age Distribution ofReported Tetanus Cases,1991-1995 and 1996-2000

Tetanus Toxoid

• Formalin-inactivated tetanus toxin

• Schedule Three or four doses + boosterBooster every 10 years

• Efficacy Approximately 100%

• Duration Approximately 10 years

• Should be administered with diphtheriatoxoid as DTaP, DT, Td, or Tdap

Pertussis

• Highly contagious respiratory infectioncaused by Bordetella pertussis

• Outbreaks first described in 16thcentury

• Bordetella pertussis isolated in 1906

• Estimated 294,000 deaths worldwidein 2002

• Primarily a toxin-mediated disease

Bordetella pertussis

• Fastidious gram-negative bacteria

• Antigenic and biologically activecomponents:

– pertussis toxin (PT)

– filamentous hemagglutinin (FHA)

– agglutinogens

– adenylate cyclase

– pertactin

– tracheal cytotoxin

Pertussis Pathogenesis

• B. pertussis binds to and multiplies on

ciliated cells (respiratory mucosa). The

infection is not systemic.

• Inflammation occurs which interferes

with clearance of pulmonary secretions

• B. pertussis binds via at least 2 adhesion

proteins to the ciliated cells

•Filamentous hemagglutinin

•Pertussis toxin (Ptx, A5B exotoxin)

• Ptx is also released into the extracellular

fluid and can affect host cells

Host Cell

Pertussis Clinical Features

• Incubation period 5-10 days(range 4-21 days)

• Insidious onset, similar to minorupper respiratory infection withnonspecific cough

• Fever usually minimal throughoutcourse of illness

Pertussis Clinical Features

• Catarrhal stage 1-2 weeks

• Paroxysmalcough stage 1-6 weeks

• Convalescence Weeks tomonths

Pertussis Among Adolescentsand Adults

• Disease often milder than in infantsand children

• Infection may be asymptomatic, ormay present as classic pertussis

• Persons with mild disease maytransmit the infection

• Older persons often source ofinfection for children

Pertussis Complications*

Condition

Pneumonia

Seizures

Encephalopathy

Hospitalization

Death

Percent reported

4.9

0.7

0.1

16

0.2

*Cases reported to CDC 2001-2003 (N=28,998)

Pertussis Complications byAge

0

10

20

30

40

50

60

70

<6 m 6-11 m 1-4 y 5-9 y 10-19 y 20+ y

Age group

Pe

rce

nt

Pneumonia Hospitalization

*Cases reported to CDC 1997-2000 (N=28,187)

Pertussis Epidemiology

• Reservoir HumanAdolescents and adults

• Transmission Respiratory droplets

• Communicability Maximum in catarrhal stageSecondary attack rateup to 80%

0

50000

100000

150000

200000

250000

1940 1950 1960 1970 1980 1990 2000

Cases

Pertussis—United States, 1940-2005

Year

0

5000

10000

15000

20000

25000

30000

1980 1985 1990 1995 2000 2005

Cases

Pertussis—United States, 1980-2005

Year

Reported Pertussis by AgeGroup, 1990-2005

0

5000

10000

15000

20000

25000

30000

1990 1993 1996 1999 2002 2005

Year

Cases

<11 11-18 >18

Pertussis-containing Vaccines

• DTaP (pediatric)

–approved for children 6 weeks through 6 years(to age 7 years)

–contains same amount of diphtheria andtetanus toxoid as pediatric DT

• Tdap (adolescent and adult)

–approved for persons 10-18 years (Boostrix)and 11-64 years (Adacel)

–contains lesser amount of diphtheria toxoidand acellular pertussis antigen than DTaP

Composition* of AcellularPertussis Vaccines

Product

Tripedia

Infanrix

PT

23

25

PERT

--

8

FHA

23

25

*mcg per dose

Efficacy ~80-85%

Interchangeability of DifferentBrands of DTaP Vaccine

• Whenever feasible, the same DTaPvaccine should be used for alldoses of the series

• Limited data suggest that “mix andmatch” DTaP schedules do notadversely affect safety andimmunogenicity

• If vaccine used for earlier doses isnot known or not available, anybrand may be used to complete theseries

DTaP Adverse Reactions

• Local reactions 20%-40%

(pain, redness, swelling)

• Temp of 101oF 3%-5%

or higher

• More severe adverse reactionsnot common

• Local reactions more commonfollowing 4th and 5th doses

DTaP Contraindications

• Severe allergic reaction to vaccinecomponent or following a priordose

• Encephalopathy not due to anotheridentifiable cause occurring within7 days after vaccination

DTaP Precautions*

• Moderate or severe acute illness

• Temperature >105°F (40.5°C) or higherwithin 48 hours with no other identifiablecause

• Collapse or shock-like state (hypotonichyporesponsive episode) within 48 hours

• Persistent, inconsolable crying lasting >3hours, occurring within 48 hours

• Convulsions with or without feveroccurring within 3 days

*may consider use in outbreaks

Pertussis-Containing VaccinesStorage and Handling

• Stored at 35°–46°F (2°–8°C) at all times

• Must never be frozen

• Vaccine exposed to freezingtemperature must not be administeredand should be discarded

• Do not be used after the expirationdate printed on the box or label