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