Dr. Rezai MSPediatrics infectious disease sub specialist

ETIOLOY

Bordetella pertussisBordetella parapertussis is an occasional causeExclusive pathogens of humans and some

primates.B. bronchiseptica is a common animal pathogen.

Protracted coughingMycoplasma Parainfluenza or influenza virusesEnterovirusesRespiratory syncytial virusAdenoviruses.

EPIDEMIOLOY

60 million cases of pertussis each year >500,000 deaths.Widespread use of pertussis vaccine led to a

>99% decline in cases.Pertussis is increasingly endemic.

EPIDEMIOLOYApproximately 60% of cases are in

adolescents and adults.Infants have the highest morbidityPertussis is extremely contagious

attack rates as high as 100%

EPIDEMIOLOYChronic carriage by humans is not documentedChronic carriage by humans is not documented.After intense exposure as in households, the rate

of subclinical infection is as high as 80% in fully immunized or previously infected individuals.

EPIDEMIOLOYNeither natural disease nor vaccination provides

complete or lifelong immunity against reinfection or disease.

Protection against typical disease wane 3-5 yr after vaccination unmeasurable after 12 yr

PATHOGENESB.ordetella organisms are tiny, fastidious,

gramnegative coccobacilli that only colonize ciliated epithelium.

Only B. pertussis expresses pertussis toxin (PT), the major virulence protein.

(PT), histamine sensitivity, insulin secretion, leukocyte dysfunction

PATHOGENESPT causes lymphocytosis immediatelyTracheal cytotoxin, adenylate cyclase, and PT

appear to inhibit clearance of organisms.Tracheal cytotoxin, dermonecrotic factor, and

adenylate cyclase are postulated to be predominantly responsible for the local epithelial damage that produces respiratory symptoms and facilitates absorption of PT.

CLINICAL MANIFESTATION

3stages Catarrhal paroxysmal convalescent

CLINICAL MANIFESTATIONincubation period ranging from 3-12 dayscatarrhal stage (1-2 wk) begins insidiously

congestion and rhinorrhea, lacrimationlow-grade feversneezing conjunctival suffusion

CLINICAL MANIFESTATIONparoxysmal stage (2-6 wk).The cough begins as a dry, intermittent, irritative

hack and evolves into the inexorable paroxysms that are the hallmark of pertussis.

anxious aura, whoop follows after caughPost-tussive emesis is common

CLINICAL MANIFESTATIONAt the peak of the paroxysmal stage, patients may

have more than 1 episode hourly.

CLINICAL MANIFESTATIONConvalescent stage (≥2 wk) The number, severity, and duration of

episodes diminish.

CLINICAL MANIFESTATIONInfants <3 mo of ageInfants <3 mo of ageDo not display classical stages.Cough (expiratory grunt) may not be prominent.Whoop infrequently occurs in infants <3 mo Cyanosis can follow a coughing paroxysmApnea may be the only symptom.Apnea can occur without a cough

CLINICAL MANIFESTATIONParadoxically, in infants, cough and whooping may

become louder and more classic in convalescence. Convalescence includes intermittent paroxysmal

coughing throughout the 1st year of life, including "exacerbations" with subsequent respiratory illnesses; these are not due to recurrent infection or reactivation of B.pertussis.

CLINICAL MANIFESTATIONImmunized children have foreshortening of all

stages of pertussis.Signs of lower respiratory tract disease are not

expected unless complicating secondary bacterial pneumonia is present.

Conjunctival hemorrhages and petechiae on the upper body are common.

DIAGNOSIS

Clinical suspectLeukocytosis (15,000-100,000 cells/mm3) due to

absolute lymphocytosis is characteristic in the catarrhal stage.

Lymphocytes are of T- and B-cell origin and are normal small cells, rather than the large atypical lymphocytes seen with viral infections.

DIAGNOSISEosinophilia is not a manifestation of pertussis.A severe course and death are correlated with

extreme leukocytosis (median peak white blood cell count fatal vs nonfatal cases, 94 vs 18 x 109 cells/L) and thrombocytosis (median peak platelet count fatal vs nonfatal cases, 782 vs 556 x 109/L)

DIAGNOSISMild hyperinsulinemia and reduced glycemic

response to epinephrineHypoglycemia is reported only occasionally.Parenchymal consolidation suggests secondary

bacterial infection. Pneumothorax, pneumomediastinum, and air in

soft tissues can be seen occasionally.

DIAGNOSISIsolation of B. pertussis in culture remains the

gold standard for diagnosis.deep nasopharyngeal aspiration or by use of a

flexible swab, preferably a dacron or calcium alginate swab, held in the posterior nasopharynx for 15-30 sec (or until coughing).

A 1.0% casamino acid liquid is acceptable for holding a specimen up to 2 hr; Stainer-Scholte broth or Regan-Lowe semisolid transport medium is used for longer periods, up to 4 days.

Direct testing of nasopharyngeal secretions by DFA is a rapid test

PCR to test nasopharyngeal wash specimensLess than 10% of any of these test results are

positive in partially or remotely immunized individuals tested in the paroxysmal stage.

DIAGNOSISSerologic tests in acute and convalescent

samples are the most sensitive tests in immunized individuals and are useful epidemiologically.

(lgG) antibody to pertussis toxin elevated >2 standard deviations above the mean of the immunized population indicates recent infection.

DIAGNOSISIgA and IgM pertussis antibody tests are not

reliable methods for diagnosis.

DIAGNOSISAdenoviral infections are usually distinguishable

by associated features, such as fever, sore throat, and conjunctivitis.

Mycoplasma and B. pertussis in young adults can be difficult to distinguish on clinical grounds.

DIAGNOSISChlamydia trachomatis B. pertussis is not associated with staccato cough

(breath with every cough), purulent conjunctivitis, tachypnea, rales or wheezes

TREATMEN

Goals of therapy are to limit the number of paroxysms,to observe the severity of the cough, to provide assistance when necessary

Infants <3 mo of age are admitted to hospital almost without exception

3-6 mo unless witnessed paroxysms are not severe, and those of any age if significant complications occur.

Typical paroxysms that are not life threatening

Duration <45 sec Red but not blue color change Tachycardia, bradycardia (not <60 beats/min in

infants) Oxygen desaturation that spontaneously resolves

at the end of the paroxysm Whooping or strength for self-rescue at the end of

paroxysmself-expectorated mucus plugpost-tussive exhaustion but not unresponsiveness.

TREATMEN

Mist by tent can be useful in some infants with thick, tenacious secretions and excessively irritable airways.

Large volume feedings are avoided.Portable oxygen, monitoring, or suction

apparatus should not be needed at home.

Hospital discharge

If over a 48-hr period disease severity is unchanged or diminished

No intervention is required during paroxysms, Nutrition is adequate, no complication has

occurredParents are adequately prepared for care at home.

AntibioticsAntibiotics

given when pertussis is suspected or confirmed primarily to limit the spread of infection and secondarily for possible clinical benefit.

A 7- to 10-fold relative risk for infantile hypertrophic pyloric stenosis (IHPS) has been reported in neonates treated with orally administered erythromycin.

Azithromycin is the preferred agent for use in neonates.

AntibioticsAntibiotics

AntibioticsAntibiotics

Adjunct Therapies

Corticosteroids clinical use is not warranted.Beneficial effect of beta2-adrenergic is not

documented

Isolation

Respiratory isolation with use of masks by all health care personnel entering the room.

Children and staff with pertussis in child-care facilities or schools should be excluded until macrolide prophylaxis has been taken for 5 days.

Care of Household and Other Close Contacts.

A macrolide agent should be given promptly to all household contacts and other close contacts, such as those in daycare, regardless of age, history of immunization, or symptoms

Children <7 yr of age who received a 3rd dose >6 mo before exposure or a 4th dose ≥3 yr before exposure should receive a booster dose.

Care of Household and Other Close Contacts

Individuals ≥9 yr should be given a booster if they have not previously received Tdap and >2 yr have passed since receipt of a diphtheria containing vaccine

Coughing health care workers, with or without known exposure to pertussis, should be promptly evaluated for pertussis

COMPLICATION

Infants <6 mo of age have excessive mortality and morbidity

Infants <4 mo of age account for 90% of cases of fatal pertussis.

Preterm birth and young maternal age are significantly associated with fatal pertussis.

COMPLICATIONProgressive pulmonary hypertension or

hemorrhage (especially in very young infants) and secondary bacterial pneumonia are usual causes of death. mortality rate of >80%.

otitis media pneumonia(S. aureus, S. pneumoniae)Seizure

COMPLICATIONSeizures are usually a result of hypoxemia, but

hyponatremia from excessive secretion of antidiuretic hormone during pneumonia can occur.

infants with apnea raises the possibility of a primary effect of PT on the CNS.

COMPLICATIONConjunctival and scleral hemorrhages

petechiae on the upper body, epistaxisHemorrhage in the central nervous system

(CNS) and retinaPneumothorax and subcutaneous

emphysema, and umbilicalInguinal hernias.

COMPLICATIONChildren ≤2 yr may have abnormal pulmonary

function into adulthood.Laceration of the lingual frenulum is not

uncommon.

PREVENTION

2, 4, and 6 mo of age.Booster:15-18 mo, 4-6 yrA 5th dose is not necessary if the 4th dose in

the series is administered on or after the 4th birthday.

The preferred age for Tdap vaccination is 11-12 yr

Tetanus(Clostridium tetani) lockjaw

C. tetani is not a tissue-invasive organism and instead causes illness through the effects of a single toxin, tetanospasmin

The human lethal dose of tetanus toxin is estimated to be 10-5 mg/kg.

EPIDEMIOLOGTetanus occurs worldwide and is endemic in

approximately 90 developing countries.The most common form, neonatal (or

umbilical) tetanus, kills approximately 500,000 infants each year, with about 80% of deaths in just 12 tropical Asian and African countries.

It occurs because the mother was not immunized.

maternal tetanus that results from postpartum, postabortal, or postsurgical wound infection with C.tetani.

Most non-neonatal cases of tetanus are associated with a traumatic injury, often a penetrating wound inflicted by a dirty object such as a nail, splinter, fragment of glass, or unsterile injection.

Tetanus occurring after illicit drug injection is becoming more common. (quinine)

PATHOGENESISToxin is released after vegetative bacterial cell

death and lysis.Tetanus toxin binds at the neuromuscular

junction and enters the motor nerve by endocytosis, after which it undergoes retrograde axonal transport to the cytoplasm of the a motoneuron.

PATHOGENESISThe autonomic nervous system is also rendered

unstable in tetanus.C. tetani is not an invasive organism, its toxin

producing vegetative cells remain where introduced into the wound.

CLINICAL MANIFESTATIONGeneralized,which is more commonLocalized The incubation period typically is 2-14 days,

but it may be as long as months after the injury.

In generalized tetanusAbout half of cases is trismus (masseter muscle

spasm, or lockjaw).Headache, restlessness, and irritability are early

symptoms, often followed by stiffness, difficulty chewing, dysphagia, and neck muscle spasm.

The so-called sardonic smile of tetanus (risus sardonicus) results from intractable spasms of facial and buccal muscles.

OpisthotonosLaryngeal and respiratory muscle spasm can lead

to airway obstruction and asphyxiation.Because tetanus toxin does not affect sensory

nerves or cortical function, the patient unfortunately remains conscious, in extreme pain, and in fearful anticipation of the next tetanic seizure.

These seizures are characterized by sudden, severe tonic contractions of the muscles, with fist clenching, flexion, and adduction of the arms and hyperextension of the legs.

Without treatment, the seizures range from a few seconds to a few minutes in length with intervening respite periods, but as the illness progresses, the spasms become sustained and exhausting.

The smallest disturbance by sight, sound, or touch may trigger a tetanic spasm.

Dysuria and urinary retention result from bladder sphincter spasm; forced defecation may occur.

Fever, occasionally as high as 40°CNotable autonomic effects include tachycardia,

dysrhythmias, labile hypertension, diaphoresis, and cutaneous vasoconstriction.

The tetanic paralysis usually becomes more severe in the 1st wk after onset, stabilizes in the 2nd wk, and ameliorates gradually over the ensuing 1-4 wk

Neonatal tetanus (tetanus neonatorum)

The infantile form of generalized tetanus, typically manifests within 3-12 days of birth

As progressive difficulty in feeding (sucking and swallowing),associated hunger, and crying.

Paralysis or diminished movement

>270,000 cases worldwide per year

stiffness and rigidity to the touch, and spasms, with or without opisthotonos, are characteristic.

The umbilical stump may hold remnants of dirt, dung, clotted blood, or serum, or it may appear relatively benign.

Localized tetanus results in painful spasms of the muscles adjacent to the wound site and may precede generalized tetanus.

Cephalic tetanusRarebulbar musculature that occurs with wounds or

foreign bodies in the head, nostrils, or faceIt also occurs in association with chronic otitis

media. Cephalic tetanus is characterized by retracted

eyelids, deviated gaze, trismus, risus sardonicus, and spastic paralysis of the tongue and pharyngeal musculature.

DIAGNOSIS D iagnosis may be established clinicallyWho was injured or born within the preceding 2

wk, who presents with trismus, other rigid muscles, and a clear sensorium.

Routine laboratory studies are usually normal.

A peripheral leukocytosis may result from a secondary bacterial infection

The cerebrospinal fluid is normal, although the intense muscle contractions may raise intracranial pressure.

Neither the electroencephalogram nor the electromyogram shows a characteristic pattern.

C. tetan; is not always visible on Gram stain of wound material, and it is isolated in only about 1/3 of cases

DIFFERENTIAL DIAGNOSIS Trismus may result from para pharyngeal,

retropharyngeal, or dental abscesses,or rarely, from acute encephalitis involving the brainstem.

Rabies may be distinguished from tetanus by hydrophobia, marked dysphagia predominantly clonic seizures, and pleocytosis

Strychnine poisoning : seldom produces trismus, and unlike tetanus, general relaxation usually occurs between spasms

Hypocalcemia: trismus is absent.epileptic seizuresnarcotic withdrawal

TREATMENTSurgical wound excision and debridementSurgery should be performed promptly after

administration of human tetanus immunoglobulin (TIG) and antibiotics.

Excision of the umbilical stump in neonatal tetanus is no longer recommended.

Tetanus toxin cannot be neutralized by TlG after it has begun its axonal ascent to the spinal cord

A single intramuscular injection of 500 U of TIG is sufficient

Infiltration of TIG into the wound is now considered unnecessary.

IVIG contains 4-90 U/mL of TIG

The human-derived immunoglobulins are much preferred because of their longer half-life (30 days) and the virtual absence of allergic and serum sickness adverse effects.

Intrathecal TIG, given to neutralize tetanus toxin in the spinal cord, is not effective.

Penicillin G (100,000 U/kg/day divided every 4-6 hr IV for 10-14 days) remains the antibiotic of choice

Metronidazole (500 mg every 8 hr IV for adults) appears to be equally effective.

Erythromycin and tetracycline (for persons >8 yr of age) are alternatives for penicillin-allergic patients.

All patients with generalized tetanus need muscle relaxants.

Diazepam provides both relaxation and seizure control.

The initial dose of 0.1-0.2/kg every 3-6 hr given intravenously is subsequently titrated to control the tetanic spasms, after which it is sustained for 2-6 wk before its tapered withdrawal.

Magnesium sulfate, other benzodiazepines (midazolam), chlorpromazine, dantrolene, and baclofen are also used.

B aclofen should be used only in an intensive care unit setting.

The highest survival rates in generalized tetanus are achieved with neuromuscular blocking agents such as vecuronium and pancuronium

Autonomic instability is regulated with standard α and β or (both) blocking agents; morphine has also proved useful.

SUPPORTIVE CAREProtected from all unnecessary sounds, sights

and touchProphylactic subcutaneous heparin may be of

valueEndotracheal intubation may not be required,

but it should be done to prevent aspiration of secretions before laryngospasm develops.

Early tracheostomy should be considered in severe cases not managed by pharmacologically induced flaccid paralysis.

COMPLICATIONAspiration of secretions and pneumoniaPneumothorax and mediastinal emphysema.Rhabdomyolysis, renal failurelong bone or spinal fracturesVenous thrombosis, pulmonary embolism, gastric

ulceration

Cardiac arrhythmiasUnstable blood pressurelabile temperature regulation

PROGNOSISMortality is highest in the very young and the

very old. An unfavorable prognosis :

<7 days between the injury and the onset of trismus <3 days between trismus and the onset of generalized tetanic spasms

A favorable prognosis :long incubation period Absence of feverlocalized disease.

Most fatalities occur within the 1st wk of illness.fatality rates for generalized tetanus are 5-35%,

and for neonatal tetanus extend from <10% with intensive care treatment to >75% without it.

Cephalic tetanus has an especially poor prognosis because of breathing and feeding difficulties

PREVENTIONAntibody titer of ≥0.01 U/mL is considered

protective.Vaccinaion:2, 4, and 6 mo of age, with a booster at

4-6 yr of age and at 10 yr intervals thereafter throughout adult life (Td or Tdap).

Immunization of women at least 2 doses

Arthus reactions (type III hypersensitivity reactions)

For unimmunized persons >7 yr of age, the primary immunization series consists of 3 doses of Td toxoid given intramuscularly, with the 2nd given 4-6 wk after the 1st and the 3rd given 6-12 mo after the 2nd.

Wound ManagementTetanus prophylaxis is an essential part of all

wound managementAll non minor wounds require human TIG except

those in a fully immunized patient.TIG 250 U should be given intramuscularly, with

500 U for highly tetanus-prone wounds (i.e., unable to be debrided, with substantial bacterial contamination, or >24 hr since injury).

IVIGEquine- or bovine-derived TAT 3,000-5,000 U

surgical cleansing and debridementA booster is administered to injured persons who

have completed their primary immunization series if (1) the wound is clean and minor but ≥1 0 yr have passed since the last booster or (2) the wound is more serious and ≥5 yr have passed since the last booster.

Persons who experienced an Arthus reaction after a dose of tetanus toxoid-containing vaccine should not receive Td more frequently than every 10 yr, even for tetanus prophylaxis as part of wound management.

I can make a sea From my tears But alas evenI can’t believe it

EtiologyCorynebacterium diphtheriae and rarely toxigenic

strains of Corynebacterium ulcerans.Aerobic, nonencapsulated, nonspore-forming,

mostly nonmotile, pleomorphic, gram-positive bacilli.

Diphthera is Greek for leather

C. diphtheriae biotypes :Mitis, Intermedius,Belfanti,GravisUlcerans is urease-positive.Capable of causing diphtheria:

Toxigenic and nontoxigenic strains are indistinguishable by colony type, microscopy, or biochemical tests.

Demonstration of diphtheritic toxin:In vitro by the agar immunoprecipitin technique (Elek test) In vivo toxin neutralization test in guinea pigs PCR testing for carriage of the toxin gene

Gram +ve Bacilli and Colonies

Diphtheria EpidemiologyReservoir Human carriers

Usually asymptomatic

Transmission Respiratory Skin and fomites rarely

Temporal pattern Winter and spring

Communicability Up to several weekswithout antibiotics

EPIDEMIOLOG

C. diphtheriae is an exclusive inhabitant of human mucous membranes and skin.

Spread :Airborne respiratory dropletsDirect contact with respiratory secretions of symptomatic individuals, or exudate from infected skin lesions.

EPIDEMIOLOGAsymptomatic respiratory tract carriage is

important in transmission. Where diphtheria is endemic, 3-5% of healthy

individuals can carry toxigenic organisms.

EPIDEMIOLOGSkin infection and skin carriage are silent

reservoirs of C. diphtheriae,Organisms can remain viable in dust or on fomites

for up to 6 mo.Transmission through contaminated milk and an

infected food handler has been proved or suspected

EPIDEMIOLOGCutaneous diphtheria:Outbreaks are associated with homelessness,

crowding,poverty, alcoholism, poor hygiene, contaminated fomites, underlying dermatosis, and introduction of new strains from exogenous sources.

PATHOGENES

Toxigenic and nontoxigenic C. diphtheriae cause skin and mucosal infection, and rarely can cause focal infection after bacteremia.

The major virulence of the organism lies in its ability to produce the potent 62-kd polypeptide exotoxin, which inhibits protein synthesis and causes local tissue necrosis.

PATHOGENES

pseudomembranea dense necrotic coagulum of organisms,

epithelial cells, fibrin, leukocytes, and erythrocytes forms,

Removal is difficult and reveals a bleeding edematous submucosa.

Paralysis of the palate and hypopharynx is an early local effect of diphtheritic toxin.

PATHOGENES

Toxin absorption can lead to systemic manifestations:kidney tubule necrosis, thrombocytopenia, cardiomyopathy, and/or demyelination of nerves. occur 2-10 wk after mucocutaneous infection, the pathophysiology in some cases is suspected to be immunologically mediated.

CLINICAL MANIFESTATION

RespiratoryTract DiphtheriaCutaneous DiphtheriaInfection at Other Sites.

RespiratoryTract Diphtheria

Tonsils or pharynx (94%)Nose and larynx the next 2 most common sites.average incubation period of 2-4 daysInfection of the anterior nares, which is more

common among infants, causes serosanguineous, purulent,erosive rhinitis with membrane formation.

Shallow ulceration of the external nares and upper lip is characteristic.

In tonsillar and pharyngeal diphtheria

sore throat is the universal early symptom only half of patients have fever, and fewer have

dysphagia, hoarseness, malaise, or headache. Mild pharyngeal injection is followed by

unilateral or bilateral tonsillar membrane formation, which can extend to involve the uvula (which may cause toxin mediated paralysis), soft palate, posterior oropharynx, hypopharynx, or glottic areas

Underlying soft tissue edema and enlarged lymph nodes can cause a bull-neck appearance.

The characteristic adherent membrane, extension beyond the faucial area, dysphagia, and relative lack of fever help differentiate diphtheria from exudative pharyngitis caused by Streptococcus pyogenes or Epstein-Barr virus.

Vincent angina, infective phlebitis with thrombosis of the jugular veins, and mucositis in patients undergoing cancer chemotherapy are usually differentiated by the clinical setting.

Infection of the larynx, trachea, and bronchi can be primary or a secondary extension from the pharyngeal infection.

Hoarseness, stridor, dyspnea, and croupy cough are clues. Differentiation from bacterial epiglottitis, severe viral laryngotracheobronchitis, and staphylococcal or streptococcal tracheitis hinges partially on the relative paucity of other signs and symptoms in patients with diphtheria and primarily on visualization of the adherent pseudomembrane at the time of laryngoscopy and intubation.

Patients with laryngeal diphtheria are at significant risk for suffocation because of local soft tissue edema and airway obstruction by the diphtheritic membrane, a dense cast of respiratory epithelium, and necrotic coagulum.

Establishment of an artificial airway and resection of the pseudomembrane can be lifesaving, but further obstructive complications are common, and systemic toxic complications are inevitable.

Cutaneous Diphtheria

Classic cutaneous diphtheria is an indolent,non progressive infection characterized by a superficial, ecthymic, nonhealing ulcer with a gray-brown membrane.

Diphtheritic skin infections cannot always be differentiated from streptococcal or staphylococcal impetigo, and they frequently coexist.

In most cases, a primary process-dermatosis , laceration, burns, bite, or impetigo-becomes secondarily infected with C. diphtheriae.

Extremities are more often affected than the trunk or head. Pain, tenderness, erythema, and exudate are typical.

Local hyperesthesia or hypesthesia is unusual. Respiratory tract colonization or symptomatic infection with toxic complications occurs in the minority of patients with cutaneous diphtheria.

Skin Lesions

Infection at Other Sites.the ear (otitis external, the eye (purulent

and ulcerative conjunctivitis), and the genital tract (purulent and ulcerative vulvovaginitis).

Sporadic cases of pyogenic arthritis, mainly due to nontoxigenic strains, have been reported in adults and children.

Diphtheroids isolated from sterile body sites should not be routinely dismissed as contaminants without careful consideration of the clinical setting.

DIAGNOSIS

Specimens for culture should be obtainedThe laboratory must be notified to use

selective medium.Culture isolates of coryneform organisms

should be identified to the species level, and toxigenicity and antimicrobial susceptibility tests

COMPLICATION

Toxic Cardiomyopathy.Toxic Neuropathy

Toxic Cardiomyopathy.

Toxic cardiomyopathy occurs in 10-25% of patients with respiratory diphtheria and is responsible for 50-60% of deaths.

the risk for significant complications correlates directly with the extent and severity of exudative local oropharyngeal disease and delay in administration of antitoxin.

The 1st evidence of cardiac toxicity characteristically occurs during the 2nd and 3rd weeks of illness as the pharyngeal disease improves, but can appear acutely as early as the 1st wk, a poor prognostic sign, or insidiously as late as the 6th wk of illness.

Tachycardia out of proportion to fever is common and may be evidence of cardiac toxicity or autonomic nervous system dysfunction.

A prolonged PR interval and changes in the ST-T wave on an electrocardiographic tracing are relatively frequent findings; dilated and hypertrophic cardiomyopathy detected by echocardiogram has been described.

Single or progressive cardiac dysrhythmias can occur, including 1st, 2nd and 3rd degree heart block Temporary transvenous pacing may improve outcomes.

Heart failure may appear insidiously or acutely. Elevation of the serum aspartat aminotransferase

concentration closely parallels the severity of myonecrosis.

Recovery from toxic myocardiopathy is usually complete,although survivors of more severe dysrhythmias can have permanent conduction defects.

Toxic Neuropathy

Neurologic complications parallel the severity of primary infection and are multiphasic in onset.

Acutely or 2-3 wk after onset of oropharyngeal inflammation, it is common for hypresthesia and local paralysis of the soft palate to occur.

Weakness of the posterior pharyngeal, laryngeal, and facial nerves may follow, causing a nasal quality in the voice, difficulty in swallowing, and risk for aspiration.

Cranial neuropathies characteristically occur in the 5th wk, leading to oculomotor and ciliary paralysis, which can cause strabismus, blurred vision, or difficulty with accommodation.

Symmetric polyneuropathy has its onset 10 days to 3 mo after oropharyngeal infection and causes principally motor deficits with diminished deep tendon reflexes.

Distal muscle weakness in the extremities that progresses proximally is more commonly described than proximal muscleweakness with distal progression.

Clinical and cerebrospinal fluid findings in the former are indistinguishable from those of Guillain-Barre syndrome. Paralysis of the diaphragm may ensue.

Complete neurologic recovery is likely, but rarely, 2-3 wk after onset of illness, vasomotor center dysfunction can cause hypotension or cardiac failure.

Recovery from the myocarditis and neuritis is often slow but usually complete. Corticosteroids do not diminish these complications and are not recommended.

TREATMENT

Specific antitoxin is the mainstay of therapy and should be administered on the basis of clinical diagnosis.

Because it neutralizes only free toxin, antitoxin efficacy diminishes with elapsed time after the onset of mucocutaneous symptoms.

Antitoxin is administered as a single empirical dose of 20,000-120,000 U based on the degree of toxicity, site and size of the membrane, and duration of illness.

Antitoxin is probably of no value for local manifestations of cutaneous diphtheria, but its use is prudent because toxic sequelae can occur.

Commercially available intravenous immunoglobulin preparations contain low titers of antibodies to diphtheria toxin; their use for therapy of diphtheria is not proven or approved.

Antitoxin is not recommended for asymptomatic carriers.

The role of antimicrobial therapy is to halt toxin production, treat localized infection, and prevent transmission of the organism to contacts.

C. diphtheriae is usually susceptible to various agents in vitro, including penicillins, erythromycin, clindamycin, rifampin, and tetracycline. Resistance to erythromycin is common in populations if the drug has been used broadly.

Only erythromycin or penicillin is recommended; erythromycin is marginally superior to penicillin for eradication of nasopharyngeal carriage.

Appropriate therapy is erythromycin (40-50 mg/kg/day divided every 6 hr PO or IV; maximum 2 g/day), aqueous crystalline penicillin G (100,000-150,000 U/kg/day divided every 6 hr IV or 1M), or procaine penicillin (25,000-50,000 U/kg/day divided every 12 hr 1M). Antibiotic therapy is not a substitute for antitoxin therapy. Therapy is given for 14 days.

Some patients with cutaneous diphtheria have been treated for 7-10 days.

Elimination of the organism should be documented by at least 2 successive negative cultures from the nose and throat (or skin) obtained 24 hr apart after completion of therapy.

Treatment with erythromycin is repeated if either culture yields C. diphtheriae.

SUPPORTIVE CARE

Cutaneous wounds are cleaned thoroughly with soap and water.

Bed rest is essential during the acute phase of disease, usually for ~2 wk until the risk for symptomatic cardiac damage has passed, with a return to physical activity guided by the degree of toxicity and cardiac involvement.

PROGNOSIS

Protection against serious disease caused by imported or indigenously acquired C. diphtheriae depends on immunization.

The presumed minimum is 0.01-0.10 IU/mL. In outbreaks, 90% of individuals with clinical disease have had antibody values of <0.01 IU/mL, and 92% of asymptomatic carriers have had values of >0.1 IU/mL.

The risk for developing diphtheria after household exposure to a case is approximately 2%, and the risk is 0.3% after similar exposure to a carrier.

Asymptomatic Case Contacts.

All household contacts and those who have had intimate respiratory or habitual physical contact with a patient are closely monitored for illness through the 7 day incubation period.

Cultures of the nose, throat, and any cutaneous lesions are performed.

Antimicrobial prophylaxis is presumed effective and is administered regardless of immunization status using erythromycin (40-50 mg/kg/day divided qid PO for 7 days; maximum 2 g/day) or a single injection of benzathine penicillin G (600,000 U 1M for <30 kg, 1,200,000 U 1M for ~30

kg).

Diphtheria toxoid vaccine, in age-appropriate form, is given to immunized individuals who have not received a booster dose within 5 yr.

Children who have not received their 4th dose should be vaccinated.

Those who have received fewer than 3 doses of diphtheria toxoid or who have uncertain immunization status are immunized with an age-appropriate preparation on a primary schedule.

Asymptomatic Carriers

When an asymptomatic carrier is identified, antimicrobial prophylaxis is given for 7 days and an ageappropriate preparation of diphtheria toxoid is administered immediately if a booster has not been given within 1 yr.

Individuals are placed on droplet precautions (respiratory tract colonization) or contact precautions (cutaneous colonization only) until at least 2 subsequent cultures obtained 24 hr apart after cessation of therapy are negative.

Repeat cultures are performed about 2 wk after completion of therapy for cases and carriers, and, if positive, an additional 10 day course of oral erythromycin should be given and follow-up cultures performed.

Susceptibility testing of isolates should be performed as erythromycin resistance is reported.

Neither antimicrobial agent eradicates carriage in 100% of individuals.

Antitoxin is not recommended for asymptomatic close contacts or carriers, even if inadequately immunized.

Only those with an unusual contact with respiratory or oral secretions should be managed as contacts.

Vaccine

Although immunization does not preclude subsequent respiratory or cutaneous carriage of toxigenic C. diphtheriae, it decreases local tissue spread, prevents toxic complications, diminishes transmission of the organism, and providesherd immunity when at least 70-80% of a population is immunized.

DTaP, DT) contains 6.7-25.0 Lf units of diphtheria toxoid per 0.5 mL dose; the adult preparation (dT) contains no more than 2 Lf units of toxoid per 0.5 mL dose.

For children from 6 wk to 7 yr of age, five 0.5-mL doses of diphtheria-containing (D) vaccine are given in a primary series, including 3 doses at 2, 4, and 6 mo of age, with a 4th dose, anintegral part of the primary series, 9-12 mo after the third dose.

A booster dose is given at 4-6 yr of age (unless the 4th primary dose was administered after the 4th birthday).

For persons 7 yr of age and older, three 0.5 mL doses of diphtheria-containing (d) vaccine are given in a primary series of 2 doses 4-8 wk apart and a 3rd dose 6-12 mo after the 2nd dose.

The only contraindication to tetanus and diphtheria toxoid is a history of neurologic or severe hypersensitivity reaction after a previous dose

For those beginning at around1 yr of age, the primary series is three 0.5 mL doses of diphtheria containing (D) vaccine, with a booster given at 4-6 yr, unless the 3rd dose was given after the 4th birthday.

A booster dose, consisting of an adult preparation of Tdap, is recommended at 11-12 yr of age. Adolescents 13-18 yr of age who missed the 11-12 year old Td or Tdap booster dose or in whom it has been ~5 yr since the Td booster dose also should receive a single dose of Tdap if they have completed the DTPIDTaP series.

There is no association of DT or dT with convulsions.

Local adverse effects alone do not preclude continued use.

Persons who experience Arthus-type hypersensitivity reactions or a temperature >103°F (39.4°C) after a dose of dT, which is rare, usually have high serum tetanus antitoxin levels and should not be given dT more frequently than every 10 yr, even if a significant tetanusprone injury is sustained. DT or dT preparation can be given concurrently with other vaccines.

Haemophi/us influenzae conjugate vaccines containing diphtheria toxoid (PRP-D) or the variant of diphtheria toxin, CRM197protein (HbOC), are not substitutes for diphtheria toxoid immunization and do not affect reactogenicity.