Dr. Rezai MS

Pediatrics infectious disease sub specialist

ETIOLOY



Bordetella pertussis

 Bordetella parapertussis is an occasional cause  Exclusive pathogens of humans and some primates.

 B. bronchiseptica is a common animal pathogen.

Protracted coughing

 Mycoplasma  Parainfluenza or influenza viruses  Enteroviruses  Respiratory syncytial virus  Adenoviruses.

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.

EPIDEMIOLOY

 Approximately 60% of cases are in adolescents and adults.

 Infants have the highest morbidity  Pertussis is extremely contagious attack rates as high as

100%

EPIDEMIOLOY

 Chronic 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.

EPIDEMIOLOY

 Neither 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

PATHOGENES

 B.ordetella organisms are tiny, fastidious, gramnegative coccobacilli that only colonize ciliated epithelium.

 Only B. pertussis expresses virulence protein .

pertussis toxin (PT), the major  (PT), histamine sensitivity, insulin secretion, leukocyte dysfunction

PATHOGENES

 PT causes lymphocytosis immediately  Tracheal cytotoxi n, adenylate cyclase , and PT appear to inhibit clearance of organisms.

 Tracheal cytotoxin, cyclase are postulated to be predominantly responsible for the dermonecrotic local epithelial damage factor, and adenylate that produces respiratory symptoms and facilitates absorption of PT.

CLINICAL MANIFESTATION

  

3stages

Catarrhal paroxysmal convalescent

CLINICAL MANIFESTATION

 incubation period ranging from 3-12 days  catarrhal stage (1-2 wk) begins insidiously congestion and rhinorrhea, lacrimation low-grade fever sneezing conjunctival suffusion

CLINICAL MANIFESTATION

 paroxysmal stage (2-6 wk).

 The cough begins as a dry, intermittent, evolves into the inexorable of pertussis.

paroxysms irritative that are the hack and

hallmark

 anxious aura, whoop follows after caugh  Post-tussive emesis is common

CLINICAL MANIFESTATION

 At the peak of the paroxysmal stage, patients may have more than 1 episode hourly.

CLINICAL MANIFESTATION

 Convalescent stage (≥2 wk)  The number, severity, and duration of episodes diminish.

CLINICAL MANIFESTATION



Infants <3 mo of age

 Do not display classical stages.

 Cough (expiratory grunt) may not be prominent.

 Whoop infrequently occurs in infants <3 mo  Cyanosis can follow a coughing paroxysm  Apnea may be the only symptom.

 Apnea can occur without a cough

CLINICAL MANIFESTATION

 Paradoxically, 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 MANIFESTATION

 Immunized 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 suspect  Leukocytosis (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.

DIAGNOSIS

 Eosinophilia 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)

DIAGNOSIS

 Mild hyperinsulinemia and reduced glycemic response to epinephrine  Hypoglycemia is reported only occasionally.

 Parenchymal consolidation suggests secondary bacterial infection.  Pneumothorax, pneumomediastinum, and air in soft tissues can be seen occasionally.

DIAGNOSIS

 Isolation of B. pertussis in

culture

for diagnosis.

remains the gold standard  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 specimens  Less than 10% of any of these test results are positive in partially or remotely immunized individuals tested in the paroxysmal stage.

DIAGNOSIS

 Serologic tests the in acute and convalescent samples are 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.

DIAGNOSIS

 IgA and IgM pertussis antibody tests are not reliable methods for diagnosis.

DIAGNOSIS

 Adenoviral 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.

DIAGNOSIS



Chlamydia 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 observe the severity of the cough number of paroxysm s,to , 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 paroxysm self-expectorated mucus plug

post-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 occurred  Parents are adequately prepared for care at home.

Antibiotics

 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.

Antibiotics

Antibiotics

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.

COMPLICATION

 Progressive 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

COMPLICATION

 Seizures are usually a result of from excessive secretion of hypoxemia , but hyponatremia antidiuretic hormone during pneumonia can occur.

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

COMPLICATION

 Conjunctival and scleral hemorrhages petechiae on the upper body, epistaxis  Hemorrhage in the central nervous system (CNS) and retina  Pneumothorax and subcutaneous emphysema, and umbilical  Inguinal hernias.

COMPLICATION

 Children ≤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 yr  A 5th dose is not necessary if the 4th dose in the series is administered on or after the 4 th 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.



EPIDEMIOLOG

Tetanus 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)

PATHOGENESIS

 Toxin 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.

PATHOGENESIS

 The 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 MANIFESTATION

 Generalized,which is more common  Localized  The incubation period typically is

2-14 days

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

 In

generalized tetanus

 About

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.

 Opisthotonos  Laryngeal and respiratory muscle spasm can lead to airway obstruction and asphyxiation.

 Because tetanus toxin cortical function , the does not affect sensory nerves or 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 trigger a tetanic spasm.

sight, sound, or touch may  Dysuria and urinary retention result from bladder sphincter spasm; forced defecation may occur.

 Fever, occasionally as high as 40 ° C  Notable autonomic dysrhythmias, labile effects hypertension, cutaneous vasoconstriction.

include tachycardia, diaphoresis, and

 The tetanic paralysis usually becomes wk more severe in the 1st 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 tetanus

 Rare  bulbar musculature that occurs with wounds or foreign bodies in the head, nostrils, or face  It 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 clinically  Who 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 electromyogram shows a characteristic pattern.

the  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 or dental abscesses,or involving the brainstem.

para pharyngeal, retropharyngeal, rarely, from acute encephalitis  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 seizures  narcotic withdrawal

TREATMENT

 Surgical wound excision and debridement  Surgery 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 CARE

 Protected from all unnecessary sounds, sights and touch  Prophylactic subcutaneous heparin may be of value  Endotracheal 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.

COMPLICATION

 Aspiration of secretions and pneumonia  Pneumothorax and mediastinal emphysema.

 Rhabdomyolysis, renal failure  long bone or spinal fractures  Venous thrombosis, pulmonary embolism, gastric ulceration

 Cardiac arrhythmias  Unstable blood pressure  labile temperature regulation

PROGNOSIS

 Mortality 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 tetanic spasms trismus and the onset of generalized

 A

favorable prognosis

: long incubation period Absence of fever localized 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

PREVENTION

 Antibody 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 Management

 Tetanus prophylaxis is an essential part of all wound management  All 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).

 IVIG  Equine- or bovine-derived TAT 3,000-5,000 U surgical cleansing and debridement  A 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 even



I can’t believe it

Etiology

 Corynebacterium 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,Gravis

 Ulcerans 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 Epidemiology

 Reservoir Human carriers Usually asymptomatic  Transmission Respiratory Skin and fomites rarely  Temporal pattern  Communicability Winter and spring Up to several weeks without antibiotics

EPIDEMIOLOG

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

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

EPIDEMIOLOG

 Asymptomatic respiratory tract carriage is important in transmission.  Where diphtheria is endemic, 3-5% of healthy individuals can carry toxigenic organisms.

EPIDEMIOLOG

 Skin 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

EPIDEMIOLOG

 Cutaneous diphtheria:  Outbreaks are associated strains from exogenous sources.

with homelessness, crowding,poverty, alcoholism, poor hygiene, contaminated fomites, underlying dermatosis, and introduction of new

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

 pseudomembrane  a 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 local effect of diphtheritic toxin. is an early

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 Diphtheria



Cutaneous Diphtheria



Infection at Other Sites.

RespiratoryTract Diphtheria

 Tonsils or pharynx (94%)  Nose and larynx the next 2 most common sites.

 average incubation period of 2-4 days  Infection 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 lack of fever adherent membrane, extension beyond the faucial area, dysphagia, and relative 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 intubation.

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

 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 obtained  The 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, 2 nd 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 cause hypotension or cardiac failure.

, but rarely, 2-3 wk after onset of illness, vasomotor center dysfunction can 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 population is immunized.

of the organism, and providesherd immunity when at least 70-80% of a 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 around 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.

1 yr of age, the  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.