++
Diphtheria, caused by Corynebacterium diphtheriae,
occurs worldwide. Toxigenic strains produce a protein toxin that
leads to the formation of pseudomembranes in the pharynx and respiratory
tract, as well as systemic toxicity including myocarditis and polyneuropathy. It may
present at any time of the year, although it is most common during
winter. Because humans are the only significant reservoir, closeness
and duration of contact with an ill person or a healthy carrier
are important determinants of infection spread. As a result, attack
rates in households and in crowded living conditions are high.
++
Human nasopharyngeal carriers of C diphtheriae are
the principal source of new infections, but cutaneous lesions can
transmit infection as well. In temperate climates, the skin lesions
of diphtheria are superficial, indolent sores that resemble impetigo.
Individuals with skin lesions generally do not develop toxic manifestations.
Untreated, healthy nasopharyngeal carriers can be colonized for
many weeks.
++
The incidence of diphtheria is inversely related to the percentage
of immune individuals in an area and remains a common disease in
countries without effective immunization programs. The incidence
of diphtheria in the United States has declined dramatically since aggressive
immunization efforts were begun in 1980; in fact, less than five
patients with diphtheria are reported annually. Concurrently, diphtheria
has shifted from a disease of children to a disease of adults with
waning immunity.1 The potential for outbreaks continues,
however, if segments of a community are not immunized.
++
C diphtheriae is comprised of irregularly staining
gram-positive, nonspore-forming, unencapsulated slender rods. Branching
and clubbed ends result in a cuneiform appearance. Metachromatic
granules are common. There are three phenotypes of the organism: gravis,
intermedius, and mitis, differentiated by colony morphology, growth
characteristics, and biochemical reactions. All are capable of elaborating
a cytotoxic exotoxin, which interferes with protein synthesis in
host cells. The ability of a strain of C diphtheriae to
produce toxin is conferred by a lysogenic bacteriophage that carries
the gene for toxin production. The clinical signs and symptoms depend
on the primary site of infection. Toxins produced by the three types
are qualitatively similar, but the gravis and intermedius strains
produce more toxin than does the mitis strain.
+++
Clinical Manifestations
++
Diphtheria presents with respiratory infection that can cause
respiratory obstruction, or with infected skin lesions that lack
a characteristic appearance. With either presentation, toxin produced
by the organism results in further symptoms.
+++
Respiratory
Diphtheria
++
This usually has an insidious onset with symptoms of a mild sore
throat with slight redness and low-grade fever. Systemic signs of
illness are absent in the early stages. Within 1 or 2 days, areas
of yellow or “dirty” white exudate appear, most
frequently on or adjacent to the tonsils; these areas subsequently
coalesce to form a light reflective, sharply outlined pseudomembrane
on the mucous membranes of the pharynx, tonsils, and uvula. Pseudomembranes
consist of necrotic epithelium embedded in an inflammatory, organized
exudate at the surface. Less frequently, such lesions are found
in the nose, larynx, and lower respiratory tract. Rarely, pseudomembranous
lesions extend to the middle ear, the esophagus or the stomach,
or involve the skin or mucosa of the genitalia. Inflammatory changes
in underlying epithelium may extend into the submucosa, where hemorrhage
may be present. The bacilli remain in these surface lesions and
rarely invade deeper structures or cause bacteremia. Diphtheria
toxin is absorbed from the local lesion, causing damage in distant
organs and tissues.
++
Persons with partial antitoxic immunity may not progress beyond
the exudative stage. In those lacking immunity, the pseudomembrane may
spread to the soft palate and to the posterior pharynx, but not
anteriorly. There is bleeding with attempts to remove the pseudomembrane. Cervical
lymph nodes may be mildly enlarged, but the single large, anterior cervical nodes
characteristic of streptococcal infection are not found. With extensive
membrane formation, there may be dysphagia and drooling. After approximately
5 days, the pseudomembrane changes to a grayish color secondary
to hemorrhage as it loosens and sloughs. In approximately 10% of
patients, the illness has a hyperacute presentation with high fever,
systemic toxicity, cerebral obtundation, and rapid proliferation
of the pseudomembrane associated with marked edema of the face and
neck, a phenomenon referred to as “bull neck” diphtheria,
which has a grave prognosis.
++
In less than 5% of patients, diphtheria of the laryngotracheal
area occurs in the absence of tonsillopharyngeal involvement, but
in about 10% of patients, there is secondary downward spread
from the pharynx. Varying degrees of hoarseness, stridor, and respiratory
embarrassment occur, depending on the extent and thickness of the
membrane in relation to the caliber of the airway. Young children
are at higher risk of compromise because of small airways. Rarely,
the membrane extends into the bronchi, resulting in a virtual cast
of the airway, which is invariably fatal.
++
Primary nasal diphtheria is more common in infants and young
children. The discharge is mucoid, profuse, and grayish in color. After
a few days when the membrane begins sloughing, there is often blood
in the discharge. This is the mildest form of diphtheria and seldom has
toxic manifestations.
+++
Skin and Mucous
Membranes
++
Rarely, the primary site of infection is the mucous membrane
of the eye, vagina, or ear. An ulcerating lesion with exudate or
pseudomembrane forms, but these self-limited lesions are only rarely
associated with toxicity. Skin lesions are most often superficial,
have no characteristic appearance, and are not associated with pseudomembranes.
Occasionally, ulcerating or ecthymatous lesions develop. They occur
in persons with preexisting antitoxic immunity, or they induce immunity
because they are not associated with toxic manifestations. Individual
lesions heal, but new ones may form at the sites of breaks in the
integrity of skin from insect bites or trauma over a period of weeks.
++
The heart, kidneys, and neural system are susceptible to damage
by diphtheria toxin. The degree of toxic damage is determined by two
factors: (1) the extent of disease at the primary site and, hence,
the amount of toxin produced and disseminated hematogenously; and
(2) the amount of circulating antitoxin. The latter is determined
by both the preexisting antitoxin resulting from prior subclinical infection
or immunization and by the therapeutic amounts of antitoxin administered. Because
immunity wanes with the passing years, previously immunized persons
can eventually become susceptible to toxin. Electrocardiographic
evidence of myocardial toxicity is present in many patients with diphtheria,
but clinical myocarditis develops in about 10% of patients.
Myocarditis generally develops during the first week of illness, but
onset can be delayed for 1 month or longer. Dysrhythmias are common.
Death occurs more often from severe dysrhythmia (including complete
heart block) than from heart failure. On histology, myocarditis
is characterized by degenerative or “toxic” damage, rather
than by inflammation. Minute hemorrhages may be present, or, in
some areas, an accompanying round-cell infiltration may be seen.
The conducting system is frequently involved.
++
Renal failure is rare, but minor injury as reflected by changes
in the urinalysis (proteinuria, cylindruria, increased cells) is
common. If toxic nephropathy develops, it is almost uniformly fatal.
Hemolytic uremic syndrome has been reported in diphtheria. The kidneys
may exhibit cloudy swelling, with swollen granular epithelial cells
of the convoluted tubules. Interstitial nephritis may occur. Lesions
in the adrenal cortex, similar to those present in meningococcemia,
are often found in fatal infections. Hepatic function may be mildly
impaired; liver cells show degenerative changes at autopsy, with
scattered areas of focal necrosis.
++
Neural involvement occurs in 5% to 10% of patients,
and can be manifested as isolated peripheral nerve palsies or as
a symptom complex mimicking Guillain-Barré syndrome. Contiguous
muscles in the palate, pharynx, or larynx are most commonly involved
and tend to be affected earlier in the disease course than the extraocular
muscles, diaphragm, or muscles supplied by peripheral nerves. Paralysis
can occur as early as the first week of illness, but more often
develops between the second and sixth week after onset of the respiratory
illness. If the patient does not succumb to respiratory complications
of paralysis, full recovery can be expected within a few weeks.
Degenerative changes in the nervous system occur in nearly all fatal
infections. In the spinal cord, changes are seen in the ganglion
cells of the anterior horns and in the posterior root ganglia. The
cranial nerves and their centers can be affected, but the cortex
is spared. Other lesions encountered are degenerative changes in
the spleen and lymph nodes; occasionally, subcapsular hemorrhages
in these organs are seen. Subcutaneous hemorrhages are frequent.
++
Many bacterial and viral pathogens can cause pseudomembranous
tonsillitis, the most common being Streptococcus pyogenes, adenoviruses,
and Epstein-Barr virus. Although there is sometimes exudate on the
part of the uvula touching the enlarged tonsil in these conditions,
the pseudomembrane does not otherwise extend away from the tonsil.
In rare instances of laryngeal diphtheria without oropharyngeal
involvement, the diagnosis is suspected if there is a history of
exposure to diphtheria or when a pseudomembrane is seen at the time
of laryngoscopy or bronchoscopy. Otherwise, the differential diagnosis
from viral causes of croup is exceedingly difficult.
++
When diphtheria is suspected, attempts should be made to isolate
the organism from the local lesion. It is advisable to take specimens for
culture from the nasopharynx as well as the throat because the yield
of positive results is 20% greater with two cultures as
opposed to one culture. If transport time to the laboratory is longer
than 24 hours, the swabs should be placed in a laboratory-recommended
commercial transport medium. Specimens should be inoculated onto
recommended media (usually a Loeffler or Pai slant, a cystine-tellurite
agar plate, and a 5% sheep’s blood agar plate)
and incubated overnight at 35°C (95°F). Growth from slants may be
stained with Neisser or Loeffler methylene blue and examined for
the characteristic morphologic appearance of C diphtheriae (eg,
metachromatic granules). Toxigenicity is usually determined using
the modified Elek immunodiffusion test in reference or state laboratories.
++
The degree of leukocytosis in the peripheral blood generally
reflects the severity of disease. In mild to moderate disease, the
leukocyte count is between 10,000 and 20,000/μL. The
likelihood of a fatal outcome rises sharply in patients with leukocyte
counts higher than 25,000/μL. Thrombocytopenia
and disseminated intravascular coagulation (DIC) are rare. Some
patients develop mild anemia.
++
In postdiphtheritic paralysis, protein concentrations increase
in the cerebrospinal fluid (CSF), but there is no increase in the
number of cells and the glucose content is normal, as occurs in
idiopathic Guillain-Barré syndrome. The protein content
continues to increase during the initial weeks of neurologic symptoms and
slowly returns to normal after clinical recovery.
++
Albuminuria is common, and in severe disease, there may be cells
and casts in the urine.
++
Diphtheria antitoxin neutralizes circulating toxin but has no
effect on toxin that is bound to cells. It should be administered
as soon as possible after onset of disease. Therefore, the decision
to treat is usually made before culture results are available and
is based on a compatible clinical picture in a susceptible individual.
Diphtheria antitoxin is an equine serum, so tests for sensitivity
must be done by instilling a 1:10 dilution into the conjunctival sac
or by performing an intradermal test dose with a 1:100 dilution
of the antiserum. If the patient has an immediate reaction, a desensitization
procedure is done. Details of appropriate sensitivity testing and
interpretations of results are usually provided with antitoxin available
from the Centers for Disease Control and Prevention.
++
The dosage of antitoxin is empirical and based on the extent
of disease. Dosage is not based on body weight, but on the estimated amount
of toxin present. Suggested dosages are presented in eTable
261.1. The antiserum is administered
intravenously. Antitoxin is of dubious value for patients with cutaneous
diphtheria, but some authorities recommend it because toxic manifestations
have occasionally been reported.
++
++
Antibiotic therapy has little or no effect on the clinical evolution
of diphtheria. It is given primarily to render the patient noncontagious. C
diphtheriae is susceptible to penicillin and erythromycin,
and probably to other macrolides (eg, clarithromycin, azithromycin)
as well. Erythromycin (40 mg/kg/d divided every 6
hours) is given by mouth. Effective dosage and duration of the newer
macrolides have not been defined, nor have these drugs been evaluated
in clinical cases or in carriers. Alternatively, daily procaine
penicillin G (25,000–50,000 U/kg in two divided
doses) can be given intramuscularly, or aqueous crystalline penicillin
G (100,000–150,000 U/kg divided in four doses)
can be given to the patient. Treatment is given for 14 days. After
completion of antibiotic therapy, the throat and nasopharynx should
be cultured three times, at least 24 hours apart, to determine whether
the pathogen has been eradicated. Respiratory isolation precautions
are maintained until there is culture confirmation of eradication
of the pathogen from the nasopharynx. Some patients with cutaneous
diphtheria have asymptomatic respiratory tract colonization with C diphtheriae,
and thus, throat and nasopharyngeal cultures are necessary in these
patients as well.2 If there is persistent nasopharyngeal carriage
after the first course of therapy, a repeat course of erythromycin
therapy should be given.
++
Corticosteroid therapy (to mitigate myocarditis or nephritis)
is ineffective and is not recommended.3 Carnitine
is a cofactor in the transport of fatty acids to the interior of
cell mitochondria. Because fatty acids accumulate in the cytoplasm
of human heart cells in patients with diphtheritic myocarditis,
carnitine might be beneficial. In one study, 10% DL-carnitine
(100 mg/kg/d in two divided doses for 4 days)
decreased the incidence of myocarditis as compared with a control
group, but this needs to be confirmed before carnitine can be recommended
as routine therapy.4 Treatment is otherwise supportive.
++
A patent airway must be maintained in patients with diphtheria. Nasotracheal
intubation or tracheostomy may be needed. Patients should be monitored
carefully for signs or symptoms of myocarditis, nephropathy, or neuropathy.
Patients should be observed closely for signs of laryngeal, pharyngeal,
or diaphragmatic paralysis. If there is difficulty with swallowing,
oral feedings should be withheld and parenteral nutrition provided. Respiratory
paralysis is managed by standard procedures. During the stage of
sloughing of the pseudomembrane, tracheal suction may be successful
in removing obstructive fragments.
++
Exposed household and other close contacts of an index patient
with diphtheria are at increased risk of becoming asymptomatic carriers
or of developing disease. Immunization provides antitoxic immunity,
but no immunity to infection with C diphtheriae. All
exposed persons should be examined promptly. Individuals with symptoms
consistent with diphtheria should be investigated and treated appropriately.
Cultures should be obtained from all exposed, asymptomatic persons,
and they should be considered potentially contagious until the culture
results are known. All close contact should be kept under surveillance for
7 days.
++
Previously immunized contacts should be given a booster dose
of diphtheria toxoid if they have not received a booster within
5 years. Individuals who are not immunized, or whose immunization
status is uncertain, should be given prophylaxis with erythromycin
(40 mg/kg/d in four divided doses for 7 days)
or a single intramuscular injection of 50,000 U benzathine penicillin
G per kilogram (maximum 1,200,000 U). Immunization with DtaP, Td,
or Tdap, depending on age, should be initiated. If the individual
cannot be kept under surveillance, some authorities recommend giving
5000 to 10,000 U of diphtheria antitoxin intramuscularly. In most circumstances,
the risk of allergic reactions makes this practice inadvisable.
++
Overall, the fatality rate is about 10%, but the prognosis
depends on type of disease, age, and general condition of the patient,
and the interval from onset of disease to receipt of antitoxin therapy. More
than half the patients with bull neck diphtheria die despite aggressive
intensive care. If myocarditis or renal failure occurs early in
the course of disease, the prognosis is grim. If the patient is
managed in an intensive care facility, death from airway obstruction
is unlikely, unless pseudomembrane extends into the bronchi. After
recovering from the acute illness, patients remain at risk for late
development of paralysis or myocarditis. There are no permanent
sequelae of diphtheria unless anoxic damage has occurred.
++
Because an attack of diphtheria does not provide reliable immunity
to the toxin, recovered patients should receive diphtheria toxoid.
Immunity is associated with a level of specific antibodies of 0.01
IU/mL. Newborn infants have transient immunity from maternal
antibodies when the mother is immune. Immunization recommendations
are found in Chapter 244.