19 Diphtheria Toxoid Tejpratap S.P. Tiwari and Melinda Wharton Respiratory diphtheria is an acute communicable upper respi- Schick introduced a skin test for immunity that consisted of the ratory illness caused by toxigenic strains of Corynebacterium injection of a small, measured amount of diphtheria toxin; in diphtheriae, a Gram-positive bacillus. The illness is character- immune persons, circulating antibody neutralized the toxin, ized by a membranous inflammation of the upper respiratory and no local lesion was observed.2 The Schick skin test was tract, usually of the pharynx but sometimes of the posterior widely used to distinguish immune individuals and target nasal passages, larynx, and trachea, and by widespread damage immunization to those susceptible. In the early 1920s, Ramon to other organs, primarily the myocardium and peripheral showed that diphtheria toxin, when treated with heat and for- nerves. Extensive membrane production and organ damage malin, lost its toxic properties but retained its ability to produce are caused by local and systemic actions of a potent exotoxin serologic protection against the disease. Thus the current produced by toxigenic strains of C. diphtheriae. A cutaneous immunizing preparation, diphtheria toxoid, came into being.6 form of diphtheria commonly occurs in warmer climates or tropical countries. WHY THE DISEASE IS IMPORTANT HISTORY OF THE DISEASE Before the introduction of diphtheria immunization, diphthe- ria was a major cause of childhood mortality, and it remains Historical descriptions of diphtheria-like illness (throat mem- endemic in many developing countries. A large outbreak of brane, neck swelling, frequent suffocation) first appeared in diphtheria in the newly independent states of the former ancient Egyptian writings from the second millennium BC1 Soviet Union in the 1990s highlighted the potential for this with increasingly detailed descriptions by Greek writers, ancient scourge to reemerge in countries that fail to maintain including Hippocrates (fifth century BC), Aretaeus (second high levels of population immunity through immunization.7 century AD), and Aëtius (sixth century AD).2–4 Only isolated reports of the disease appeared until the 17th century, when devastating outbreaks occurred in Spain.3 Indeed, in Spanish BACKGROUND history, 1613 is known as the Year of Diphtheria (Año de los Clinical Description Garrotillos).2 Successive outbreaks occurred in southwestern Europe approximately every 12 years through the 18th century. Classic diphtheria has an insidious onset after an incubation The earliest definitive description of diphtheria in America was period of 1 to 5 days (rarely longer). The gradual onset of that of Samuel Bard in New York in 1771, although outbreaks diphtheria is in contrast to the usually sudden, almost explo- had previously been noted in the American colonies.2,3,5 In the sive manifestations of streptococcal pharyngitis. Symptoms of early 19th century, Bretonneau clearly delineated the clinical diphtheria are initially nonspecific and mild; throughout the picture of diphtheria, convincingly argued for its communica- course of the disease, the patient’s temperature usually does bility, successfully pioneered tracheostomy as a method of not exceed 38.5°C. Other early symptoms in children include treatment, and gave the disease its name, derived from the diminished activity and some irritability. At the very onset of Greek word for leather or tanned skin.2,3 symptoms, the pharynx is inspected on examination but no In the second half of the 19th century, increasingly severe membrane is present. About a day after onset, small patches epidemics swept many parts of Europe and the large cities of of exudate appear in the pharynx. Within 2 or 3 days, the the United States, and vigorous efforts were made by research- patches of exudate spread and become confluent and may ers in the new field of bacteriology to identify the causative form a membrane that covers the entire pharynx, including agent.4 In 1883, Klebs first described the characteristic organ- the tonsillar areas, soft palate, and uvula. This membrane isms in stained preparations of diphtheritic membranes, and becomes grayish, thick, and firmly adherent to the underlying Löffler reported the successful growth of these organisms in mucosa. Efforts to dislodge the membrane result in bleeding. culture a year later.3 Other investigators soon confirmed the Anterior cervical lymph nodes become markedly enlarged and pathogenicity of the organism for guinea pigs, and in 1888, tender. In a proportion of patients, the lymph node swelling Roux and Yersin demonstrated the presence of a potent exo- is associated with considerable inflammation and edema of toxin (see “Passive Immunization,” later). Over the next the surrounding soft tissues, giving rise to the so-called bull- decade, antisera produced in animals by injection of sublethal neck appearance, which is associated with a higher morbidity or inactivated cultures were first shown to prevent death in and mortality. Although fever is rarely high, the patient char- nonimmune animals that were challenged with virulent acteristically appears toxic and displays a rapid, thready pulse. organisms, and then to prevent death in children with clinical In untreated patients, the membrane begins to soften about a diphtheria.2,3 week after onset and gradually sloughs off, usually in pieces The concept of active immunization began with Theobald but sometimes as a single unit. As the membrane detaches, Smith in 1907, who noted that long-lasting immunity to diph- acute systemic symptoms, such as fever, begin to disappear. theria could be produced in guinea pigs by the injection of Although pharyngeal diphtheria is by far the most common mixtures of diphtheria toxin and antitoxin and suggested that form of disease seen in unimmunized populations, other skin these mixtures might do the same for humans. After successful or mucosal sites may be involved. Laryngeal diphtheria occurs immunization of children by von Behring with toxin–antitoxin in 25% of cases; in 75% of these instances, the pharynx is also mixtures, immunization programs began in selected European involved. Isolated nasal diphtheria is uncommon (approxi- and American cities. However, these immunizations, although mately 2% of cases). Cutaneous, aural, vaginal, and conjunc- usually effective, were not free of adverse reactions. In 1913, tival diphtheria together account for only approximately 2% 261 Downloaded for Pediatrijas katedra ([email protected]) at Riga Stradins University from ClinicalKey.com by Elsevier on January 18, 2020. For personal use only. No other uses without permission. Copyright ©2020. Elsevier Inc. All rights reserved. 262 SECTION 2 Licensed Vaccines and Vaccines in Development of cases and are often secondary to nasopharyngeal infection. local symptoms of diphtheria in the respiratory tract are resolv- Laryngeal diphtheria may occur at any age, but is particularly ing and the patient is otherwise improving. likely to occur in children younger than 4 years. It is marked In either early or late myocarditis, a wide variety of clinical by an insidious onset with gradually increasing hoarseness and electrocardiographic findings may be noted.24 Tachycar- and stridor. Fever is usually slight. The diagnosis is often dia, distant heart sounds, and a weak pulse may be observed. missed or delayed when the pharynx is not simultaneously Electrocardiography most often shows conduction changes involved. Laryngeal diphtheria is associated with greater and alterations in T waves. Supraventricular and ventricular morbidity and mortality as a result of airway obstruction and ectopic rhythms are common in severe diphtheria, even in the the greater degree of toxin absorption from the extensive absence of evidence of heart failure.26 The earlier electrocar- membrane. diographic changes appear, the worse is the prognosis. Com- Cutaneous diphtheria is an indolent skin infection that plete heart block frequently occurs and is usually fatal; often occurs at sites of burns or other wounds and may act as a ventricular pacing may not improve survival.27–30 Echocardio- source of respiratory infection in others.8–12 It is more common grams show decreased contractility and ventricular dilation in warmer climates and in poor social conditions.8–11 Although proportional to the severity of the clinical carditis; a left ven- sufficient diphtheria toxin is absorbed from skin lesions to tricular ejection fraction of less than 35% is associated with frequently produce immunity, systemic complications are an increased risk for death.31,32 Although electrocardiograms uncommon with cutaneous diphtheria. In warmer climates, and echocardiograms return to normal in most survivors, the high incidence of cutaneous diphtheria appears to have residual changes are seen in some survivors of severe carditis played a major role in producing immunity in the population for up to several years after illness.26,31,33 Left bundle-branch in the absence of high rates of respiratory diphtheria. block at hospital discharge has a poor prognosis.34 Invasive disease caused by C. diphtheriae occurs rarely, Neurologic complications of diphtheria are primarily toxic most commonly as a result of nontoxigenic strains. Bacteremia, peripheral neuropathies, and they occur in approximately endocarditis, osteomyelitis, and arthritis have been reported.13–17 15% to 20% of cases.35,36 The manifestations are more motor Molecular epidemiology studies show that several