Diphtheria



Diphtheria


Julia A. McMillan

Ralph Feigin



Corynebacterium diphtheriae may infect the skin or the respiratory tract. Acute disease results when the infecting strain elaborates an extracellular protein toxin and the human host is not protected by antitoxin antibody.


ETIOLOGY

C. diphtheriae is a gram-positive, nonmotile, nonsporulating, pleomorphic bacillus. The organism was first described in 1826 by Brettoneau, who called it la diphtherite (Greek for leather) because of the leathery membrane formed in the throat of infected individuals. The clubbed shape of the organism led to the name Corynebacterium, from coryne (Greek for club). In 1884, Löffler grew C. diphtheriae in pure culture from patients with diphtheria and produced disease in animals. Subsequent investigation demonstrated that infection causes local invasion but that widespread complications, including neuropathy, carditis and arrhythmias, and adrenal hemorrhage are the result of a protein exotoxin. The toxin is produced only in C. diphtheriae that are lysogenic for a phage carrying the gene for toxin production. The quantity of toxin elaborated by lysogenic strains is increased by reduced concentration of inorganic iron in culture media and by exposure to ultraviolet light. The clinical significance of these in vitro findings is not known.

C. diphtheriae may be grown on a variety of selective media, including tellurite agar or specially enriched Löffler, Pai, or Tinsdale medium. Gram staining of typical colonies may provide presumptive identification after 24 to 48 hours. Toxin production is confirmed using the Elek immunoprecipitin technique, polymerase chain reaction, or an in vivo toxin neutralization test in guinea pigs. Toxigenic strains are not distinguishable by growth characteristics or morphology. Three biotypes of C. diphtheriaemitis, intermedius, and gravis—are distinguishable by colony morphology, hemolysis, and fermentation reactions, but the toxin elaborated by all three is identical, and the severity of disease generally is not determined by the biotype isolated.


EPIDEMIOLOGY

Infection due to C. diphtheriae occurs throughout the world. Humans are the only known reservoir, although other “diphtheroids” are ubiquitous in nature. In the United States, approximately 125,000 cases were reported per year during the 1920s, with approximately 13,000 to 15,000 deaths annually. Frequency of disease fell sharply after widespread use of the diphtheria toxoid vaccine so that, during the 1980s and 1990s, five or fewer cases of respiratory disease were reported per year (51 total cases).

C. diphtheriae is acquired through contact with respiratory secretions or skin of an infected or colonized individual. Rarely, contaminated dust, fomites, or food has been thought to be the source of cutaneous infection. Asymptomatic carriage occurs but is infrequent in countries where vaccine use is prevalent. Immunization of 70% to 80% of a population is postulated to prevent endemic spread of disease.

Historically, diphtheria has occurred most often in children younger than 15 years, who usually are not immunized. In highly immunized populations, however, proportionally more older adolescents, adults, and elderly individuals are susceptible because of waning vaccine-related immunity. The U.S. goal of eradication of diphtheria among individuals up to 25 years old by the year 2000 was prompted by the success of widespread immunization. Less than five cases per year have been reported in the United States during the past 5 years.

The incubation period after exposure is approximately 2 to 5 days. Communicability among untreated infected persons continues for up to 2 weeks and is reduced to fewer than 4 days with treatment. Chronic carriage persists occasionally, even in treated individuals. Among nonimmunized populations, diphtheria occurs most often during fall and winter, although summer outbreaks have occurred. Disease spreads more quickly and is more prevalent in poor socioeconomic conditions where crowding occurs and immunization rates are low. The vulnerability of populations in which large numbers of children and adults remain unprotected by vaccine was demonstrated during
the early 1990s in the newly independent states of the former Soviet Union. In the largest diphtheria outbreak reported since the 1960s, more 157,000 cases and 5,000 deaths were documented between 1990 and 1998, with a case fatality rate of 3% to 23%. Infant immunization rates in those countries had fallen as low as 60% in the early 1990s, partially due to public perception regarding the risks of immunization. School-age children were affected in some countries, but 60% to 80% of cases were older than 15 years of age.

Serologic surveys in countries in which childhood immunization rates are high, including the United States, have demonstrated that susceptibility persists among adults who have not received booster doses of vaccine.


PATHOGENESIS

Respiratory infection is initiated when C. diphtheriae enter the mucosal surfaces of the nose, mouth, eye, or genitalia. The skin may also serve as a point of entry, usually at a site of previous minor trauma. If the infecting organism is lysogenized by the βtox+ bacteriophage, toxin will be elaborated and released after the incubation period of approximately 2 to 5 days. Diphtheria toxin is a protein made up of two fragments. The B fragment attaches to host cell receptors and brings about entry of the toxin into the cell. The A fragment interrupts cellular protein synthesis by preventing elongation of amino acid chains.

Toxin acts locally to produce necrosis and edema. In the mouth or throat, a patchy exudate appears, followed by deeper tissue involvement and the development of a gray-black, adherent membrane composed of epithelial cells, fibrin, inflammatory cells, erythrocytes, and organisms. The membrane may become so extensive that it causes upper airway obstruction and even suffocation. At the site of cutaneous infection, an ulcer with sharp borders develops and becomes covered with a gray membrane. Infection of the skin or throat often is complicated by coinfection with group A streptococcus.

As it is produced, toxin is disseminated by the hematogenous route and through the lymphatics to reach distant organs. Absorption of toxin varies depending on the site of initial infection; nasal diphtheria may result only in a mild serosanguineous discharge, without systemic illness, as absorption of toxin from the nose is limited.

Effects of toxin on cardiac and nervous tissue can be life-threatening. In the heart, cellular infiltrate develops with fatty accumulation, particularly involving the conducting system. Clinically apparent cardiac involvement may be present during the first few days of illness, although it often is delayed until the second week or later. Fatty degeneration of the myelin sheaths of nerves can cause paralysis both locally (in the muscles of the palate and hypopharynx) and at distant sites (including the muscles of respiration). Neurologic consequences of toxin generally are not seen until 2 to 3 weeks after onset of infection and may appear as late as 10 weeks. Necrosis of renal tubules and hepatic parenchyma, amegakaryocytic thrombocytopenia, and adrenal hemorrhage may also occur as a result of dissemination of toxin.

Antitoxin neutralizes circulating diphtheria toxin, but it has no effect once toxin has entered cells. To be effective in preventing serious consequences of disease, therefore, it should be given as early as possible.


CLINICAL MANIFESTATIONS

Severity of disease due to C. diphtheriae depends on the site of infection, the immunization status of the patient, and the dissemination of toxin, the last being influenced by administration of antitoxin. Initial infection usually is localized and is categorized by the site of involvement. Tonsillar and pharyngeal diphtheria are most common; symptoms begin with a sore throat, usually in the absence of systemic complaints. Fever, if it occurs, is usually less than 102°F, and malaise, dysphagia, and headache are not prominent features. In nonimmune, infected individuals, membrane formation begins after the 2- to 5-day incubation period and grows to involve the pharyngeal walls, tonsils, uvula, and soft palate. It may even extend to the larynx and trachea, causing airway obstruction and eventual suffocation. Underlying tissue of the throat and neck becomes edematous, and lymphadenopathy develops. Marked edema of the neck may lead to a bull-neck appearance, with a distinct collar of swelling; the patient throws his or her head back to relieve pressure on the throat and larynx. “Erasure” edema associated with pharyngeal diphtheria obliterates the angle of the jaw, the borders of the sternocleidomastoid muscle, and the medial border of the clavicles. Swallowing may be made difficult by unilateral or bilateral paralysis of the muscles of the palate. If toxin production is unopposed by antitoxin and severe disease occurs, early localized signs and symptoms give way to circulatory collapse, respiratory failure, stupor, coma, and death. If antitoxin is given promptly, less severe disease resolves with the sloughing of the membrane within 7 to 10 days (or earlier). Disseminated effects of toxin, including myocarditis and nervous system complications, may occur late in the illness, even if the initial respiratory disease was mild.

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Jul 24, 2016 | Posted by in ORTHOPEDIC | Comments Off on Diphtheria

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