Diphtheria

Diphtheria is an infection caused by the bacterium *Corynebacterium diphtheriae*. Many people who catch it show no symptoms or only mild ones, but during certain outbreaks, around 10% of those infected die.

Signs can range from mild to severe and usually appear two to five days after exposure. They tend to come on slowly, starting with a sore throat and fever. In serious cases, a gray or white patch called a pseudomembrane forms in the throat. This tough, leathery layer gradually blocks the airway. A barking cough—similar to croup—may develop, and the neck can swell, partly because the facial lymph nodes enlarge. The pseudomembrane can spread across much of the throat, leading to strangulation and death.

The infection can also affect the skin, eyes, or genitals. Complications include myocarditis (which can cause an abnormal heart rate), nerve inflammation (which can lead to paralysis), kidney problems, and bleeding issues due to low platelet counts.

Diphtheria usually spreads through direct contact, through the air, or by touching contaminated objects. People without symptoms can still transmit it, and chronic infections are possible. Different strains of *C. diphtheriae* account for much of the variation in how deadly the disease is. The symptoms and lethality are caused by an exotoxin the bacteria produce. Doctors often diagnose it by looking at the throat, and they confirm it with a microbiological culture. Having had diphtheria before does not guarantee protection against getting it again.

A vaccine is effective for prevention and comes in several forms. Three or four doses, given along with tetanus and pertussis vaccines, are recommended during childhood. Booster doses of the diphtheria–tetanus vaccine are advised every ten years. Protection can be checked by measuring antitoxin levels in the blood. For those exposed, diphtheria can be prevented or treated with antibiotics like erythromycin or benzylpenicillin. In severe cases, a tracheotomy may be needed to open the airway.

In 2015, 4,500 cases were officially reported worldwide, down from nearly 100,000 in 1980. Before the 1980s, about a million cases a year are believed to have occurred. Today, diphtheria is most common in sub-Saharan Africa, South Asia, and Indonesia. In 2015, it caused 2,100 deaths, down from 8,000 in 1990. In areas where it is still common, children are most affected. It is rare in the developed world because of widespread vaccination, but it can come back if vaccination rates drop. In the United States, 57 cases were reported between 1980 and 2004. Of those diagnosed, 5–10% die. The disease was first described in the 5th century BC by Hippocrates, and the bacterium was identified in 1882 by Edwin Klebs.

Symptoms usually begin two to seven days after infection. They include fever of 38 °C (100.4 °F) or higher, chills, fatigue, bluish skin (cyanosis), sore throat, hoarseness, cough, headache, trouble swallowing, painful swallowing, difficulty breathing, rapid breathing, foul-smelling and bloodstained nasal discharge, and swollen lymph nodes. Within two to three days, diphtheria can destroy healthy tissue in the respiratory system. The dead tissue forms a thick, gray coating—the pseudomembrane—that builds up in the throat or nose. It can cover the nose, tonsils, voice box, and throat, making breathing and swallowing very hard. Symptoms can also include heart rhythm problems, myocarditis, and paralysis of cranial and peripheral nerves.

Laryngeal diphtheria can cause a characteristic swollen neck and throat, sometimes called "bull neck." This swelling is often paired with a serious respiratory condition marked by a brassy or barking cough, stridor, hoarseness, and difficulty breathing. Historically, this was called "diphtheritic croup," "true croup," or simply "croup." It is extremely rare in countries where diphtheria vaccination is routine, so the term "croup" now usually refers to a milder viral illness with similar symptoms.

The bacteria spread from person to person through the air when an infected person coughs or sneezes. Breathing in these particles causes infection. Contact with skin lesions can also spread diphtheria, though this is uncommon. Indirect spread is possible too—if an infected person touches a surface, the bacteria can survive there. Some evidence suggests diphtheria might be zoonotic, but this is not confirmed. *Corynebacterium ulcerans* has been found in some animals, hinting at that possibility.

Diphtheria toxin is made only by *C. diphtheriae* that have been infected with a specific type of bacteriophage. Whether the bacteria produce the toxin depends on phage conversion (also called lysogenic conversion)—the ability to make the toxin changes after infection by a particular phage. The toxin is encoded by the *tox* gene. Strains of corynephage are either *tox*+ (like corynephage β) or *tox*− (like corynephage γ). The *tox* gene integrates into the bacterial genome. The chromosome of *C. diphtheriae* has two different but functionally equivalent attachment sites for integrating the β prophage.

The diphtheria toxin precursor is a protein with a molecular weight of 60 kDa. Certain proteases, such as trypsin, selectively cut the toxin to produce two peptide chains: fragment A (DT-A) at the amino end and fragment B (DT-B) at the carboxyl end, held together by a disulfide bond. DT-B is the recognition subunit that lets the toxin enter the host cell.