Diphtheria

 

Diphtheria is an infection caused by the bacterium Corynebacterium diphtheriae. Signs and symptoms may vary from mild to severe. They usually start two to five days after exposure. Symptoms often come on fairly gradually, beginning with a sore throat and fever. In severe cases, a grey or white patch develops in the throat. This can block the airway and create a barking cough as in croup. The neck may swell in part due to enlarged lymph nodes. A form of diphtheria that involves the skin, eyes, or genitals also exists. Complications may include myocarditis, inflammation of nerves, kidney problems, and bleeding problems due to low levels of platelets. Myocarditis may result in an abnormal heart rate and inflammation of the nerves may result in paralysis.

Diphtheria is usually spread between people by direct contact or through the air. It may also be spread by contaminated objects. Some people carry the bacteria without having symptoms, but can still spread the disease to others. The three main types of C. diphtheriae cause different severities of disease. The symptoms are due to a toxin produced by the bacteria. Diagnosis can often be made based on the appearance of the throat with confirmation by microbiological culture. Previous infection may not protect against future infection.

A diphtheria vaccine is effective for prevention and available in a number of formulations. Three or four doses, given along with tetanus vaccine and pertussis vaccine, are recommended during childhood. Further doses of diphtheria-tetanus vaccine are recommended every ten years. Protection can be verified by measuring the antitoxin level in the blood. Diphtheria can be treated with the antibiotics erythromycin or benzylpenicillin. These antibiotics may also be used for prevention in those who have been exposed to the infection. A tracheotomy is sometimes needed to open the airway in severe cases.

In 2015, 4,500 cases were officially reported worldwide, down from nearly 100,000 in 1980. About a million cases a year are believed to have occurred before the 1980s. Diphtheria currently occurs most often in sub-Saharan Africa, India, and Indonesia. In 2015, it resulted in 2,100 deaths, down from 8,000 deaths in 1990. In areas where it is still common, children are most affected. It is rare in the developed world due to widespread vaccination. In the United States, 57 cases were reported between 1980 and 2004. Death occurs in 5% to 10% of those affected. The disease was first described in the 5th century BC by Hippocrates. The bacterium was identified in 1882 by Edwin Klebs.

Signs and Symptoms
The symptoms of diphtheria usually begin two to seven days after infection. Symptoms of diphtheria include fever of 38 °C (100.4 °F) or above, chills, fatigue, bluish skin coloration (cyanosis), sore throat, hoarseness, cough, headache, difficulty swallowing, painful swallowing, difficulty breathing, rapid breathing, foul-smelling and bloodstained nasal discharge, and lymphadenopathy. Within two to three days, diphtheria may destroy healthy tissues in the respiratory system. The dead tissue forms a thick, gray coating that can build up in the throat or nose. This thick gray coating is called a “pseudomembrane.” It can cover tissues in the nose, tonsils, voice box, and throat, making it very hard to breathe and swallow. Symptoms can also include cardiac arrhythmias, myocarditis, and cranial and peripheral nerve palsies.

Diphtheritic croup
Laryngeal diphtheria can lead to a characteristic swollen neck and throat, or “bull neck”. The swollen throat is often accompanied by a serious respiratory condition, characterized by a brassy or “barking” cough, stridor, hoarseness, and difficulty breathing, and historically referred to variously as “diphtheritic croup”, “true croup”, or sometimes simply as “croup”. Diphtheritic croup is extremely rare in countries where diphtheria vaccination is customary. As a result, the term “croup” nowadays most often refers to an unrelated viral illness that produces similar but milder respiratory symptoms.

Transmission
Human-to-human transmission of diphtheria typically occurs through the air when an infected individual coughs or sneezes. Breathing in particles released from the infected individual leads to infection. Contact with any lesions on the skin can also lead to transmission of diphtheria, but this is uncommon. Indirect infections can occur, as well. If an infected individual touches a surface or object, the bacteria can be left behind and remain viable. Also, some evidence indicates diphtheria has the potential to be zoonotic, but this has yet to be confirmed. Corynebacterium ulcerans has been found in some animals, which would suggest zoonotic potential.

Mechanism
Diphtheria toxin is produced by C. diphtheriae only when infected with a bacteriophage that integrates the toxin-encoding genetic elements into the bacteria.

Diphtheria toxin is a single, 60-kDa-molecular weight protein composed of two peptide chains, fragment A and fragment B, held together by a disulfide bond. Fragment B is a recognition subunit that gains the toxin entry into the host cell by binding to the EGF-like domain of heparin-binding EGF-like growth factor on the cell surface. This signals the cell to internalize the toxin within an endosome via receptor-mediated endocytosis. Inside the endosome, the toxin is split by a trypsin-like protease into its individual A and B fragments. The acidity of the endosome causes fragment B to create pores in the endosome membrane, thereby catalysing the release of fragment A into the cell’s cytoplasm.

Fragment A inhibits the synthesis of new proteins in the affected cell by catalyzing ADP-ribosylation of elongation factor EF-2—a protein that is essential to the translation step of protein synthesis. This ADP-ribosylation involves the transfer of an ADP-ribose from NAD+ to a diphthamide (a modified histidine) residue within the EF-2 protein. Since EF-2 is needed for the moving of tRNA from the A-site to the P-site of the ribosome during protein translation, ADP-ribosylation of EF-2 prevents protein synthesis.

ADP-ribosylation of EF-2 is reversed by giving high doses of nicotinamide (a form of vitamin B3), since this is one of the reaction’s end products, and high amounts drive the reaction in the opposite direction.

Diagnosis
The current clinical case definition of diphtheria used by the United States’ Centers for Disease Control and Prevention is based on both laboratory and clinical criteria.

Laboratory criteria
Isolation of C. diphtheriae from a Gram stain or throat culture from a clinical specimen,
Histopathologic diagnosis of diphtheria by Albert’s stain
Clinical criteria
Upper respiratory tract illness with sore throat
Low-grade fever (above 39 °C (102 °F) is rare)
An adherent, dense, grey pseudomembrane covering the posterior aspect of the pharynx: in severe cases, it can extend to cover the entire tracheobronchial tree.
Case classification
Probable: a clinically compatible case that is not laboratory-confirmed and is not epidemiologically linked to a laboratory-confirmed case
Confirmed: a clinically compatible case that is either laboratory-confirmed or epidemiologically linked to a laboratory-confirmed case
Empirical treatment should generally be started in a patient in whom suspicion of diphtheria is high.

Prevention
Quinvaxem is a widely administered pentavalent vaccine, which is a combination of five vaccines in one that protect babies from diphtheria, among other common childhood diseases. Diphtheria vaccine is usually combined at least with tetanus vaccine (Td) and often with pertussis (DTP, DTaP, TdaP) vaccines, as well.

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