Diphtheria
Diphtheria is an infection caused by the bacterium Corynebacterium diphtheriae. Most infections are asymptomatic or have a mild clinical course, but in some outbreaks, the mortality rate approaches 10%. Signs and symptoms may vary from mild to severe, and usually start two to five days after exposure. Symptoms often develop gradually, beginning with a sore throat and fever. In severe cases, a grey or white patch develops in the throat called a pseudomembrane. This tough, leathery membrane slowly blocks the airway. Starting with a barking cough similar to what is observed in croup, the neck may also swell, in part due to the enlargement of the facial lymph nodes. The pseudomembrane can grow to cover a wide area of the throat leading to strangulation and death. Diphtheria can also involve the skin, eyes, or genitals, and can cause complications, including myocarditis, inflammation of nerves, kidney problems, and bleeding problems due to low levels of platelets.
Diphtheria is usually spread between people by direct contact, through the air, or through contact with contaminated objects. Asymptomatic transmission and chronic infection are also possible. Different strains of C. diphtheriae are the main cause in the variability of lethality. The lethality and symptoms themselves are caused by the exotoxin 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 reinfection.
A diphtheria vaccine is effective for prevention, and is 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 the diphtheria–tetanus vaccine are recommended every ten years. Protection can be verified by measuring the antitoxin level in the blood. Diphtheria can be prevented in those exposed, as well as treated with the antibiotics 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. About a million cases a year are believed to have occurred before the 1980s. Diphtheria currently occurs most often in sub-Saharan Africa, South Asia, 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, but can re-emerge if vaccination rates decrease. In the United States, 57 cases were reported between 1980 and 2004. Death occurs in 5–10% of those diagnosed. 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. They include fever of 38 °C or above; chills; fatigue; bluish skin coloration ; 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, known as a pseudomembrane, that can build up in the throat or nose. 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 cause 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
is produced only by C. diphtheriae infected with a certain type of bacteriophage. Toxinogenicity is determined by phage conversion ; i.e., the ability of the bacterium to make DT changes as a consequence of infection by a particular phage. DT is encoded by the tox gene. Strains of corynephage are either tox+ or tox−. The tox gene becomes integrated into the bacterial genome. The chromosome of C. diphtheriae has two different but functionally equivalent bacterial attachment sites for integration of β prophage into the chromosome.The diphtheria toxin precursor is a protein of molecular weight 60 kDa. Certain proteases, such as trypsin, selectively cleave DT to generate two peptide chains, amino-terminal fragment A and carboxyl-terminal fragment B, which are held together by a disulfide bond. DT-B is a recognition subunit that gains entry of DT 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, DT is split by a trypsin-like protease into DT-A and DT-B. The acidity of the endosome causes DT-B to create pores in the endosome membrane, thereby catalysing the release of DT-A into the 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 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, 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.
Toxin demonstration
- In vivo tests : Subcutaneous and intracutaneous tests.
- In vitro test: Elek's gel precipitation test, detection of tox gene by PCR, ELISA, ICA.
Clinical criteria
- Upper respiratory tract illness with sore throat.
- Low-grade fever.
- 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.
Prevention
Diphtheria prevention relies primarily on vaccination with the diphtheria toxoid, an inactivated form of the toxin produced by Corynebacterium diphtheriae. Introduced in the 1920s and widely adopted after World War II, the toxoid vaccine triggers strong antitoxin immunity that prevents the severe respiratory and systemic effects of the disease. Today it is administered as part of combination vaccines such as DTaP and Tdap or Td, with booster doses recommended every 10 years to maintain protection. Widespread immunization has reduced diphtheria from a common childhood killer to a rare disease in most countries, though cases can still occur in areas with low vaccination coverage.Pentavalent vaccines, which vaccinate against diphtheria and four other childhood diseases simultaneously, Hepatitis B, and Haemophilus influenzae type b ), are frequently used in disease prevention programs in developing countries by organizations such as UNICEF.
Treatment
The disease may remain manageable, but in more severe cases, lymph nodes in the neck may swell, and breathing and swallowing are more difficult. People in this stage should seek immediate medical attention, as obstruction in the throat may require intubation or a tracheotomy. Abnormal cardiac rhythms can occur early in the course of the illness or weeks later, and can lead to heart failure. Diphtheria can also cause paralysis in the eye, neck, throat, or respiratory muscles. Patients with severe cases are put in a hospital intensive care unit, and given diphtheria antitoxin. Since antitoxin does not neutralize toxin that is already bound to tissues, delaying its administration increases risk of death. Therefore, the decision to administer diphtheria antitoxin is based on clinical diagnosis, and should not await laboratory confirmation.Antibiotics have not been demonstrated to affect healing of local infection in diphtheria patients treated with antitoxin. Antibiotics are used in patients or carriers to eradicate C. diphtheriae, and prevent its transmission to others. The Centers for Disease Control and Prevention recommends either:
- Metronidazole
- Erythromycin is given for 14 days, or
- Procaine penicillin G is given intramuscularly for 14 days ; patients with allergies to penicillin G or erythromycin can use rifampin or clindamycin.