Diphtheria
The bacterium Corynebacterium diphtheriae produces a specific exotoxin known as diphtheria toxin. This toxin is not produced by all strains of the bacteria but only those infected with a particular type of bacteriophage. The gene responsible for this toxin, called tox, becomes integrated into the bacterial genome through a process known as lysogenic conversion. Strains carrying this genetic material are designated as tox positive, while others remain tox negative.
Diphtheria toxin precursor has a molecular weight of 60 kilodaltons. Certain proteases like trypsin cleave this precursor to generate two peptide chains: an amino-terminal fragment A and a carboxyl-terminal fragment B. These fragments stay connected by a disulfide bond. Fragment B acts as a recognition subunit that binds to heparin-binding EGF-like growth factor on the surface of host cells. This binding signals the cell to internalize the toxin within an endosome via receptor-mediated endocytosis.
Inside the acidic environment of the endosome, the toxin splits again. Fragment B creates pores in the endosome membrane, allowing fragment A to enter the cytoplasm. Once inside, fragment A inhibits protein synthesis by catalyzing ADP-ribosylation of elongation factor EF-2. This modification transfers an ADP-ribose group from NAD+ to a diphthamide residue within the EF-2 protein. Since EF-2 is essential for moving tRNA during translation, its inhibition stops new protein production and leads to cell death.
Symptoms of diphtheria typically begin two to seven days after infection. Patients develop a fever of 38 degrees Celsius or higher along with chills and fatigue. The throat becomes sore and hoarseness develops alongside difficulty swallowing. A thick gray coating known as a pseudomembrane forms on the tonsils, voice box, and throat within two to three days. This membrane can cover tissues in the nose and trachea making breathing extremely difficult.
The swollen neck sometimes referred to as bull neck often accompanies laryngeal diphtheria. A brassy barking cough characterizes this respiratory condition historically called true croup. Stridor and rapid breathing accompany these symptoms. Cyanosis may appear as bluish skin coloration due to oxygen deprivation. Cardiac arrhythmias and cranial nerve palsies can occur weeks later.
Diagnosis relies on laboratory criteria including isolation of Corynebacterium diphtheriae from Gram stains or throat cultures. Histopathologic diagnosis uses Albert's stain while toxin demonstration involves Elek's gel precipitation test. Clinical criteria require an upper respiratory tract illness with sore throat and an adherent dense grey pseudomembrane covering the posterior aspect of the pharynx. Probable cases are clinically compatible but not laboratory confirmed while confirmed cases link epidemiologically to lab results.
Immediate medical attention is required when lymph nodes swell and breathing becomes difficult. Intubation or tracheotomy may be necessary to open obstructed airways. Patients receive diphtheria antitoxin consisting of antibodies isolated from horse serum that has been challenged with diphtheria toxin. Antitoxin does not neutralize toxin already bound to tissues so delaying administration increases death risk.
Antibiotics like erythromycin or benzylpenicillin eradicate Corynebacterium diphtheriae and prevent transmission to others. Erythromycin is given orally or by injection for 14 days at doses up to two grams daily. Procaine penicillin G is administered intramuscularly for 14 days depending on patient weight. Patients allergic to these drugs can use rifampin or clindamycin instead.
Severe cases progress beyond throat infection as toxin spreads through blood affecting heart and kidneys. Damage to the heart affects pumping ability while kidney damage impairs waste clearance. Nerve damage eventually leads to paralysis in eye neck throat or respiratory muscles. About forty to fifty percent of untreated patients die from complications including myocarditis and bleeding problems due to low platelet levels.
Diphtheria prevention relies primarily on vaccination with diphtheria toxoid an inactivated form of the toxin produced by Corynebacterium diphtheriae. Introduced in the 1920s and widely adopted after World War II the vaccine triggers strong antitoxin immunity. Today it is administered as part of combination vaccines such as DTaP for children and Tdap or Td for adolescents and adults. Booster doses are recommended every ten years to maintain protection.
Alexander Thomas Glenny increased effectiveness of diphtheria toxoid by treating it with aluminum salts in 1926. Vaccination with toxoid was not widely used until the early 1930s. Dr. Nora Wattie introduced immunization clinics across Glasgow between 1934 and 1964 resulting in virtual eradication of the infection in that city. Widespread vaccination pushed cases in the United States down from 4.4 per 100,000 inhabitants in 1932 to 2.0 in 1937.
In Nazi Germany authorities preferred treatment and isolation over vaccination until about 1939 to 1941. Cases rose over the same period from 6.1 to 9.6 per 100,000 inhabitants. Pentavalent vaccines vaccinating against five childhood diseases simultaneously are frequently used in developing countries by organizations like UNICEF.
Diphtheria remains fatal in five to ten percent of cases globally. In children under five years and adults over forty years fatality rates may reach twenty percent. In 2015 four thousand five hundred cases were officially reported worldwide down from nearly one hundred thousand in 1980. About a million cases occurred annually before the 1980s. Diphtheria currently occurs most often in sub-Saharan Africa South Asia and Indonesia.
Historical epidemics demonstrate the disease's devastating potential. In 1735 an epidemic swept through New England where thirty-two percent of children under ten died. One town lost three out of four children while others lost all their offspring. In 1925 the Great Race of Mercy delivered diphtheria antitoxin to Nome Alaska during an outbreak that killed thousands.
After the breakup of the former Soviet Union in 1991 vaccination rates fell so low that an explosion of cases occurred. Between 1991 and 1998 as many as two hundred thousand cases were reported in the Commonwealth of Independent States resulting in five thousand deaths. In November 2019 an unvaccinated eight-year-old boy died of diphtheria in Athens Greece. Outbreaks continued into 2022 with cases recorded in northern New South Wales Australia.
Records of diphtheria begin as early as the fifth century BCE in writings by Hippocrates. Epidemics were first described by Aëtius of Amidia in the sixth century. Before 1826 the disease was known by different names across the world including Boulogne sore throat in England. In 1826 Pierre Bretonneau gave the disease its current name derived from Greek meaning leather describing the pseudomembrane appearance.
In 1883 Edwin Klebs identified the bacterium causing diphtheria and named it Klebs-Loeffler bacterium. The club shape helped differentiate it from other bacteria. Friedrich Loeffler became the first person to cultivate Corynebacterium diphtheriae in 1884. He isolated the organism cultured it and reproduced the disease in guinea pigs and rabbits fulfilling Koch's postulates.
Emile Roux and Alexandre Yersin showed that a substance produced by the bacteria caused symptoms in animals in 1888. Shibasaburō Kitasato and Emil von Behring immunized guinea pigs with heat-treated toxin in 1890. Von Behring won the first Nobel Prize in medicine for his work on diphtheria in 1901. Paul Ehrlich developed a standardized unit of measure for antitoxin in 1897 initiating federal regulation of biologic products.
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Common questions
What causes diphtheria toxin production in Corynebacterium dipheriae?
Diphtheria toxin is produced only by strains of Corynebacterium diphtheriae infected with a specific bacteriophage. The tox gene integrates into the bacterial genome through lysogenic conversion, making these strains tox positive.
How does diphtheria toxin kill host cells after entering the body?
Fragment A of the toxin enters the cytoplasm and inhibits protein synthesis by ADP-ribosylating elongation factor EF-2. This modification transfers an ADP-ribose group from NAD+ to a diphthamide residue within the EF-2 protein, stopping translation and causing cell death.
When do symptoms of diphtheria typically appear after infection occurs?
Symptoms of diphtheria begin two to seven days after infection. Patients develop fever above 38 degrees Celsius along with chills, fatigue, sore throat, and hoarseness within this timeframe.
Who discovered the bacterium that causes diphtheria and when was it identified?
Edwin Klebs identified the bacterium in 1883 and named it the Klebs-Loeffler bacterium. Friedrich Loeffler became the first person to cultivate Corynebacterium diphtheriae in 1884 and fulfilled Koch's postulates using guinea pigs and rabbits.
What historical event delivered diphtheria antitoxin to Nome Alaska during an outbreak?
The Great Race of Mercy delivered diphtheria antitoxin to Nome Alaska in 1925 during an outbreak that killed thousands. This event highlighted the critical need for rapid medical intervention during respiratory epidemics.