Diphtheria

Diphtheria is a highly contagious disease of bacterial origin, known since remote antiquity. It mainly affects the upper respiratory tract, causing symptoms such as pharyngitis and laryngitis, and can lead to death in more severe cases. In tropical countries it can also present as a cutaneous form, which causes ulcers.

This potentially fatal disease has claimed many lives over the years, but following the discovery of a vaccine it has now been contained in wealthier countries. However, it is still responsible for serious epidemics in developing countries.

CAUSES

The infectious agent responsible for diphtheria is a bacterium called Corynebacterium diphtheriae. It is a Gram+, immobile, asporigenic, capsule-less bacillus belonging to the facultative aerobic and anaerobic Cornynebacteriaceae family.

There are four different biotypes of Corynebacterium diphtheriae: gravis, mitis, intermedius, and belfanti. All four can cause the disease, giving rise to epidemic outbreaks via human-to-human transmission. There are also two other, less common strains, called Corynebacterium ulcerans and Corynebacterium pseudotuberculosis, which can give rise to zoonosis (transmission from vertebrate animals to humans).

Corynebacterium diphtheriae usually has a low invasive capability. The symptoms of the disease are caused by the production of an exotoxin protein (or diphtheria toxin). This toxin represents the virulence factor of the bacterium, which is able to block protein synthesis in the cells, which leads to their death. The toxin has two subunits: A, which is responsible for the bacteria’s pathogenic action, and B, which facilitates entry of subunit A into the cell.

TRANSMISSION

Diphtheria is commonly transmitted by direct contact with airborne droplets when an infected person coughs, sneezes, or even talks.

In addition, the disease can be transmitted by direct contact with the infected person's skin or contaminated clothing or objects (less frequently).

GEOGRAPHICAL DISTRIBUTION

In the pre-vaccine era, diphtheria was one of the most feared diseases as it was a leading cause of childhood death, with a fatality rate of 5-10%, which goes up to 20% in children under 5 years of age and adults over 40 years of age.

The only reservoir of the disease are humans. Diphtheria is still an endemic disease in some areas of the world, and is usually found in temperate climates (frequently during winter and spring), such as Southeast Asia (especially in India, Indonesia, Philippines, Malaysia), Africa, and Brazil. Sporadic cases have also been reported in Europe, such as Latvia, UK, France, Germany and Italy.

The fight against diphtheria goes back many, many years to the discovery of a diphtheria and tetanus vaccine by German scientist Emil Adolf von Behring and his Japanese colleague Shibasburo Kitasato, at the Berlin Institute of Hygiene, which is based on the administration of antitoxin drugs. Conducted in 1880, their study demonstrated the preventive and therapeutic effectiveness of administering diphtheria- and tetanus-immune blood serum in animals.

However, despite the effectiveness and extensive use of vaccination, diphtheria has still not been completely eradicated. Incidence of the disease certainly decreased dramatically with the introduction of the diphtheria-tetanus-pertussis (DTP) vaccine after World War II. In developing countries, cases declined following the launch of the WHO’s Expanded Program on Immunization (EPI), in 1974, with the aim of administering a 3-dose schedule of the DTP vaccine to all children by 6 months of age. 

Epidemiological data

According to the latest data published by WHO, reported cases have definitely decreased in the period between 2000 and 2017, with two major peaks between 2004 and 2005, and another in 2014. These two spikes are related to two outbreaks that occurred in the Southeast Asian area. In Africa, a peak was recorded in 2016.

The average number of annual cases reported worldwide during the most recently reported 5-year period (2013-2017) was 6,582, a 37% increase from the previous 5-year average of 4,809 cases from 2008-2012.

In Europe, 39 cases of toxin-producing corynebacterium diphtheria were reported to the ECDC in 2017, with a higher frequency in Germany.

Cases of diphtheria from toxigenic strains of C. diphtheriae and C. ulcerans have been reported. Predominantly, cases from C. diphtheriae are higher in younger age groups. In fact, it is the only strain among children between 0 and 4 years of age, with a higher peak in the age group between 25 and 44 years. Whereas, the C. ulcerans strain is more prevalent in adults of 45 years and over.

In Italy, vaccination against diphtheria has been mandatory since 1939, leading to a decrease in the number of cases over the years, and has now become a sporadic disease. In the period between 2000 and 2018, Italy recorded 5 cases of respiratory and cutaneous diphtheria. In the same period, 16 cases of infection due to non-toxin-producing strains of C. diphtheriae were also reported.

SYMPTOMS

The first symptoms of diphtheria present after an incubation period, which ranges from 2 to 5 days, or up to 10 days in some cases. The most common symptoms are usually a mild fever of approximately 38°C, accompanied by tachycardia, pallidity, asthenia, headache, and nausea.

Diphtheria can manifest in several forms:

• Diphtheria pharyngitis: the disease is characterised by the formation of a pseudomembrane and satellite adenopathy (swollen neck glands). This form occurs in unvaccinated individuals. The appearance of the pseudomembrane generally occurs within the first 24-48 hours and consists of patches of thick, greyish-coloured, foul-smelling excretions that coat the throat and tonsils.
• Diphtheria laryngitis: this condition is more common in children, and is characterised by the formation of a pseudomembrane of the throat and soft palate, which primarily causes inspiratory dysponea (difficulty breathing) and dysphonia (hoarseness). Clinically known as croup, diphtheria laryngitis is characterised by obstruction of the airways that can lead to abnormal bluish discoloration of the skin and mucous membranes (cyanosis) and asphyxia, which debilitates the respiratory muscles, leading to functional exhaustion and eventually death.
• Diphtheria rhinitis: this very rare form of the disease occurs in new-borns and infants. It affects the nasal septum and turbinals, causing lesions.
• Cutaneous diphtheria: this disease is usually found among disadvantaged communities in countries with a tropical and temperate climate. It presents in the form of ulcers that appear covered with a grey or brownish membrane, accompanied by redness, pain, and swelling of the affected area.

Complications of diphtheria

If not treated promptly, the disease can cause serious damage to the myocardium (heart muscle tissue) and peripheral nervous system. Complications generally result from the release of toxins by the bacterium, which can spread throughout the body, damaging various tissues.

On a cardiac level, the toxin can interfere with the metabolism of certain fatty acids, causing myocardial degeneration, which manifests in approximately 10-25% of diphtheria cases.

After approximately 3 to 6 weeks after the onset of the disease, patients may experience neurological neuropathy of the skeletal and respiratory muscles, which can sometimes be fatal.

With a fatality rate of 5-10%, diphtheria is not a disease that should be underestimated.

DIAGNOSIS

First of all, diagnosis of diphtheria is based on observation of the clinical symptoms of the disease. This is followed by taking an oral sample of the infected tissue for microbiological investigation to detect the presence of Corynebacterium diphtheriae.

As well as IgM antibody detection, the PCR (polymerase chain reaction) method can also be used to identify diphtheria toxins in the blood.

TREATMENT

In the case of a patient with diphtheria, respiratory and contact isolation measures are put in place, and hospitalisation is important to ensure appropriate medical observation. Isolation should be continued until confirmation of 2 consecutive negative culture tests, which should be performed 24 to 48 hours after the end of the antibiotic treatment course.

Treatment of diphtheria involves the administration of diphtheria anatoxin and antibiotics. Anatoxin is injected intramuscularly or intravenously and is able to neutralise the toxin in the bloodstream. However, it has no effect on toxins that have already penetrated the cells.

Administration of anatoxin is combined with the necessary antibiotics to eliminate the bacterium. One of the following two antibiotics may be used: erythromycin (10mg/kg), to be taken orally or intramuscularly every 6 hours for 14 days; penicillin G intramuscularly for 14 days every 12 hours.

PREVENTION

Diphtheria has been a vaccine-preventable disease since 1920. It is a very effective vaccine against the disease and contains a bacterial toxin treated with formaldehyde. This removes the pathogenic element, while still enabling it to stimulate our immune system to produce antibodies.

There are three types of diphtheria toxoid vaccine, some of which are combined with other diseases. The basic cycle consists of 3 doses, with a booster shot every 10 years.

According to the current vaccination calendar, diphtheria vaccination is among the mandatory vaccinations to be given from the third month of life combined with; tetanus, pertussis, polio, hepatitis B and haemophilus influenzae type B. It is administered at 3, 5 and 11 months of age, with a booster at around 5-6 years of age. This is followed by an additional booster at 12 years of age, with successive booster doses every 10 years.

The vaccine is administered intramuscularly in the avastus lateralis muscle of the thigh in children, and the deltoid muscle of the upper arm in adults.

Following vaccination, some individuals may suffer from slight drowsiness (42.7%), anorexia (21.7%) and vomiting (12.6%). Less frequently, the vaccine may cause fever, redness, and swelling at the injection site.

In Italy, diphtheria vaccination is delivered through the National Vaccination Plan.

Bibliography

Un po' di storia, wikivaccini, 2018, available on: wikivaccini.regione.lombardia.it; last access 10/01/2021

Informazioni generali, Istituto Superiore di Sanità, available on: epicentro.iss.it/difterite; ultimo accesso il 10/01/2021

Obbligo vaccinale: un po’ di storia, Istituto Superiore di Sanità, 2016, available on the website: vaccini/ObbligoVaccinaleStoria; last accessed on 10/01/2021

Difterite, Ministero della Salute, 2019, available on: salute.gov.it/malattieInfettive; ultimo accesso il 10/01/2021

Kristie C., MacNeil A., Hadler S., Scott C., Tiwari T., and Cherian T., Global Epidemiology of Diphtheria, 2000–2017, Centers for Disease Control and Prevention, 2019, available on: cdc.gov/25/10/19-0271_article; last access 10/01/2021

Diphtheria, World Health Organization, 2017, available on: website WHO diphtheria; last access 11/01/2021

Diphtheria, Annual Epidemiological Report for 2017, 2019, available in pdf a: ecdc.europa.eu/diphtheria-annual-epidemiological-report-2017.pdf; last access 10/01/2021

Vaccino antidifterite-tetano-pertosse acellulare (DTPa e dTpa): reazioni avverse e rischi correlati alle malattie, istituto superiore di sanità, 2018, available on: Sito Epicentro dell'ISS, Reazioni Avverse DTPa; last access 14/01/2021

Rugarli C., Obiass M., Medicina interna Sistematica, Quinta Edizione. Masson 2015.