Diphtheria

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 family Cornynebacteriaceae.
There are four different biotypes of Corynebacterium diphtheriae: gravis, mitis, intermedius and belfanti. All four can cause the disease, giving rise to epidemic outbreaks through interhuman transmission. Two other, less common strains are distinguished, Corynebacterium ulcerans and Corynebacterium pseudotuberculosis, which can give rise to zoonoses.
Corynebacterium diphtheriae generally has little invasive ability, and the effects of the disease are due to the production of a protein exotoxin (or diphtheria toxin). This toxin represents the virulence factor of the bacterium, capable of blocking the protein production of the cell and thus leading to its death. The toxin has two subunits: A (responsible for pathogenic action) B (facilitates the entry of subunit A into the cell).

Diphtheria is easily transmitted by air via direct contact with droplets, that is, droplets emitted by the infected person through sneezing, coughing or even talking.
The disease can also be transmitted by direct contact with the infected person's skin or by contaminated clothing or objects (less frequently).

In the pre-vaccine era, diphtheria was one of the most feared diseases as it was a leading cause of death in childhood, with a lethality rate of 5-10% and up to 20% in children under 5 years of age and adults over 40 years of age. The only reservoir of the disease is humans. Diphtheria is still an endemic disease in some areas of the world, generally in temperate climates and most 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 the diphtheria and tetanus vaccine, which is based on the administration of antitoxin, by German Emil Adolf von Behring and his Japanese colleague Shibasburo Kitasato at the Berlin Institute of Hygiene. Their study, conducted in 1880, demonstrated the preventive and therapeutic efficacy of administering blood serum immune to diphtheria and tetanus in animals. Despite the effectiveness and extensive use of vaccination, diphtheria is still not completely eliminated. The 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 decreased following the launch of the Expanded Program on Immunization by WHO in 1974 with the goal of a 3-dose course with the DTP vaccine 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 peaks are related to two epidemics 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 during 2008-2012. In Europe, 39 cases of toxin-producing corynebacterium diphtheria were reported to ECDC in 2017. With a higher frequency in Germany. Diphtheria cases were reported from toxigenic strains of C. diphtereriae and C. ulcerans. Predominantly, cases from C. diphtereriae are highest in young ages; in fact, it presents the only strain in the age group of 0-4 years, with a major peak in the age group of 25-44 years. While the C. ulcerans strain is more prevalent in adults aged 45 and older. In Italy, vaccination against diphtheria has been compulsory since 1939, leading to a decrease in the number of cases over the years until, nowadays, it has become a sporadic disease. In the period between 2000 and 2018, Italy recorded 5 cases of diphtheria, both respiratory and cutaneous. In the same period, 16 cases of infection due to non-toxin-producing strains of C. diphtheriae were also reported.

Following an incubation period, ranging from 2 to 5 days and in some cases up to 10 days, the first symptoms of diphtheria occur. The most common symptoms are fever, usually a modest one of about 38°C and accompanied by tachycardia, pallor, asthenia, headache and nausea.

Diphtheria manifests itself in several forms:

- Diphtheria pharyngitis: characterized by pseudomembrane formation and satellite adenopathy (swelling of the neck glands). This form occurs in unvaccinated individuals. The appearance of the pseudomembrane generally occurs in the first 24-48 hours; they are grayish-colored (patina), foul-smelling patches of confluent exudate.
- Diphtheria laryngitis: a condition more common in children, characterized by pseudomembrane formation and edema of the soft parts, causing predominantly inspiratory dyspnea and dysphonia. Diphtheria laryngitis is clinically defined as croup, characterized by airway obstruction, can lead to cyanosis and asphyxia by debilitating the respiratory muscles which can lead to functional exhaustion and eventually death.
- Diphtheria rhinitis: a very rare form that occurs in infants and infants, with involvement of the septum and anterior turbinates leading to lesions.
- Cutaneous diphtheria: this clinical manifestation is generally seen in tropical and temperate climate countries, among the poorer social classes. It presents with the formation of ulcers that appear covered with a gray or brownish membrane. Accompanied by redness of the affected area, pain and swelling.

Complications of diphtheria
If not treated promptly, the disease can cause serious damage to the myocardium and peripheral nervous system. Complications generally result from the production of toxins by the bacterium, which are able to spread throughout the body damaging various tissues. At the cardiac level, the toxin can interfere with the metabolism of certain fatty acids by provoking myocardial degeneration manifesting itself in about 10-25% of diphtheria cases. After a period, ranging from 3 to 6 weeks after the onset of the disease, subjects may manifest neurological neuropathy, involving skeletal and respiratory muscles, sometimes fatal. Diphtheria is not a disease to be underestimated as it has a lethality rate of 5-10%.

First, diagnosis of diphtheria is low on observation of clinical symptoms of the disease. This is followed by sampling the infected tissue from the oral cavity for microbiological investigations and thus the presence of Corynebacterium diphtheriae.
The PCR (polymerase chain reaction) technique may also be applied to identify diphtheria toxin in the blood, in addition to IgM antibody detection.

In the case of a person with diphtheria, respiratory and contact isolation measures are implemented, and hospitalization is important to ensure medical observation. Isolation should be continued until 2 culture tests, performed 24 to 48 hours after the end of antibiotic therapy, are negative.
Diphtheria therapy involves the administration of diphtheria anatoxin and antibiotics. The anatoxin is injected intravenously or intramuscularly and is able to neutralize the toxin in the bloodstream, but has no effect on the toxins that have already penetrated the cells.
Administration of the anatoxin is combined with the administration of antibiotics necessary to eliminate the bacterium. Either of the following two antibiotics may be used; erythromycin (10mg/kg) orally or intramuscularly every 6 hours for 14 days. Or penicillin G intramuscularly for 14 days every 12 hours.

Diphtheria is one of the vaccine-preventable diseases, available since 1920. It is a very effective vaccine against the disease, containing the bacterial toxin treated with formaldehyde so as to eliminate the pathogenic part, but able to activate our immune system to produce antibodies. There are three different types of vaccines that contain the diphtheria toxoid combined with other diseases, the basic cycle is formulated by 3 doses, and a booster is scheduled 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, poliomyelitis, hepatitis B and haemophilus influenzae type b. It is given at the 3rd, 5th and 11th months, a booster around 5-6 years of age and an additional booster at 12 years of age, and thereafter a dose is required every 10 years. The vaccine is administered intramuscularly in the anterolateral part of the thigh in children and in the upper deltoid area of adults. Following vaccination, subjects may complain of some drowsiness in 42.7 percent of cases, anorexia 21.7 percent and vomiting 12.6 percent. Less frequently, fever, redness and swelling in the areas of inoculation. In Italy, diphtheria vaccination is made available by the National Vaccination Plan.