Diphtheria: causes, symptoms, diagnosis, treatment, prognosis, and prevention

Diphtheria is an acute respiratory infection caused by airborne droplets of Corynebacterium diphtheriae. Diphtheria toxin is the main pathogenic factor. The clinical features are mucosal congestion and swelling of the pharynx, larynx, and nose that are covered with grayish white pseudomembrane, as well as systemic poisoning symptoms caused by bacterial exotoxin. Severe patients may develop toxic myocarditis and peripheral nerve paralysis.


Causes

Corynebacterium diphtheriae is an about 2 - 3μm long, 0.5 - 1μm wide, non-spore-forming, nonmotile, Gram-positive bacillus, often presenting V, X, Y arrangement on the smear, with metachromatic granules in the polar regions, called polar granules. In Neisser stain, the bacteria are yellowish brown, and the metachromatic granules are bluish black. In Albert stain, the bacteria are green, and the metachromatic granules are bluish black. In Ponder stain, the bacteria are light blue, and the metachromatic granules are dark blue. The bacteria grow well in the potassium citrate medium.

The bacteria have weak invasiveness and only grow and reproduce in local mucosa or skin. The exotoxin produced by the bacteria is the main virulence factor and is a heat-labile polypeptide with strong toxicity, and the lethal dose for humans is 130ng/kg. The nerves, myocardium, and adrenal glands are often invaded. The bacterial strains lysogenized by β-phage carrying the toxin-producing gene Tox have the ability to produce exotoxin, and other strains do not produce exotoxin. The virulence is controlled by the phage gene, and the invasive ability is controlled by the bacterial gene.

The bacteria are more resistant to the external environment, are resistant to cold and dryness, and can survive for several days on the toys and clothes, causing indirect transmission. The bacteria are sensitive to humidity and chemical disinfectants, and be disinfected in 0.1% mercuric chloride and 5% phenol solution in 1 minute, and die at 58 °C in 10 minutes.

The source of infection is patients and carriers. Diphtheria patients are contagious at the end of the incubation period and carry the bacteria generally no more than 4 days and maximally 12 days in the recovery stage. Atypical and mild patients are more likely to transmit the bacteria, because they cannot be diagnosed in time. Healthy carrier count varies, depending on the region, season, prevalence, and degree of exposure, generally accounting for 0.5% - 5% of the population, up to 10% - 20% during epidemics.

The bacteria are mainly transmitted by respiratory droplets, followed by contaminated hands, toys, stationery, utensils, and handkerchiefs, as well as contact with damaged skin and mucous membranes of patients.

Pathogenesis

Corynebacterium diphtheriae has weak invasiveness. After invading the upper respiratory tract mucosa, the bacteria only grow and reproduce in the epithelial cells of the surface, and generally do not cause bacteremia. When the local mucosa is damaged, for instance, measles, scarlet fever, pertussis or upper respiratory tract infection occurs, the invasiveness is enhanced. Exotoxin produced during the reproduction can not only cause local lesions, but also cause systemic poisoning lesions, and is the main pathogenic factor. The toxin is composed of subunit A and B, and the two subunits are connected with a disulfide bond. Subunit B has no direct toxicity, but it has a receptor binding domain and a translocation region. Subunit B can bind with the cell surface specific receptor, such as membrane receptor pro-hHB-EG. Subunit A can be transported into the host cytoplasm through the translocation region.

Subunit A is toxic and can inactivate the cellular elongation factor-2 (EF-2), which is an essential enzyme for the peptide chain synthesis translocation reaction. After EF-2 is inactivated, the peptide chain being synthesized on the acceptor site of the ribosome cannot be translocated to the donor site, so that the aminoacyl-tRNA cannot bind with the ribosome, the peptide chain elongation reaction stops, and the target cell dies due to the inability to synthesize protein. Therefore, the diphtheria toxin has direct lethal effect in mammalian cells. The bacteria cause mucosal epithelial cell necrosis of local tissue, vasodilation, massive fibrin exudation, and leukocyte infiltration. The strong toxic effect of exotoxin in cells aggravates the local inflammation and necrosis, and the massively exuded fibrin, necrotic cells, leukocytes, and bacteria coagulate and cover the surface of the damaged mucosa, forming pseudomembrane. The pseudomembrane is generally grayish white, yellow, dirty when with mixed infections, or black when accompanied by hemorrhage. The pseudomembrane is initially thin and then thickens gradually, and the edges are neat. The pseudomembrane is not easily separated, and the bleeding spots can be seen when removed forcefully. The site with pseudomembrane and the peripheral tissue are mildly congested and swollen. The pseudomembrane on the laryngeal, tracheal, and bronchial coverage composed of columnar epithelium cannot adhere firmly to the mucous membrane, and the abscission can cause asphyxia. Exotoxin absorbed locally causes systemic poisoning symptoms. The amount of toxin absorption is different and depends on the pseudomembrane site and area. The most toxin absorption site is the pharynx, followed by the tonsils, throat, and trachea successively. The larger the pseudomembrane is, the more the toxin absorption is, and the more severe the disease is. The toxin adsorbed on the cell surface can be neutralized by antitoxin, but toxin in the cells cannot be neutralized. Therefore, early and sufficient application of antitoxin is emphasized clinically. Exotoxin can cause systemic pathological changes after binding to various tissue cells, including myocardium and peripheral nerves. The heart often enlarges in the early stage, and cloudy swelling and fatty degeneration often occur in the heart muscle. Subsequently, multiple focal hyaline degeneration, myocardial necrosis, and mononuclear cell infiltration are present, and the conductive bundle can also be involved. Eventually, there may be connective tissue hyperplasia, and occasionally cardiac thrombosis is present. Neuropathy is more common in peripheral nerves, fatty degeneration is often visible in the myelin sheath, and the neuraxis may be also fractured. Sensory nerves and motor nerves can be involved, but mainly motor nerves. The ninth and tenth cranial nerves are most susceptible. The damaged nerves are rarely necrotic, so paralysis in diphtheria can heal. Cloudy swelling and exfoliation of renal tubular epithelial cells may be present in the kidneys. Congestion, degeneration, or hemorrhage may occur in the adrenal glands. Fatty degeneration of the hepatocytes and central necrosis in the hepatic lobules may be present.


Signs and Symptoms

The incubation period is 1 - 7 days, usually 2 - 4 days. According to the lesion, the disease can be divided into pharyngeal diphtheria, laryngeal diphtheria, nasal diphtheria, and other diphtheria. Pharyngeal diphtheria occurs mostly in adults and old children, and other diphtheria is more common in young children.

Pharyngeal diphtheria

Pharyngeal diphtheria is the most common, accounting for about 80% of all diphtheria. According to the extent of the lesion and the severity of symptoms, it can be divided into non-membranous pharyngeal diphtheria, localized pharyngeal diphtheria, disseminated pharyngeal diphtheria, and poisoning pharyngeal diphtheria.

Non-membranous pharyngeal diphtheria

Non-membranous pharyngeal diphtheria is more common in the epidemics. Some patients may only have upper respiratory symptoms, such as sore throat, and mild systemic symptoms, with no or mild fever. Mild inflammation in the throat is present. The tonsils can be swollen, but there is no pseudomembrane formation, or only a small amount of fibrinous exudate. Bacterial culture is positive. Misdiagnosis and missed diagnosis may occur in these patients.

Localized pharyngeal diphtheria

Localized pharyngeal diphtheria includes tonsillar diphtheria and pharyngeal diphtheria.

Tonsillar diphtheria is with a pseudomembrane only on the unilateral or bilateral tonsils.

Pharyngeal diphtheria is with a pseudomembrane only on the palatine arch or palatine uvula or both, more common in adults and old children with some immunity. Slow onset, mild or moderate fever, systemic symptoms such as general malaise, fatigue, anorexia, sore throat, tonsil congestion, and local swelling may be present. The pseudomembrane is punctate or flaky, enlarging and fusing into a patch within 1 - 2 days. The pseudomembrane is grayish white, sharply demarcated, and inseparable, and forced separation can cause basal hemorrhage. The submandibular lymph nodes are often swollen and mildly painful, but the peripheral tissue is not edematous.

Disseminated pharyngeal diphtheria

If patients with localized pharyngeal diphtheria are not treated promptly and effectively, the pseudomembrane can spread to the palatine uvula, soft palate, posterior pharyngeal wall, nasopharynx, throat, and oral mucosa. The disease is more common in young children. The pseudomembrane is large, thick, grayish white, yellow, dirty gray, or black. The peripheral mucous membrane is red and swollen, the tonsils are swollen, and the submandibular lymph nodes and cervical lymph nodes are swollen. Tenderness is present, and edema around the lymph nodes may be present. Patients have obvious systemic symptoms such as high fever of 40 °C, dizziness, headache, weakness, nausea, vomiting, circulatory failure, paleness, weak pulse, and tachycardia.

Poisoning pharyngeal diphtheria

Poisoning pharyngeal diphtheria can be derived from localized and disseminated pharyngeal diphtheria, or can be primary, predominantly a mixed infection. The extensive pseudomembrane turns to dark due to hemorrhage. The tonsils and pharynx are severely swollen, and the laryngopharynx can be obstructed, with necrosis and ulceration, with special malodor. The cervical lymph nodes are enlarged and edema occurs in the peripheral tissue, causing swelling of the neck or even the tissue near the collarbone. Patients present with high fever, irritability, tachypnea, paleness, lip cyanosis, weak pulse, tachycardia, and hypotension. Some may develop cardiomegaly and arrhythmia such as gallop rhythm. If untreated promptly, most patients die within 2 weeks.

Laryngeal diphtheria

Laryngeal diphtheria is found in about 20% of patients, of which 1/4 is primary, patients have no lesions in the pharynx, and 3/4 is derived from the spread of pharyngeal diphtheria. Primary laryngeal diphtheria is more common in children aged 1 - 3 years, and barking cough, hoarseness or even aphonia are present. The presence of pseudomembrane in the throat and trachea causes varying degrees of dyspnea, mainly inspiratory dyspnea. If the pseudomembrane spreads to trachea and bronchus, dyspnea is more serious. If tracheal intubation or tracheotomy is not performed in time, patients often die within two days. The adhesion of the laryngeal and tracheal pseudomembrane and mucous membrane is not very strong, sometimes the tubular pseudomembrane can be aspirated or expectorated, and dyspnea can be alleviated. Because the toxin is less absorbed, the systemic poisoning symptoms are not serious.

Nasal diphtheria

Nasal diphtheria is rare and is more common in infants and young children. The disease is mainly characterized by nasal congestion, bloody and serous secretions, and refractoriness. The anterior nares and upper lip often present with superficial ulcers due to the erosion of secretions and are covered by crusts. In simple nasal vestibular diphtheria, the pseudomembrane can be unilateral or bilateral. Patients present with no or mild fever, breastfeeding difficulties, mouth breathing, sleep disturbance, and weight loss. The disease may be secondary to pharyngeal diphtheria.

Other diphtheria

The bacteria can invade the conjunctival mucosa, ear, external genitals, neonatal umbilicus, and the disrupted skin, and pseudomembrane and purulent secretions appear in the different sites. Diphtheria in the eyes, ears, and external genitals is mostly secondary. Cutaneous diphtheria is often preceded by trauma, often accompanied by mixed infection. The pseudomembrane is yellow or gray, necrosis and ulceration can form, nearby lymph nodes can be swollen, and skin lesions are refractory, leaving hyperpigmentation after healing. Systemic poisoning symptoms are often absent, but peripheral nerve paralysis may occur. The incidence of cutaneous diphtheria is not high, but significantly increased in some areas, more common in the tropics.

In addition to traumatic diphtheria, primary cutaneous diphtheria can also occur.

In primary cutaneous diphtheria, sudden onset is present. An initial tender pustule evolves into a round, oval, or irregular, punched-out ulcer, covered firmly by a grayish white or brownish gray pseudomembrane, with undermined edges. The pseudomembrane is inseparable, and forced separation can cause hemorrhage. Eventually, the ulcer is deeply depressed, the edema is obvious, and the edges are raised. The nearby lymph nodes are moderately enlarged. Skin lesions are more common in the lips, umbilicus, postauricular areas, areas between the external genitals and the anus, and interdigital areas. In addition, there are some atypical skin lesions, such as eczematoid, varicelloid, impetiginous, and ecthymatous diphtheria. Eventually, the ulcer occurs, and the ulcer gradually heals in 6 - 12 weeks.


Diagnosis

Diphtheria should be considered when the following non-specific symptoms occur: pharyngitis, cervical adenitis, low fever, systemic poisoning symptoms, hoarseness, palate paralysis, and stridors. A typical pseudomembrane suggests the diagnosis.

Bacterial culture requires a specialized culture medium, and polymerase chain reaction (PCR) can rapidly detect the genes of the bacteria and diphtheria toxin.


Treatment

Patients with symptomatic respiratory diphtheria should be hospitalized and treated in the intensive care unit (ICU), and complications should be monitored. Respiratory tract isolation and careful contact should be conducted to avoid infection, until two consecutive negative cultures 24 - 48 hours after the end of the antibiotic treatment.

Diphtheria antitoxin

Because antitoxins only neutralize toxins that do not bind to cells, diphtheria antitoxin should be administered immediately, and there is no need to wait for culture confirmation.

Diphtheria antitoxin is extracted from horses. Therefore, a skin test should be performed prior to administration. The dose ranges from 20,000 - 100,000 units, depending upon the site, severity, duration, and complications.

If allergies occur, subcutaneous, intramuscular, or intravenous 1:1000 adrenaline 0.01mL/kg should be immediately administered. Intravenous antitoxins are contraindicated in patients with severe allergies.

Antibiotics

Antibiotics are needed to kill bacteria and prevent transmission, and antibiotics cannot be replaced by antitoxins.

Erythromycin 40mg/kg/day, maximally 2g/day, orally or intramuscularly once every 6 hours for 14 days can be administered.

Procaine G penicillin 300,000 units/day in patients with body weight ≤10 kg and 600,000 units/day in patients with body weight >10 kg intramuscularly for 14 days can be given.

When the patient is able to tolerate oral medication, the injection should be switched to penicillin 250mg orally four times a day or erythromycin 500mg orally once every 6 hours for 14 days.

For children patients, procaine G penicillin 12,500 - 25,000 units/kg intramuscularly once every 12 hours or erythromycin 10 - 15mg/kg, maximally 2g/day, intravenously once every 6 hours can be used. When the patient is able to tolerate oral medications, the injection can be switched to oral medications.

Vancomycin or linezolid can be used to test the antibiotic resistance. 1 - 2 days and 2 weeks after the end of the antibiotic treatment, two consecutive negative cultures from the throat or nasopharynx can determine whether the bacteria are eliminated.

Other treatment

Cutaneous diphtheria can be treated with soapy water and systemic antibiotics for 10 days.

Diphtheria patients need to be vaccinated after rehabilitation, because infection does not necessarily acquire immunity.

Recovery is slow in severe diphtheria and patients should be advised not to resume exercise too soon. Normal physical activity may be detrimental to the recovery of myocarditis.


Prognosis

The prognosis of diphtheria is associated with the age, severity, presence or absence of complications, and early or late treatment. The mortality rate of infants and young children is higher than that of old children and adults, about 3% - 10%. Severe pharyngeal diphtheria can cause serious poisoning symptoms, and toxic myocarditis occurs mostly 2 - 3 weeks after onset, which is the main cause of death. Laryngeal diphtheria can cause suffocation.


Prevention

Vaccination

The diphtheria vaccine contains diphtheria toxoid, and can be used in combination with other vaccines.

Everyone should be vaccinated at the specified intervals.

All diphtheria contacts, including medical workers, who have not completed the initial vaccination or their last booster vaccination to date >5 years should be reinjected with diphtheria vaccine. If the immune status is unknown, vaccination should be performed.

Postexposure prophylaxis with antibiotics

Treatment of asymptomatic contacts is erythromycin 500mg orally in adults and 10 - 15mg/kg in children once every 6 hours for 7 days. If compliance is not guaranteed, penicillin G benzathine 600,000 units for patients with body weight less than 30kg and 1,200,000 units for patients with body weight greater than 30kg intramuscularly in a single dose should be performed.

If the culture is positive, the treatment with erythromycin should be extended for 10 days. Carriers should not use antitoxin, and can continue to work 3 days after treatment, but must continue antibiotic treatment. Bacterial culture should be performed 24 hours after the end of the antibiotic treatment, and two consecutive bacterial cultures with an interval of 24 hours should be performed. If the culture is positive, a course of antibiotics should be used, and then much more cultures may be needed.