Diphtheria

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Dima Nimri, M.D. [2]

Diphtheria (Greek διφθερα (diphthera) — “pair of leather scrolls”) is an upper respiratory tract illness characterized by sore throat, low-grade fever, and an adherent membrane (a pseudomembrane) on the tonsils, pharynx, and/or nasal cavity.^[1][2] A milder form of diphtheria can be restricted to the skin. It is caused by Corynebacterium diphtheriae, a facultatively anaerobic gram-positive bacterium.^[3]

Diphtheria is a highly contagious disease that is spread via direct physical contact or breathing the aerosolized secretions of infected individuals. Once quite common, diphtheria has largely been eradicated in developed nations through widespread vaccination. In the United States, for instance, there were only 57 reported cases of diphtheria between 1980 and 2004 (and only five cases since 2000),^[4] as the DPT(Diphtheria–Pertussis–Tetanus) vaccine is given to all schoolchildren. Boosters of the vaccine are recommended for adults, since the benefits of vaccination decrease with age; they are particularly highly recommended for those traveling to areas where the disease has not yet been eradicated.

Before 1826, diphtheria was known by different names across the world. In 1826, the term “diphtheria” was introduced by French physician Pierre Bretonneau. The name alludes to the leathery, sheath-like membrane that grows on the tonsils, throat, and in the nose in patients with the disease.^[5][6]

Diphtheria can be classified according to the type of Corynebacterium that causes a specific case. It can also be classified according to the resulting clinical presentation into respiratory, systemic, or cutaneous diphtheria.^[7][8]

C. diphtheriae is a facultatively anaerobic, gram positive organism that is characterized by non-encapsulated, non-sporulated, immobile, straight or curved rods with a length of 1 to 8 µm and width of 0.3 to 0.8 µm. These rods form ramified aggregations in culture that have been described as looking like “Chinese characters.” The bacterium may contain polymetaphosphate aggregates called Volutin granules. It is only pathogenic in humans.^[9]

Respiratory diphtheria must be differentiated from respiratory tract or other infections that present with fever, neck swelling, cough, and/or pharyngeal exudates. Cutaneous diphtheria must be differentiated from other bacterial and fungal causes of skin ulceration.^[10][11]

Diphtheria is observed worldwide, though it is rare in the United States due to widespread vaccination. Diphtheria is a significant cause of illness and death in developing countries, where vaccination coverage tends to be lower.

Common risk factors in the development of diphtheria include lack of immunization, history of travel to areas endemic for diphtheria, exposure to overcrowding and/or poor sanitary conditions, and immunocompromised status.^{[12][13][14][15][16]}

There are no screening recommendations for diphtheria.^[17]

Diphtheria is a vaccine-preventable disease that can lead to such severe complications as respiratory failure, myocarditis, polyneuropathies, and death.^{[18][19][20][21][22][23]} The overall case-fatality rate for diphtheria is 5–10%, with higher death rates (up to 20%) among patients younger than 5 or older than 40 years of age.^[24]

Respiratory diphtheria presents with a wide range of systemic and respiratory symptoms.^[18] Cutaneous diphtheria usually presents with ulcers or pustular lesions, which can involve various different parts of the body. Lesions may be covered by a grayish-white pseudomembrane, similar to tonsillar exudates of respiratory diphtheria.^[25]

A patient with diptheria usually looks ill; systemic signs such as fever, tachypnea, and tachycardia are common. Pharyngeal, respiratory, neurologic, cardiac, and other physical examination findings depend upon the extent and severity of the infection.^[18][26][27]

A presumptive diagnosis of diphtheria is usually based on clinical features. A definitive diagnosis is made by growing the specific Corynebacterium species on special cultures from the respiratory tract secretions or cutaneous lesions. Culture of the lesion is performed to confirm the diagnosis. It is critical to take a swab of the pharyngeal area, especially any discolored areas, ulcerations, and tonsillar crypts. Culture medium containing tellurite is preferred. PCR assays can also be performed on isolates, swabs, or membrane specimens to rapidly confirm the presence of the tox gene responsible for the production of diphtheria toxin.^[28][29][30]

Diphtheric myocarditis may result in systolic ventricular heart failure, which is evident by cardiomegaly on chest x-ray (CXR).^[19] Diphtheric patients may also present with bronchopneumonia. In this case, CXR may be normal, or it may show increased pulmonary vascular markings and/or inflammatory infiltrates. ^[31]

In cases of respiratory diphtheria, a CT scan may reveal swelling of the soft tissue of the nasopharynx, oropharynx, larynx uvula, and soft palate.^[31]

An MRI may be performed to document diphtheric neuropathy.^[32]

An ECG in patients with diphtheria may be normal. However, in patients with diphtheria myocarditis, a wide range of abnormalities related to conduction and rhythm may be observed.

Echocardiography may be performed to document ejection fraction (EF) and any signs of ventricular systolic dysfunction if diphtheria infection has been complicated by systemic involvement of the myocardium.^[33]

There are no other imaging findings in cases of diphtheria.

There are no other diagnostic studies for diphtheria.

The treatment of diphtheria consists of administering the diphtheria antitoxin (if the disease is identified early), administering the proper antibiotic therapy, and identifying individuals in close contact with the patient so as to provide them with the appropriate prophylaxis.^{[34][35][36][37][38][39]}

There is no role for surgery in the management of diphtheria.

The best way to prevent diphtheria is to get vaccinated. In the United States, there are four vaccines used to prevent diphtheria: DTaP, Tdap, DT, and Td. Each of these vaccines prevents diphtheria and tetanus. The current childhood immunization schedule for diphtheria includes five doses of DTaP for children younger than seven years old. Preteens get a booster dose of Tdap at 11 or 12 years old, and teens who did not get Tdap when they were 11 or 12 years old should get a dose the next time they see their doctor. Adults should get a dose of Td every 10 years, according to the adult immunization schedule.^[40]

There are no established guidelines for the secondary prevention of diphtheria. However, early diagnosis and prompt and adequate treatment with the appropriate antibiotic therapy and diphtheria antitoxin, good nursing care, and adequate airway management may help reduce the progression of the disease and prevent complications in affected individuals.^[41]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Luke Rusowicz-Orazem, B.S.

Diphtheria was first identified in 1826 by French physician Pierre Bretonneau. Before its official discovery, diphtheria was prevalent in 18th- and 19th-century society. Between 1735 and 1740, a diphtheria epidemic in the New England colonies was thought to be responsible for the death of 80% of children under 10 years of age in select towns. During the late 19th century, diphtheria was also prevalent in the British royal family. In the 1920s, there were an estimated 100,000 to 200,000 cases of diphtheria per year in the United States, which resulted in between 13,000 and 15,000 deaths. In the 1880s, one of the first effective treatments for diphtheria was discovered by French physician Eugène Bouchut and American physician Joseph O’Dwyer: tubes that were inserted into the throat, preventing patients from suffocating due to the membrane sheath that would otherwise obstruct airways. In the 1890s, German physician Emil von Behring developed the first antitoxin serum therapy that neutralized the diphtheria toxins in the bodies of patients. Americans William H. Park and Anna Wessels Williams and Pasteur Institute scientists Emile Roux and Auguste Chaillou also independently developed diphtheria antitoxin in the 1890s. In 1923, the first successful vaccine for diphtheria was developed by French biologist Gaston Ramon. The emergence of sulfa drugs in the post-World War II era led to the adoption of penicillin as the first successful anti-diphtheria antibiotic treatment. In 1968, the WHO established recommendations for the production and quality control of diphtheria vaccines. In 1974, the WHO included the DPT vaccine in their Expanded Programme on immunization for developing countries.

• Diphtheria was first identified in 1826 by French physician Pierre Bretonneau.^[1]
• The name alludes to the leathery, sheath-like membrane that grows on the tonsils, throat, and in the nose of affected patients.^[2][3]

• Between 1735 and 1740, a diphtheria epidemic in the New England colonies was thought to be responsible for the death of 80% of children under 10 years of age in select towns.^[4]
• During the late 19th century, diphtheria was also prevalent in the British royal family.^[5]
  • Famous cases included a daughter and granddaughter of Britain’s Queen Victoria.
  • Princess Alice of Hesse, the second daughter of Queen Victoria, died of diphtheria after she contracted it from her children in December 1878.
  • One of Princess Alice’s daughters, Princess May, died of diphtheria in November of 1878.^[5]
• In the 1920s, there were an estimated 100,000-200,000 cases of diphtheria per year in the United States, which resulted in between 13,000 and 15,000 deaths.^[6]
  • Children represented a large majority of these cases and fatalities.
• One of the most notable outbreaks of diphtheria occurred in Nome, Alaska in 1925; the trip made to get the antitoxin is now celebrated by the Iditarod Trail Sled Dog Race.^[7]

• In the 1880s, one of the first effective treatments for diphtheria was discovered by French physician Eugène Bouchut and American physician Joseph O’Dwyer: tubes that were inserted into the throat, preventing affected patients from suffocating due to the membrane sheath that would otherwise obstruct airways.^[8]
• In the 1890s, the German physician Emil von Behring developed the first antitoxin serum therapy that neutralized the diphtheria toxins in the body.^[9]
  • Americans William H. Park and Anna Wessels Williams and Pasteur Institute scientists Emile Roux and Auguste Chaillou also independently developed diphtheria antitoxin in the 1890s.^[10][11][12]
• In 1923, the first successful vaccine for diphtheria was developed by French biologist Gaston Ramon.^[13]
• The emergence of sulfa drugs in the post-World War II era led to the adoption of penicillin as the first successful anti-diphtheria antibiotic treatment.^[14]
• In 1968, the WHO established recommendations for the production and quality control of diphtheria vaccines.^[15]
• In 1974, the WHO included the DPT vaccine in their expanded Programme on immunization for developing countries.^[15]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Dima Nimri, M.D. [2]

Diphtheria can be classified according to the type of Corynebacterium that causes a specific case. It can also be divided according to the resulting clinical presentation into respiratory, systemic, or cutaneous diphtheria.

Diphtheria infection can be classified according to either the causative agent or the clinical manifestations of the infection.

Diphtheria can be caused by several Corynebacterium species including:^[1][2]

• Corynebacterium diphtheria, which can be further divided into 4 types based on morphologic and biochemical properties:^[3]
  • Var. gravis
  • Var. mitis
  • Var. belfanti
  • Var. intermedius
• Corynebacterium ulcerans
• Corynebacterium hemolyticum
• Corynebacterium pseudotuberculosis

Diphtheria infection can present in any of the following ways:^[4]

• Respiratory diphtheria, which can be further divided into nasal, pharyngeal, and laryngeal diphtheria^[5]
• Systemic diphtheria, which results from the dissemination of diphtheria toxin into the heart^[6][7], kidneys and nervous system^[5]
• Cutaneous diphtheria, which is caused by toxigenic and non-toxigenic strains of Corynebacterium diphtheria^[8]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Susceptible persons may acquire toxigenic diphtheria bacilli in the nasopharynx. The organism produces a toxin that inhibits cellular protein synthesis and is responsible for local tissue destruction and membrane formation. The toxin produced at the site of the membrane is absorbed into the bloodstream and then distributed to the tissues of the body. The toxin is responsible for the major complications of myocarditis and neuritis and can also cause low platelet counts (thrombocytopenia) and protein in the urine (proteinuria). Diphtheria toxin is produced by C. diphtheriae only when infected with a bacteriophage that integrates the toxin-encoding genetic elements into the bacteria.^[1][2]

Diphtheria toxin is a single, 60,000 molecular weight protein composed of two peptide chains, fragment A and fragment B, held together by a disulfide bond. Fragment B is a recognition subunit that gains the toxin entry into the host cell by binding to the EGF-like domain of heparin-binding EGF-like growth factor (HB-EGF) on the cell surface. This signals the cell to internalize the toxin within an endosome via receptor-mediated endocytosis. Inside the endosome, the toxin is split by a trypsin-like protease into its individual A and B fragments. The acidity of the endosome causes fragment B to create pores in the endosome membrane, thereby catalyzing the release of fragment A into the cell’s cytoplasm.

Fragment A inhibits the synthesis of new proteins in the affected cell. It does this 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 (a modified histidine) 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 (a form of vitamin B₃), since this is one of the reaction’s end-products, and high amounts will drive the reaction in the opposite direction.

Clinical disease associated with non-toxin-producing strains is generally milder. While rare severe cases have been reported, these may actually have been caused by toxigenic strains that were not detected because of inadequate culture sampling.Diphtheria toxin catalyzes the ADP-ribosylation of, and inactivates, the elongation factor eEF-2. In this way, it acts to inhibit translation during eukaryotic protein synthesis.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Luke Rusowicz-Orazem, B.S.

Corynebacterium diphtheriae is a pathogenic bacterium that causes diphtheria. It is a facultatively anaerobic, gram positive organism characterized by non-encapsulated, non-sporulated, immobile, straight or curved rods. The genome of C. diphtheriae contains 2,488,635 nucleotides, 2,389 genes, and 69 structural RNA genes. Gram-stain will result in a blue-purple coloration due to containing polymetaphosphate granules. Many strains of C. diphtheriae produce diphtheria toxin, a protein exotoxin, with a molecular weight of 62 kilodaltons which ADP-ribosylates host EF-2, resulting in the inhibition of protein synthesis and producing signs of diphtheria. C. diptheriae is exclusively pathogenic in humans. C. diphtheriae can be classified into following four subspecies: mitis, intermedius, gravis, and belfanti. The diagnosis of C. diphtheriae includes a Gram stain procedure; results will indicate gram-positive, pleomorphic bacteria that will dye violet-blue and resemble clubs. C.diphtheriae causes diphtheria disease in non-immunized human hosts via secreted toxins. Toxigenic strains of the bacterium will secrete toxins in nasopharyngeal or skin lesions. It is common for hosts to carry C. diphtheriae in the nasopharyngeal region without displaying symptoms. Lysogenic conversion of nontoxigenic-toxigenic phenotypes of the bacterium can occur following transmission, allowing non-human/affected hosts to transmit diphtheria to humans. C. diphtheriae is sensitive to antibiotic therapy.

• C. diphtheriae is a facultatively anaerobic, Gram positive organism that is characterized by non-encapsulated, non-sporulated, immobile, straight or curved rods.^[1][2]
• The genome of C. diphtheriae contains 2,488,635 nucleotides, 2,389 genes, and 69 structural RNA genes.^[3]
  • As a gram-positive bacteria, C. diphtheriae contains a cell membrane and a lipid-rich murein layer outside.
• Cell wall sugars of C. diphtheriae include arabinose, galactose, and mannose.
• Gram-stain will result in a blue-purple coloration due to containing polymetaphosphate granules.
• Many strains of C. diphtheriae produce diphtheria toxin, a protein exotoxin, with a molecular weight of 62 kilodaltons which ADP-ribosylates host EF-2, resulting in the inhibition of protein synthesis and producing signs of diphtheria.^[4]
  • The inactivation of this toxin with an antitoxic serum (antitoxin) is the basis of the antidiphtheric vaccination.
    • Not all strains are toxigenic; the ability to produce the exotoxin is conferred on the bacterium when it is infected by a bacteriophage through a mechanism termed lysogenic activation.
    • A non-toxigenic strain can become toxigenic by the infection of such a bacteriophage.
• C. diptheriae is exclusively pathogenic in humans.^[5]

C. diphtheriae can be classified into the following four subspecies:^[1][2]

• C. diphtheriae mitis
• C. diphtheriae intermedius
• C. diphtheriae gravis
• C. diphtheriea belfanti^[6]

• The diagnosis of C. diphtheriae includes a gram stain procedure.
  • Results will indicate gram-positive, pleomorphic bacteria that will dye violet-blue and resemble clubs.^[6]
• Additional tests include Albert’s stain and Loeffler’s stain.
• C. diphtheriae should be cultured on an erichment medium, primarily to allow it to overgrow any other organisms present in the specimen.^[7]
  • A selective plate tellurite agar which allows all Corynebacteria (including C. diphtheriae) to reduce tellurite to metallic tellurium and produce brown colonies.
    • C. diphtheriae is the only corynebacterium that will produce a black halo around the colonies.

• C.diphtheriae causes diphtheria disease in non-immunized human hosts via secreted toxins.^[1][2]
  • Toxigenic strains of the bacterium will secrete toxins in nasopharyngeal or skin lesions; it is common for hosts to carry C. diphtheriae in the nasopharyngeal region without displaying symptoms.
  • A low concentration of iron is required in the medium for toxin production; at high iron concentrations, iron molecules bind to a repressor which shuts down toxin production^[8]
• C.diphtheriae is transmitted through respiratory droplets, secretions, or direct contact.
• Lysogenic conversion of nontoxigenic-toxigenic phenotypes of the bacterium can occur following transmission, allowing non-human/affected hosts to transmit diphtheria to humans.

C. diphtheriae is sensitive to the following antibiotics:^[9]

• Benzylpenicillin
• Ampicillin
• Oxytetracycline
• Erythromycin
• Cephaloradine
• Lincomycin
• Clindamycin
• Neomycin

• CoryneRegNet – Database of Corynebacterial Transcription Factors and Regulatory Networks

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Dima Nimri, M.D. [2]

Respiratory diphtheria must be differentiated from respiratory tract or other infections that present with fever, neck swelling, cough and/or pharyngeal exudates. Cutaneous diphtheria must be differentiated from other bacterial and fungal causes of skin ulceration.

A group of respiratory diseases can present with symptoms such as fever, sore throat, pharyngeal exudates and/or neck swelling, which may mimic the symptoms of a diphtheria infection. These include:^[1]

• Infectious mononucleosis due to EBV
• Group A streptococci pharyngitis
• Epiglottitis due to Hemophilus influenza type b
• Viral pharyngitis due to influenza, HSV or adenovirus
• Vincent’s angina
• Oral candidiasis

Cutaneous diphtheria due to Corynebacterium diphtheria must be differentiated from other bacterial and fungal diseases that present with a shallow ulcer on the skin:^[2]

• Bacterial causes:
  • Pyoderma due to Staphylococcus aureus or Group A beta-hemolytic streptococci
  • Cutaneous Leishmaniasis
  • Cutaneous Anthrax due to Bacillus Anthracis
  • Cutaneous mycobacterial infections due to Mycobacterium tuberculosis, Mycobacterium marinum or Mycobacterium ulcerans
• Fungal causes:
  • Sporotrichosis
  • Mycetoma
  • Chromoblastomycosis

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Luke Rusowicz-Orazem, B.S.

Worldwide, the incidence of diphtheria is low. In 2015, the incidence was approximately .07 individuals per 100,000. The overall annual case fatality rate for diphtheria ranges between 5 and 10%. The annual case fatality rates for patients younger than 5 or older than 40 years of age tend to be higher, ranging up to 20%. Diphtheria most commonly affects children under the age of 5 years and adults over 70 years of age. This is primarily due to the higher chance that patients in these age groups have not had a vaccination or booster. The incidence of diphtheria is highest in developing countries due to the lack of comprehensive vaccination; developing countries to which diphtheria is endemic include Indonesia, Thailand, Laos, and many other countries in Asia, the South Pacific, Middle East, Haiti, Dominican Republic, South America, and Eastern Europe. Diphtheria tends to be very rare in developed, industrialized countries. The majority of cases in developed countries involve travelers from diphtheria-endemic countries or patients from developed countries who were not vaccinated or did not receive the appropriate boosters.

• Diptheria is very rare; the incidence in 2015 was approximately .07 individuals per 100,000.^[1][2]

• The overall annual case fatality rate for diptheria ranges between 5 and 10%.^[3]
  • The annual case fatality rates for patients who are younger than 5 or older than 40 years of age tend to be higher, ranging up to 20%.

• Diphtheria most commonly affects children under the age of 5 years old who have not been properly vaccinated.^[4]
• Individuals over 50 years of age are particularly susceptible to diphtheria, and especially those over 70 years of age due to the higher probability that they have not received proper vaccination.^[5][6]

• There is evidence that women may be more prone than men to diphtheria infection due to lower antitoxin responses to vaccination, which necessitates more frequent booster administrations.^[7]

There is no evidence of any racial predisposition to diphtheria.

• The incidence of diphtheria is highest in developing countries due to a lack of available vaccines and, correspondingly, low rates of vaccination.^[8]
• Developing countries to which diphtheria is endemic include Indonesia, Thailand, Laos, and many other countries in Asia, the South Pacific, Middle East, Haiti, Dominical Republic, South America, and Eastern Europe.^[9]
  • A diphtheria resurgence occurred in former Soviet states that comprise present day Eastern Europe, spreading past Europe into Asia and the Middle East.^[10]
    • By 1998, there were an estimated 200,000 cases in Eastern Europe, with 5,000 fatalities.^[11]
  • Outbreaks in Haiti and the Dominican Republic led to a resurgence in the Americas, including a rare fatal case in the United States in 2003 involving a Pennsylvania resident returning from Haiti.^[12]

Table 3-01. Countries with endemic diphtheria

• Diphtheria is rare in developed, industrialized countries due to longstanding, widespread administration of TDaP vaccine.^[11]
• The majority of cases in developed countries involve patients who are traveling from diphtheria-endemic countries, or those from developed countries who were not vaccinated and/or did not receive the appropriate boosters.^[12]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Kalsang Dolma, M.B.B.S.[2], Aysha Anwar, M.B.B.S[3]

Common risk factors in the development of diphtheria include a lack of immunization, a history of travel to areas endemic for diphtheria, exposure to overcrowding and/or poor sanitary conditions, and immunocompromised status.^{[1][2][3][4][5]}

Common risk factors in the development of diphtheria may include:^{[1][2][3][4][5]}

• Lack of immunization
• History of contact with diphtheria patients
• Presence of skin lesions
• Presence of eczema
• History of chronic health conditions
• History of travel to areas endemic for diphtheria
• Overcrowding
• Exposure to poor sanitary conditions
• Poor personal hygiene
• Sharing utensils and fomites with person suffering from diphtheria
• Presence of tonsils

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Dima Nimri, M.D. [2]

There are no official screening recommendations for diphtheria. ^[1]

There are no official screening recommendations for diphtheria. ^[1]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Kalsang Dolma, M.B.B.S.[2], Aysha Anwar, M.B.B.S[3]

Diphtheria is a vaccine-preventable disease that can lead to such severe complications as respiratory failure, myocarditis, polyneuropathies, and death.^{[1][2][3][4][5][6]} The overall case-fatality rate for diphtheria is 5%–10%, with higher death rates (up to 20%) among patients younger than 5 and older than 40 years of age.^[7]

The symptoms of diphtheria usually develop following an incubation period of 2-4 days. Early symptoms typically include sore throat, high-grade fever, myalgias, lymphadenopathy, hoarseness of voice, dyspnea, rhinorrhea, and difficulty swallowing. Without treatment, diphtheria may progress to cause airway obstruction, neuropathies, myocarditis, septicemia, shock, and death.^[1][2]

Complications that may develop as a result of diphtheria are:^{[2][8][9][10][3][4][5][6]}

• Respiratory failure
• Myocarditis
• Heart failure
• Polyneuropathies
  • 10th cranial nerve disorder
  • 9th cranial nerve disorder
  • Peripheral motor neuropathy
• Diaphragm paralysis
• Neurogenic bladder dysfunction
• Acute renal failure
• Septicemia
• Death

The overall case-fatality rate for diphtheria is 5–10%, with higher death rates (up to 20%) among patients younger than 5 and older than 40 years of age.^[7] Prognosis of diphtheria varies based on following factors:^{[11][12][13][6]}

Good prognostic factors

• Early diagnosis and treatment
• Age >15 years
• Absence of cardiac involvement

Poor prognostic factors

• Delayed diagnosis and treatment
• Age <15 years
• Presence of cardiac involvement
• Presence of complications
• Immunocompromised status

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