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Diphtheria (Clinical)

Diphtheria is an infectious disease caused by Corynebacterium diphtheriae that most often results in respiratory disease with membranous inflammation of the pharynx, sore throat, fever, swollen glands, and weakness. The hallmark sign is a sheet of thick, gray material covering the back of the throat. Diphtheria can also manifest as cutaneous disease leading to nonspecific skin lesions. In advanced stages, diphtheria can damage the heart, kidneys, and nervous system. It is diagnosed via a culture of pharyngeal swabs and treated with antibiotic therapy and the diphtheria antitoxin.

Last updated: May 19, 2023

Editorial responsibility: Stanley Oiseth, Lindsay Jones, Evelin Maza

Overview

Etiology[1–3,7]

Diphtheria Diphtheria Diphtheria is an infectious disease caused by Corynebacterium diphtheriae that most often results in respiratory disease with membranous inflammation of the pharynx, sore throat, fever, swollen glands, and weakness. The hallmark sign is a sheet of thick, gray material covering the back of the throat. Diphtheria is caused by the bacterium Corynebacterium diphtheriae Corynebacterium diphtheriae Diphtheria is an infectious disease caused by corynebacterium diphtheriae that most often results in respiratory disease with membranous inflammation of the pharynx, sore throat, fever, swollen glands, and weakness. The hallmark sign is a sheet of thick, gray material covering the back of the throat. Diphtheria.

  • Gram-positive Gram-Positive Penicillins bacillus Bacillus Bacillus are aerobic, spore-forming, gram-positive bacilli. Two pathogenic species are Bacillus anthracis (B. anthracis) and B. cereus. Bacillus
  • 4 biotypes: gravis, intermedius, mitis, and belfanti
  • Humans are the only known reservoir Reservoir Animate or inanimate sources which normally harbor disease-causing organisms and thus serve as potential sources of disease outbreaks. Reservoirs are distinguished from vectors (disease vectors) and carriers, which are agents of disease transmission rather than continuing sources of potential disease outbreaks. Humans may serve both as disease reservoirs and carriers. Escherichia coli.

Transmission[2,7]

  • Close contact with infected respiratory secretion Secretion Coagulation Studies (directly or by airborne droplets Droplets Varicella-Zoster Virus/Chickenpox)
  • Can also be transmitted through skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Skin: Structure and Functions lesions
  • Immunization has minimized toxigenic strain transmission in resource-rich countries.

Epidemiology[1,7,10]

  • Remains a widespread disease/endemic in resource-limited countries
  • Asymptomatic carriers Carriers The Cell: Cell Membrane are important in transmission.
  • 5% of populations in endemic areas have positive pharyngeal cultures.
  • Peak incidence Incidence The number of new cases of a given disease during a given period in a specified population. It also is used for the rate at which new events occur in a defined population. It is differentiated from prevalence, which refers to all cases in the population at a given time. Measures of Disease Frequency in colder months

Pathophysiology

Pathogenesis diphtheria

Pathogenesis of diseases associated with Corynebacterium: diphtheria exotoxin inactivates elongation factor (EF-2) via ADP-ribosylation.[1,2,3]
This bacteriophage, a beta prophage, introduces itself into the cell and DNA of the host organism, resulting in the encoding of diphtheria exotoxin. The exotoxin has 3 domains: 1 is present in fragment A and is catalytic, while 2 are present in fragment B for receptor binding and membrane insertion and translocation. The exotoxin is the major cause of the disease in diphtheria because it ribosylates ADP present in the elongation factor. The elongation factor, specifically elongation factor 2 (EF-2), is critical for the elongation of protein chains. Diphtheria exotoxin inhibits EF-2 so that protein is not synthesized, resulting in cellular death and secondary clinical manifestations.

Image by Lecturio.

Clinical Presentation

Respiratory diphtheria Diphtheria Diphtheria is an infectious disease caused by Corynebacterium diphtheriae that most often results in respiratory disease with membranous inflammation of the pharynx, sore throat, fever, swollen glands, and weakness. The hallmark sign is a sheet of thick, gray material covering the back of the throat. Diphtheria[2–4,7,9]

  • Symptoms begin 2–5 days after infection.
  • Gradual onset of:
    • Sore throat Sore throat Pharyngitis is an inflammation of the back of the throat (pharynx). Pharyngitis is usually caused by an upper respiratory tract infection, which is viral in most cases. It typically results in a sore throat and fever. Other symptoms may include a runny nose, cough, headache, and hoarseness. Pharyngitis
    • Malaise Malaise Tick-borne Encephalitis Virus
    • Cervical lymphadenopathy Lymphadenopathy Lymphadenopathy is lymph node enlargement (> 1 cm) and is benign and self-limited in most patients. Etiologies include malignancy, infection, and autoimmune disorders, as well as iatrogenic causes such as the use of certain medications. Generalized lymphadenopathy often indicates underlying systemic disease. Lymphadenopathy
    • Low-grade fever Low-Grade Fever Erythema Infectiosum
    • Mild erythematous pharynx Pharynx The pharynx is a component of the digestive system that lies posterior to the nasal cavity, oral cavity, and larynx. The pharynx can be divided into the oropharynx, nasopharynx, and laryngopharynx. Pharyngeal muscles play an integral role in vital processes such as breathing, swallowing, and speaking. Pharynx: Anatomy
  • Pseudomembranous pharyngitis Pseudomembranous pharyngitis Diphtheria:
    • Characterized by a grayish-white membrane covering the posterior pharyngeal wall and/or tonsils Tonsils Tonsillitis that bleeds heavily during attempts at removal owing to its highly vascular nature
    • Present in at least 1/3 of cases
    • Formation is induced by the toxin (made up of necrotic fibrin Fibrin A protein derived from fibrinogen in the presence of thrombin, which forms part of the blood clot. Rapidly Progressive Glomerulonephritis, WBCs, RBCs RBCs Erythrocytes, or red blood cells (RBCs), are the most abundant cells in the blood. While erythrocytes in the fetus are initially produced in the yolk sac then the liver, the bone marrow eventually becomes the main site of production. Erythrocytes: Histology, and epithelial cells) 
    • Pseudomembrane Pseudomembrane Candida/Candidiasis should not be scraped off.
  • Severe lymphadenopathy Lymphadenopathy Lymphadenopathy is lymph node enlargement (> 1 cm) and is benign and self-limited in most patients. Etiologies include malignancy, infection, and autoimmune disorders, as well as iatrogenic causes such as the use of certain medications. Generalized lymphadenopathy often indicates underlying systemic disease. Lymphadenopathy with “bull neck Neck The part of a human or animal body connecting the head to the rest of the body. Peritonsillar Abscess” appearance (pathognomonic)
  • Foul breath or mouth odor

Laryngeal diphtheria Diphtheria Diphtheria is an infectious disease caused by Corynebacterium diphtheriae that most often results in respiratory disease with membranous inflammation of the pharynx, sore throat, fever, swollen glands, and weakness. The hallmark sign is a sheet of thick, gray material covering the back of the throat. Diphtheria[2–4,11]

  • Characteristic swollen neck and throat or “bull neck”
  • Can have extensive laryngeal pseudomembrane Pseudomembrane Candida/Candidiasis formation
  • Often accompanied by the following symptoms (historically referred to as “diphtheritic croup Croup Croup, also known as laryngotracheobronchitis, is a disease most commonly caused by a viral infection that leads to severe inflammation of the upper airway. It usually presents in children < 5 years of age. Patients develop a hoarse, "seal-like" barking cough and inspiratory stridor. Croup”):

Nasal diphtheria Diphtheria Diphtheria is an infectious disease caused by Corynebacterium diphtheriae that most often results in respiratory disease with membranous inflammation of the pharynx, sore throat, fever, swollen glands, and weakness. The hallmark sign is a sheet of thick, gray material covering the back of the throat. Diphtheria[2,11]

Tracheobronchial diphtheria Diphtheria Diphtheria is an infectious disease caused by Corynebacterium diphtheriae that most often results in respiratory disease with membranous inflammation of the pharynx, sore throat, fever, swollen glands, and weakness. The hallmark sign is a sheet of thick, gray material covering the back of the throat. Diphtheria[4]

  • Develops secondary to membrane spread
  • Can result in respiratory compromise, especially in children with smaller airways

Cutaneous (wound) diphtheria Diphtheria Diphtheria is an infectious disease caused by Corynebacterium diphtheriae that most often results in respiratory disease with membranous inflammation of the pharynx, sore throat, fever, swollen glands, and weakness. The hallmark sign is a sheet of thick, gray material covering the back of the throat. Diphtheria[2,4,11]

  • Initial papule Papule Elevated lesion < 1 cm in diameter Generalized and Localized Rashes → chronic non-healing ulcer with a dirty-gray membrane
  • Local trauma is a frequent precedent (e.g., IV drug use)
  • Most often seen in homeless patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship or those with a history of drug abuse
Diphtheria skin lesion

Clinical sign of a patient with cutaneous (wound) diphtheria: chronic non-healing ulcer

Image: “A diphtheria skin lesion on the leg” by CDC/Public Health Image Library (PHIL). License: Public Domain

Systemic toxemia[4,7,11]

  • Damage to distant organs: cardiac toxicity Toxicity Dosage Calculation, neurologic toxicity Toxicity Dosage Calculation, renal failure Renal failure Conditions in which the kidneys perform below the normal level in the ability to remove wastes, concentrate urine, and maintain electrolyte balance; blood pressure; and calcium metabolism. Renal insufficiency can be classified by the degree of kidney damage (as measured by the level of proteinuria) and reduction in glomerular filtration rate. Crush Syndrome
  • Myocarditis Myocarditis Myocarditis is an inflammatory disease of the myocardium, which may occur alone or in association with a systemic process. There are numerous etiologies of myocarditis, but all lead to inflammation and myocyte injury, most often leading to signs and symptoms of heart failure. Myocarditis:
    • ST–T-wave changes on ECG ECG An electrocardiogram (ECG) is a graphic representation of the electrical activity of the heart plotted against time. Adhesive electrodes are affixed to the skin surface allowing measurement of cardiac impulses from many angles. The ECG provides 3-dimensional information about the conduction system of the heart, the myocardium, and other cardiac structures. Electrocardiogram (ECG)
    • QTc prolongation
    • Heart block
    • Onset 7–14 days after respiratory symptoms
    • Poor prognosis Prognosis A prediction of the probable outcome of a disease based on a individual’s condition and the usual course of the disease as seen in similar situations. Non-Hodgkin Lymphomas
  • Neurologic toxicity Toxicity Dosage Calculation:
    • Demyelination Demyelination Multiple Sclerosis and nerve deficits begin in the posterior oral pharynx Pharynx The pharynx is a component of the digestive system that lies posterior to the nasal cavity, oral cavity, and larynx. The pharynx can be divided into the oropharynx, nasopharynx, and laryngopharynx. Pharyngeal muscles play an integral role in vital processes such as breathing, swallowing, and speaking. Pharynx: Anatomy.
    • Local neuropathies Neuropathies Chédiak-Higashi Syndrome ( soft palate Soft palate A movable fold suspended from the posterior border of the hard palate. The uvula hangs from the middle of the lower border. Palate: Anatomy, pharyngeal area) and cranial neuropathies Neuropathies Chédiak-Higashi Syndrome (oculomotor)
    • Peripheral neuritis (can take weeks to months to develop)
  • Renal failure Renal failure Conditions in which the kidneys perform below the normal level in the ability to remove wastes, concentrate urine, and maintain electrolyte balance; blood pressure; and calcium metabolism. Renal insufficiency can be classified by the degree of kidney damage (as measured by the level of proteinuria) and reduction in glomerular filtration rate. Crush Syndrome from toxin effect

Diagnosis

General[2,9]

  • Consider the diagnosis with relevant clinical manifestations listed above along with epidemiologic risk factors.
  • Definitive diagnosis requires culture + toxin assay.
    • Physicians Physicians Individuals licensed to practice medicine. Clinician–Patient Relationship should notify the laboratory of a suspected case.
    • Treatment should not be delayed while awaiting laboratory results if the clinical picture strongly suggests diphtheria Diphtheria Diphtheria is an infectious disease caused by Corynebacterium diphtheriae that most often results in respiratory disease with membranous inflammation of the pharynx, sore throat, fever, swollen glands, and weakness. The hallmark sign is a sheet of thick, gray material covering the back of the throat. Diphtheria.

Cultures [1,2,3,4,11]

  • Source: nasal and pharyngeal swabs 
  • C. diphtheriae:
  • Special culture media are needed:
    • Agar with tellurite Tellurite Diphtheria: appear as black colonies with halos
    • Loeffler’s medium: metachromatic granules

Toxin detection

  • Elek test Elek test Diphtheria performed to determine if strain is toxigenic:[2,3,4,5,7]
    • C. diphtheriae grows on an agar culture.
    • An antitoxin-impregnated filter paper is laid over the culture, and toxin production is shown by the development of an immunoprecipitin band.
  • Enzyme immunoassay Enzyme immunoassay HIV Infection and AIDS:[2,3,4,5,7]
    • Rapid test (3 hours)
    • Sensitive and specific detection of the diphtheria Diphtheria Diphtheria is an infectious disease caused by Corynebacterium diphtheriae that most often results in respiratory disease with membranous inflammation of the pharynx, sore throat, fever, swollen glands, and weakness. The hallmark sign is a sheet of thick, gray material covering the back of the throat. Diphtheria toxin
  • Immunochromatographic strip (ICS) assay:[5,6,7]
    • Highly sensitive test to detect diphtheria Diphtheria Diphtheria is an infectious disease caused by Corynebacterium diphtheriae that most often results in respiratory disease with membranous inflammation of the pharynx, sore throat, fever, swollen glands, and weakness. The hallmark sign is a sheet of thick, gray material covering the back of the throat. Diphtheria toxin
    • No specialized equipment needed
  • PCR PCR Polymerase chain reaction (PCR) is a technique that amplifies DNA fragments exponentially for analysis. The process is highly specific, allowing for the targeting of specific genomic sequences, even with minuscule sample amounts. The PCR cycles multiple times through 3 phases: denaturation of the template DNA, annealing of a specific primer to the individual DNA strands, and synthesis/elongation of new DNA molecules. Polymerase Chain Reaction (PCR) testing can identify the gene Gene A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. Basic Terms of Genetics via subunit A.[3,4,5]
    • Detects the toxin gene Gene A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. Basic Terms of Genetics, but does not indicate toxin production
    • Culture must be run to confirm the presence of active disease due to the toxigenic organism.

Mnemonic

Key points to remember about diphtheria Diphtheria Diphtheria is an infectious disease caused by Corynebacterium diphtheriae that most often results in respiratory disease with membranous inflammation of the pharynx, sore throat, fever, swollen glands, and weakness. The hallmark sign is a sheet of thick, gray material covering the back of the throat. Diphtheria: ABCDEFG

  • ADP-ribosylation
  • Beta-prophage
  • Corynebacterium diphtheriae
  • Elongation factor 2
  • Granules

Management and Prevention

Management can vary based on location. The following information is based on US and UK public health recommendations:

General overview[2,7,11]

  • When there is clinical suspicion of diphtheria Diphtheria Diphtheria is an infectious disease caused by Corynebacterium diphtheriae that most often results in respiratory disease with membranous inflammation of the pharynx, sore throat, fever, swollen glands, and weakness. The hallmark sign is a sheet of thick, gray material covering the back of the throat. Diphtheria, the following are applied:
    • Respiratory droplet isolation for respiratory illness
    • Contact precautions for cutaneous disease
  • Airway Airway ABCDE Assessment management: Secure the airway Airway ABCDE Assessment, as individuals are at risk for airway Airway ABCDE Assessment obstruction.
  • Treatment:
    • Respiratory diphtheria Diphtheria Diphtheria is an infectious disease caused by Corynebacterium diphtheriae that most often results in respiratory disease with membranous inflammation of the pharynx, sore throat, fever, swollen glands, and weakness. The hallmark sign is a sheet of thick, gray material covering the back of the throat. Diphtheria: antibiotic therapy + diphtheria antitoxin Diphtheria antitoxin An antitoxin produced against the toxin of corynebacterium diphtheriae that is used for the treatment of diphtheria. Diphtheria
    • Cutaneous diphtheria Cutaneous diphtheria Corynebacterium:
      • Antibiotic therapy 
      • Antitoxin is generally not given owing to absence of pseudomembranes Pseudomembranes Raised yellow or off-white plaques up to 2 cm in diameter that form as a result of mucosal ulceration Pseudomembranous Colitis and cardiac manifestations, but in the United Kingdom, use in large lesions may be justified.[4,8,9] 

Antibiotic therapy[2,4,7,9,11]

  • Suppresses the toxin-producing bacteria Bacteria Bacteria are prokaryotic single-celled microorganisms that are metabolically active and divide by binary fission. Some of these organisms play a significant role in the pathogenesis of diseases. Bacteriology, reducing toxin production and transmission of the infection
  • Options (total treatment course, 14 days):
    • Erythromycin Erythromycin A bacteriostatic antibiotic macrolide produced by streptomyces erythreus. Erythromycin a is considered its major active component. In sensitive organisms, it inhibits protein synthesis by binding to 50s ribosomal subunits. This binding process inhibits peptidyl transferase activity and interferes with translocation of amino acids during translation and assembly of proteins. Macrolides and Ketolides 500 mg 4 times daily, OR
    • Procaine Procaine A local anesthetic of the ester type that has a slow onset and a short duration of action. It is mainly used for infiltration anesthesia, peripheral nerve block, and spinal block. Local Anesthetics penicillin Penicillin Rheumatic Fever G 300,000 units IM every 12 hours for patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship ≤ 10 kg and 600,000 units every 12 hours for patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship > 10 kg (Switch to oral penicillin Penicillin Rheumatic Fever V 250 mg 4 times daily when individual is able to tolerate oral intake.)

Diphtheria antitoxin Diphtheria antitoxin An antitoxin produced against the toxin of corynebacterium diphtheriae that is used for the treatment of diphtheria. Diphtheria (DAT)[2,7,8]

  • Inactivates the toxin
  • In the United States, DAT is obtained by coordinating with the state health department and contacting the CDC’s Emergency Operations Center at 770-488-7100.[2] 
  • Precautions:
    • Prior to administration, a skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Skin: Structure and Functions test is performed to rule out hypersensitivity to the animal serum.
    • Epinephrine Epinephrine The active sympathomimetic hormone from the adrenal medulla. It stimulates both the alpha- and beta- adrenergic systems, causes systemic vasoconstriction and gastrointestinal relaxation, stimulates the heart, and dilates bronchi and cerebral vessels. Sympathomimetic Drugs should be on hand Hand The hand constitutes the distal part of the upper limb and provides the fine, precise movements needed in activities of daily living. It consists of 5 metacarpal bones and 14 phalanges, as well as numerous muscles innervated by the median and ulnar nerves. Hand: Anatomy because of the risk of anaphylaxis Anaphylaxis An acute hypersensitivity reaction due to exposure to a previously encountered antigen. The reaction may include rapidly progressing urticaria, respiratory distress, vascular collapse, systemic shock, and death. Type I Hypersensitivity Reaction.
  • Dosage Dosage Dosage Calculation (given over 60 minutes IV) according to the American Academy of Pediatrics:[4]
    • Pharyngeal/laryngeal disease of < 48 hours duration: 20,000‒40,000 units 
    • Nasopharyngeal disease: 40,000‒60,000 units 
    • Illness of > 48 hours’ duration or in case of diffuse neck swelling (“bull neck”): 80,000‒120,000 units
  • Dosage Dosage Dosage Calculation according to UK Health Security Agency:[8]
    • Laryngeal/pharyngeal/nasopharyngeal disease of ≤ 48 hours’ duration: 70,000 IU
    • Laryngeal/pharyngeal/nasopharyngeal disease of > 48 hours’ duration or severe illness (“bull neck Neck The part of a human or animal body connecting the head to the rest of the body. Peritonsillar Abscess”): 100,000 IU
    • Skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Skin: Structure and Functions lesions (large size > 2 cm2): 40,000 IU

Monitoring[2,4,7,9,11]

  • Monitor for signs of cardiac involvement:
    • Serial electrocardiograms
    • Cardiac enzymes Enzymes Enzymes are complex protein biocatalysts that accelerate chemical reactions without being consumed by them. Due to the body’s constant metabolic needs, the absence of enzymes would make life unsustainable, as reactions would occur too slowly without these molecules. Basics of Enzymes (helps evaluate degree of myocardial damage)
  • Check neurologic status
  • Obtain follow-up cultures:
    • Cultures done at 24–48 hours and 2 weeks later
    • Two negative cultures (≥ 24 hours apart) are needed to discontinue isolation.
    • Individuals who continue to harbor the bacteria Bacteria Bacteria are prokaryotic single-celled microorganisms that are metabolically active and divide by binary fission. Some of these organisms play a significant role in the pathogenesis of diseases. Bacteriology are recommended to get an additional 10 days of oral erythromycin Erythromycin A bacteriostatic antibiotic macrolide produced by streptomyces erythreus. Erythromycin a is considered its major active component. In sensitive organisms, it inhibits protein synthesis by binding to 50s ribosomal subunits. This binding process inhibits peptidyl transferase activity and interferes with translocation of amino acids during translation and assembly of proteins. Macrolides and Ketolides[9]

Convalescence period[2,9] 

Patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship are given vaccination Vaccination Vaccination is the administration of a substance to induce the immune system to develop protection against a disease. Unlike passive immunization, which involves the administration of pre-performed antibodies, active immunization constitutes the administration of a vaccine to stimulate the body to produce its own antibodies. Vaccination with diphtheria Diphtheria Diphtheria is an infectious disease caused by Corynebacterium diphtheriae that most often results in respiratory disease with membranous inflammation of the pharynx, sore throat, fever, swollen glands, and weakness. The hallmark sign is a sheet of thick, gray material covering the back of the throat. Diphtheria toxoid Toxoid Preparations of pathogenic organisms or their derivatives made nontoxic and intended for active immunologic prophylaxis. They include deactivated toxins. Anatoxin toxoids are distinct from anatoxins that are tropanes found in cyanobacteria. Vaccination (as illness does not confer immunity).

Contacts[2,4,7,9,11]

  • Close contacts (e.g., family, caretakers, medical staff) need to be monitored for development of symptoms for ≥ 1 week.
  • Obtain nasal and pharyngeal swabs.
  • Antibiotic prophylaxis Prophylaxis Cephalosporins:
    • 1 dose of penicillin Penicillin Rheumatic Fever G benzathine (600,000 units IM) for those < 6 years of age, OR
    • 1 dose of penicillin Penicillin Rheumatic Fever G benzathine (1.2 million units IM) for those ≥ 6 years of age, OR)
    • Oral erythromycin Erythromycin A bacteriostatic antibiotic macrolide produced by streptomyces erythreus. Erythromycin a is considered its major active component. In sensitive organisms, it inhibits protein synthesis by binding to 50s ribosomal subunits. This binding process inhibits peptidyl transferase activity and interferes with translocation of amino acids during translation and assembly of proteins. Macrolides and Ketolides (500 mg 4 times daily) for 7‒10 days
    • Note: In the United Kingdom, 7 days of antibiotic prophylaxis Prophylaxis Cephalosporins may be offered.[11]
  • In contacts whose cultures turn positive, proceed with treatment regimen.
  • Determine diphtheria Diphtheria Diphtheria is an infectious disease caused by Corynebacterium diphtheriae that most often results in respiratory disease with membranous inflammation of the pharynx, sore throat, fever, swollen glands, and weakness. The hallmark sign is a sheet of thick, gray material covering the back of the throat. Diphtheria toxoid Toxoid Preparations of pathogenic organisms or their derivatives made nontoxic and intended for active immunologic prophylaxis. They include deactivated toxins. Anatoxin toxoids are distinct from anatoxins that are tropanes found in cyanobacteria. Vaccination vaccination Vaccination Vaccination is the administration of a substance to induce the immune system to develop protection against a disease. Unlike passive immunization, which involves the administration of pre-performed antibodies, active immunization constitutes the administration of a vaccine to stimulate the body to produce its own antibodies. Vaccination status:
    • Unknown or < 3 doses: administer diphtheria Diphtheria Diphtheria is an infectious disease caused by Corynebacterium diphtheriae that most often results in respiratory disease with membranous inflammation of the pharynx, sore throat, fever, swollen glands, and weakness. The hallmark sign is a sheet of thick, gray material covering the back of the throat. Diphtheria toxoid Toxoid Preparations of pathogenic organisms or their derivatives made nontoxic and intended for active immunologic prophylaxis. They include deactivated toxins. Anatoxin toxoids are distinct from anatoxins that are tropanes found in cyanobacteria. Vaccination and complete series
    • ≥ 3 doses, last one > 5 years ago: administer booster diphtheria Diphtheria Diphtheria is an infectious disease caused by Corynebacterium diphtheriae that most often results in respiratory disease with membranous inflammation of the pharynx, sore throat, fever, swollen glands, and weakness. The hallmark sign is a sheet of thick, gray material covering the back of the throat. Diphtheria toxoid Toxoid Preparations of pathogenic organisms or their derivatives made nontoxic and intended for active immunologic prophylaxis. They include deactivated toxins. Anatoxin toxoids are distinct from anatoxins that are tropanes found in cyanobacteria. Vaccination
    • ≥ 3 doses, last one ≤ 5 years ago: vaccination Vaccination Vaccination is the administration of a substance to induce the immune system to develop protection against a disease. Unlike passive immunization, which involves the administration of pre-performed antibodies, active immunization constitutes the administration of a vaccine to stimulate the body to produce its own antibodies. Vaccination not required (except for children with dose due)

Prevention[2]

  • Toxoid Toxoid Preparations of pathogenic organisms or their derivatives made nontoxic and intended for active immunologic prophylaxis. They include deactivated toxins. Anatoxin toxoids are distinct from anatoxins that are tropanes found in cyanobacteria. Vaccination vaccines ( DTaP DTaP Combined vaccines consisting of diphtheria toxoid; tetanus toxoid; and an acellular form of pertussis vaccine. At least five different purified antigens of b. Pertussis have been used in various combinations in these vaccines. Bordetella, DT, Td, Tdap vaccine Vaccine Suspensions of killed or attenuated microorganisms (bacteria, viruses, fungi, protozoa), antigenic proteins, synthetic constructs, or other bio-molecular derivatives, administered for the prevention, amelioration, or treatment of infectious and other diseases. Vaccination) given according to age group and schedule:
    • DTaP DTaP Combined vaccines consisting of diphtheria toxoid; tetanus toxoid; and an acellular form of pertussis vaccine. At least five different purified antigens of b. Pertussis have been used in various combinations in these vaccines. Bordetella: protection against diphtheria Diphtheria Diphtheria is an infectious disease caused by Corynebacterium diphtheriae that most often results in respiratory disease with membranous inflammation of the pharynx, sore throat, fever, swollen glands, and weakness. The hallmark sign is a sheet of thick, gray material covering the back of the throat. Diphtheria, tetanus Tetanus Tetanus is a bacterial infection caused by Clostridium tetani, a gram-positive obligate anaerobic bacterium commonly found in soil that enters the body through a contaminated wound. C. tetani produces a neurotoxin that blocks the release of inhibitory neurotransmitters and causes prolonged tonic muscle contractions. Tetanus, and pertussis Pertussis Pertussis, or whooping cough, is a potentially life-threatening highly contagious bacterial infection of the respiratory tract caused by Bordetella pertussis. The disease has 3 clinical stages, the second and third of which are characterized by an intense paroxysmal cough, an inspiratory whoop, and post-tussive vomiting. Pertussis (Whooping Cough) ( whooping cough Whooping cough Pertussis, or whooping cough, is a potentially life-threatening highly contagious bacterial infection of the respiratory tract caused by Bordetella pertussis. The disease has 3 clinical stages, the second and third of which are characterized by an intense paroxysmal cough, an inspiratory whoop, and post-tussive vomiting. Pertussis (Whooping Cough))
    • DT: protection against diphtheria Diphtheria Diphtheria is an infectious disease caused by Corynebacterium diphtheriae that most often results in respiratory disease with membranous inflammation of the pharynx, sore throat, fever, swollen glands, and weakness. The hallmark sign is a sheet of thick, gray material covering the back of the throat. Diphtheria and tetanus Tetanus Tetanus is a bacterial infection caused by Clostridium tetani, a gram-positive obligate anaerobic bacterium commonly found in soil that enters the body through a contaminated wound. C. tetani produces a neurotoxin that blocks the release of inhibitory neurotransmitters and causes prolonged tonic muscle contractions. Tetanus (given to those with adverse reactions to the acellular pertussis Pertussis Pertussis, or whooping cough, is a potentially life-threatening highly contagious bacterial infection of the respiratory tract caused by Bordetella pertussis. The disease has 3 clinical stages, the second and third of which are characterized by an intense paroxysmal cough, an inspiratory whoop, and post-tussive vomiting. Pertussis (Whooping Cough) incorporated vaccine Vaccine Suspensions of killed or attenuated microorganisms (bacteria, viruses, fungi, protozoa), antigenic proteins, synthetic constructs, or other bio-molecular derivatives, administered for the prevention, amelioration, or treatment of infectious and other diseases. Vaccination)
    • Tdap: protection against tetanus Tetanus Tetanus is a bacterial infection caused by Clostridium tetani, a gram-positive obligate anaerobic bacterium commonly found in soil that enters the body through a contaminated wound. C. tetani produces a neurotoxin that blocks the release of inhibitory neurotransmitters and causes prolonged tonic muscle contractions. Tetanus, diphtheria Diphtheria Diphtheria is an infectious disease caused by Corynebacterium diphtheriae that most often results in respiratory disease with membranous inflammation of the pharynx, sore throat, fever, swollen glands, and weakness. The hallmark sign is a sheet of thick, gray material covering the back of the throat. Diphtheria, and pertussis Pertussis Pertussis, or whooping cough, is a potentially life-threatening highly contagious bacterial infection of the respiratory tract caused by Bordetella pertussis. The disease has 3 clinical stages, the second and third of which are characterized by an intense paroxysmal cough, an inspiratory whoop, and post-tussive vomiting. Pertussis (Whooping Cough)
    • Td: protection against tetanus Tetanus Tetanus is a bacterial infection caused by Clostridium tetani, a gram-positive obligate anaerobic bacterium commonly found in soil that enters the body through a contaminated wound. C. tetani produces a neurotoxin that blocks the release of inhibitory neurotransmitters and causes prolonged tonic muscle contractions. Tetanus and diphtheria Diphtheria Diphtheria is an infectious disease caused by Corynebacterium diphtheriae that most often results in respiratory disease with membranous inflammation of the pharynx, sore throat, fever, swollen glands, and weakness. The hallmark sign is a sheet of thick, gray material covering the back of the throat. Diphtheria
  • Age-group vaccinations:
    • Children younger than 7 years of age: DTaP DTaP Combined vaccines consisting of diphtheria toxoid; tetanus toxoid; and an acellular form of pertussis vaccine. At least five different purified antigens of b. Pertussis have been used in various combinations in these vaccines. Bordetella or DT
    • Older children and adults: Tdap and Td
  • Booster every 10 years
Diphtheria-vax-recs

CDC recommendations regarding diphtheria vaccinations for all age groups.

Image: “This graphic highlights CDC’s diphtheria vaccination recommendations for young children, preteens, and adults.” by CDC. License: Public Domain

Complications

  • The most common complication involves the respiratory system, with severe cases causing airway Airway ABCDE Assessment obstruction that requires mechanical ventilation Ventilation The total volume of gas inspired or expired per unit of time, usually measured in liters per minute. Ventilation: Mechanics of Breathing.[2–5,10]
  • The rest of the complications occur in the following order:
  • Cardiac involvement carries the highest mortality Mortality All deaths reported in a given population. Measures of Health Status rate.
  • Death rate is 5%–10%, with the highest rate noted in those < 5 years or > 40 years of age.

Differential Diagnosis

The differential diagnosis of respiratory diphtheria Diphtheria Diphtheria is an infectious disease caused by Corynebacterium diphtheriae that most often results in respiratory disease with membranous inflammation of the pharynx, sore throat, fever, swollen glands, and weakness. The hallmark sign is a sheet of thick, gray material covering the back of the throat. Diphtheria includes:

  • Infectious mononucleosis Mononucleosis Infectious mononucleosis (IM), also known as “the kissing disease,” is a highly contagious viral infection caused by the Epstein-Barr virus. Its common name is derived from its main method of transmission: the spread of infected saliva via kissing. Clinical manifestations of IM include fever, tonsillar pharyngitis, and lymphadenopathy. Mononucleosis: a highly contagious viral infection most commonly caused by the Epstein-Barr virus Epstein-Barr Virus Epstein-Barr virus (EBV) is a linear, double-stranded DNA virus belonging to the Herpesviridae family. This highly prevalent virus is mostly transmitted through contact with oropharyngeal secretions from an infected individual. The virus can infect epithelial cells and B lymphocytes, where it can undergo lytic replication or latency. Epstein-Barr Virus. Clinical manifestations include fever Fever Fever is defined as a measured body temperature of at least 38°C (100.4°F). Fever is caused by circulating endogenous and/or exogenous pyrogens that increase levels of prostaglandin E2 in the hypothalamus. Fever is commonly associated with chills, rigors, sweating, and flushing of the skin. Fever, tonsillar pharyngitis Pharyngitis Pharyngitis is an inflammation of the back of the throat (pharynx). Pharyngitis is usually caused by an upper respiratory tract infection, which is viral in most cases. It typically results in a sore throat and fever. Other symptoms may include a runny nose, cough, headache, and hoarseness. Pharyngitis, and lymphadenopathy Lymphadenopathy Lymphadenopathy is lymph node enlargement (> 1 cm) and is benign and self-limited in most patients. Etiologies include malignancy, infection, and autoimmune disorders, as well as iatrogenic causes such as the use of certain medications. Generalized lymphadenopathy often indicates underlying systemic disease. Lymphadenopathy. Diagnosis is clinical and confirmed through heterophile antibody testing.
  • Group A streptococcal tonsillopharyngitis: an infection of the pharynx Pharynx The pharynx is a component of the digestive system that lies posterior to the nasal cavity, oral cavity, and larynx. The pharynx can be divided into the oropharynx, nasopharynx, and laryngopharynx. Pharyngeal muscles play an integral role in vital processes such as breathing, swallowing, and speaking. Pharynx: Anatomy caused by group A streptococci. Clinical manifestations of streptococcal pharyngitis Streptococcal Pharyngitis Rheumatic Fever include the absence of cough, the presence of tonsillar exudates, fever Fever Fever is defined as a measured body temperature of at least 38°C (100.4°F). Fever is caused by circulating endogenous and/or exogenous pyrogens that increase levels of prostaglandin E2 in the hypothalamus. Fever is commonly associated with chills, rigors, sweating, and flushing of the skin. Fever, and tender anterior cervical adenopathy. Diagnosis is confirmed via a rapid antigen detection Antigen detection Respiratory Syncytial Virus test or culture.
  • Epiglottitis Epiglottitis Epiglottitis (or “supraglottitis”) is an inflammation of the epiglottis and adjacent supraglottic structures. The majority of cases are caused by bacterial infection. Symptoms are rapid in onset and severe. Epiglottitis: inflammation Inflammation Inflammation is a complex set of responses to infection and injury involving leukocytes as the principal cellular mediators in the body’s defense against pathogenic organisms. Inflammation is also seen as a response to tissue injury in the process of wound healing. The 5 cardinal signs of inflammation are pain, heat, redness, swelling, and loss of function. Inflammation of the epiglottis Epiglottis A thin leaf-shaped cartilage that is covered with laryngeal mucosa and situated posterior to the root of the tongue and hyoid bone. During swallowing, the epiglottis folds back over the larynx inlet thus prevents foods from entering the airway. Larynx: Anatomy and surrounding structures, most commonly caused by bacteria Bacteria Bacteria are prokaryotic single-celled microorganisms that are metabolically active and divide by binary fission. Some of these organisms play a significant role in the pathogenesis of diseases. Bacteriology. Symptoms are rapid in onset, severe, and include fever Fever Fever is defined as a measured body temperature of at least 38°C (100.4°F). Fever is caused by circulating endogenous and/or exogenous pyrogens that increase levels of prostaglandin E2 in the hypothalamus. Fever is commonly associated with chills, rigors, sweating, and flushing of the skin. Fever, sore throat Sore throat Pharyngitis is an inflammation of the back of the throat (pharynx). Pharyngitis is usually caused by an upper respiratory tract infection, which is viral in most cases. It typically results in a sore throat and fever. Other symptoms may include a runny nose, cough, headache, and hoarseness. Pharyngitis, dysphagia Dysphagia Dysphagia is the subjective sensation of difficulty swallowing. Symptoms can range from a complete inability to swallow, to the sensation of solids or liquids becoming “stuck.” Dysphagia is classified as either oropharyngeal or esophageal, with esophageal dysphagia having 2 sub-types: functional and mechanical. Dysphagia, drooling Drooling Peritonsillar Abscess, and respiratory distress. Diagnosis is mainly clinical but can be confirmed by pharyngoscopy. 
  • Viral pharyngitis Pharyngitis Pharyngitis is an inflammation of the back of the throat (pharynx). Pharyngitis is usually caused by an upper respiratory tract infection, which is viral in most cases. It typically results in a sore throat and fever. Other symptoms may include a runny nose, cough, headache, and hoarseness. Pharyngitis: inflammation Inflammation Inflammation is a complex set of responses to infection and injury involving leukocytes as the principal cellular mediators in the body’s defense against pathogenic organisms. Inflammation is also seen as a response to tissue injury in the process of wound healing. The 5 cardinal signs of inflammation are pain, heat, redness, swelling, and loss of function. Inflammation and infection of the pharynx Pharynx The pharynx is a component of the digestive system that lies posterior to the nasal cavity, oral cavity, and larynx. The pharynx can be divided into the oropharynx, nasopharynx, and laryngopharynx. Pharyngeal muscles play an integral role in vital processes such as breathing, swallowing, and speaking. Pharynx: Anatomy and surrounding structures most commonly caused by a virus Virus Viruses are infectious, obligate intracellular parasites composed of a nucleic acid core surrounded by a protein capsid. Viruses can be either naked (non-enveloped) or enveloped. The classification of viruses is complex and based on many factors, including type and structure of the nucleoid and capsid, the presence of an envelope, the replication cycle, and the host range. Virology. Common etiologies include:
    • Adenovirus Adenovirus Adenovirus (member of the family Adenoviridae) is a nonenveloped, double-stranded DNA virus. Adenovirus is transmitted in a variety of ways, and it can have various presentations based on the site of entry. Presentation can include febrile pharyngitis, conjunctivitis, acute respiratory disease, atypical pneumonia, and gastroenteritis. Adenovirus
    • Coxsackie A virus Virus Viruses are infectious, obligate intracellular parasites composed of a nucleic acid core surrounded by a protein capsid. Viruses can be either naked (non-enveloped) or enveloped. The classification of viruses is complex and based on many factors, including type and structure of the nucleoid and capsid, the presence of an envelope, the replication cycle, and the host range. Virology
    • Orthomyxoviridae Orthomyxoviridae A family of RNA viruses causing influenza and other diseases. There are five recognized genera: influenzavirus a; influenzavirus b; influenzavirus c; isavirus; and thogotovirus. Influenza Viruses/Influenza
    • Epstein-Barr virus Epstein-Barr Virus Epstein-Barr virus (EBV) is a linear, double-stranded DNA virus belonging to the Herpesviridae family. This highly prevalent virus is mostly transmitted through contact with oropharyngeal secretions from an infected individual. The virus can infect epithelial cells and B lymphocytes, where it can undergo lytic replication or latency. Epstein-Barr Virus
    • Herpes simplex Herpes Simplex A group of acute infections caused by herpes simplex virus type 1 or type 2 that is characterized by the development of one or more small fluid-filled vesicles with a raised erythematous base on the skin or mucous membrane. It occurs as a primary infection or recurs due to a reactivation of a latent infection. Congenital TORCH Infections virus Virus Viruses are infectious, obligate intracellular parasites composed of a nucleic acid core surrounded by a protein capsid. Viruses can be either naked (non-enveloped) or enveloped. The classification of viruses is complex and based on many factors, including type and structure of the nucleoid and capsid, the presence of an envelope, the replication cycle, and the host range. Virology
    • Measles Measles Measles (also known as rubeola) is caused by a single-stranded, linear, negative-sense RNA virus of the family Paramyxoviridae. It is highly contagious and spreads by respiratory droplets or direct-contact transmission from an infected person. Typically a disease of childhood, measles classically starts with cough, coryza, and conjunctivitis, followed by a maculopapular rash. Measles Virus virus Virus Viruses are infectious, obligate intracellular parasites composed of a nucleic acid core surrounded by a protein capsid. Viruses can be either naked (non-enveloped) or enveloped. The classification of viruses is complex and based on many factors, including type and structure of the nucleoid and capsid, the presence of an envelope, the replication cycle, and the host range. Virology
    • Rhinovirus Rhinovirus Rhinovirus is an acid-labile, positive-sense RNA virus of the Picornavirus family. The virus, which causes the common cold, is most often acquired through the airway via the inhalation of aerosols containing rhinovirus and fomites. Rhinovirus
    • Coronavirus Coronavirus Coronaviruses are a group of related viruses that contain positive-sense, single-stranded RNA. Coronavirus derives its name from “κορώνη korṓnē” in Greek, which translates as “crown,” after the small club-shaped proteins visible as a ring around the viral envelope in electron micrographs. Coronavirus
    • Respiratory syncytial virus Respiratory Syncytial Virus Respiratory syncytial virus (RSV) is an enveloped, single-stranded, linear, negative-sense RNA virus of the family Paramyxoviridae and the genus Orthopneumovirus. Two subtypes (A and B) are present in outbreaks, but type A causes more severe disease. Respiratory syncytial virus causes infections of the lungs and respiratory tract. Respiratory Syncytial Virus
    • Parainfluenza virus Parainfluenza virus Human parainfluenza viruses (HPIVs) are single-stranded, linear, negative-sense RNA viruses of the family Paramyxoviridae and the genus Paramyxovirus. Human parainfluenza viruses are the 2nd most common cause of lower respiratory disease in children, after the respiratory syncytial virus. Parainfluenza Virus
  • Vincent’s angina: an infection of the gums commonly caused by Bacillus Bacillus Bacillus are aerobic, spore-forming, gram-positive bacilli. Two pathogenic species are Bacillus anthracis (B. anthracis) and B. cereus. Bacillus and Borrelia Borrelia Borrelia are gram-negative microaerophilic spirochetes. Owing to their small size, they are not easily seen on Gram stain but can be visualized using dark-field microscopy, Giemsa, or Wright stain. Spirochetes are motile and move in a characteristic spinning fashion due to axial filaments in the periplasmic space. Borrelia bacteria Bacteria Bacteria are prokaryotic single-celled microorganisms that are metabolically active and divide by binary fission. Some of these organisms play a significant role in the pathogenesis of diseases. Bacteriology. Clinical manifestations include acute onset of painful, bleeding gums, blunting of interdental papillae Papillae Lips and Tongue: Anatomy, and an ulcerative necrotic slough of the gingiva. Also referred to as acute necrotizing ulcerative gingivitis Gingivitis Inflammation of gum tissue (gingiva) without loss of connective tissue. Chédiak-Higashi Syndrome.
  • Oral candidiasis Candidiasis Candida is a genus of dimorphic, opportunistic fungi. Candida albicans is part of the normal human flora and is the most common cause of candidiasis. The clinical presentation varies and can include localized mucocutaneous infections (e.g., oropharyngeal, esophageal, intertriginous, and vulvovaginal candidiasis) and invasive disease (e.g., candidemia, intraabdominal abscess, pericarditis, and meningitis). Candida/Candidiasis: an overgrowth of Candida Candida Candida is a genus of dimorphic, opportunistic fungi. Candida albicans is part of the normal human flora and is the most common cause of candidiasis. The clinical presentation varies and can include localized mucocutaneous infections (e.g., oropharyngeal, esophageal, intertriginous, and vulvovaginal candidiasis) and invasive disease (e.g., candidemia, intraabdominal abscess, pericarditis, and meningitis). Candida/Candidiasis in the oropharynx Oropharynx The middle portion of the pharynx that lies posterior to the mouth, inferior to the soft palate, and superior to the base of the tongue and epiglottis. It has a digestive function as food passes from the mouth into the oropharynx before entering esophagus. Pharynx: Anatomy in typically immunocompromised immunocompromised A human or animal whose immunologic mechanism is deficient because of an immunodeficiency disorder or other disease or as the result of the administration of immunosuppressive drugs or radiation. Gastroenteritis patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship. Clinical manifestations include white plaques on the buccal mucosa Buccal mucosa Oral Cancer, palate Palate The palate is the structure that forms the roof of the mouth and floor of the nasal cavity. This structure is divided into soft and hard palates. Palate: Anatomy, tongue Tongue The tongue, on the other hand, is a complex muscular structure that permits tasting and facilitates the process of mastication and communication. The blood supply of the tongue originates from the external carotid artery, and the innervation is through cranial nerves. Lips and Tongue: Anatomy, or oropharynx Oropharynx The middle portion of the pharynx that lies posterior to the mouth, inferior to the soft palate, and superior to the base of the tongue and epiglottis. It has a digestive function as food passes from the mouth into the oropharynx before entering esophagus. Pharynx: Anatomy. Diagnosis is confirmed by Gram stain Gram stain Klebsiella or potassium Potassium An element in the alkali group of metals with an atomic symbol k, atomic number 19, and atomic weight 39. 10. It is the chief cation in the intracellular fluid of muscle and other cells. Potassium ion is a strong electrolyte that plays a significant role in the regulation of fluid volume and maintenance of the water-electrolyte balance. Hyperkalemia hydroxide preparation showing budding Budding Mycology yeast Yeast A general term for single-celled rounded fungi that reproduce by budding. Brewers’ and bakers’ yeasts are saccharomyces cerevisiae; therapeutic dried yeast is yeast, dried. Mycology.

References

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  2. Centers for Disease Control and Prevention. (2020). Diphtheria. Retrieved July 8, 2022, from https://www.cdc.gov/diphtheria/clinicians.html
  3. Corynebacterium, listeria, and bacillus. (2022). Chapter 26 of Ryan, K.J. (Ed.), Sherris & Ryan’s Medical Microbiology, 8th ed. McGraw-Hill. https://accessmedicine.mhmedical.com/content.aspx?bookid=3107&sectionid=260926758
  4. Barroso, L., Pegram, S. (2020). Clinical manifestations, diagnosis and treatment of diphtheria. UpToDate. Retrieved June 23, 2022, from https://www.uptodate.com/contents/clinical-manifestations-diagnosis-and-treatment-of-diphtheria
  5. Riedel, S., Hobden J.A., Miller, S., et al. (Eds.). (2019). Aerobic non–spore-forming gram-positive bacilli: corynebacterium, listeria, erysipelothrix, nocardia, and related pathogens. In Jawetz, Melnick, & Adelberg’s medical microbiology, 28th ed. McGraw-Hill. https://accessmedicine.mhmedical.com/content.aspx?bookid=2629&sectionid=217770586
  6. Engler, K.H., Efstratiou, A., Norn, D., et al. (2002). Immunochromatographic strip test for rapid detection of diphtheria toxin: description and multicenter evaluation in areas of low and high prevalence of diphtheria. Journal of Clinical Microbiology 40(1):80–83. https://doi.org/10.1128/JCM.40.1.80-83.2002
  7. World Health Organization. (2021). WHO laboratory manual for the diagnosis of diphtheria and other related infections. https://apps.who.int/iris/handle/10665/352275 
  8. UK Health Security Agency. (2022). Diphtheria anti-toxin: clinical guidance. Retrieved June 23, 2022, from https://www.gov.uk/government/publications/immunoglobulin-when-to-use/diphtheria-anti-toxin-clinical-guidance-issued-may-2022
  9. World Health Organization. (1994). Diphtheria: manual for the management and control of diphtheria in the European region. Retrieved June 23, 2022, from https://apps.who.int/iris/bitstream/handle/10665/108107/ICP_EPI_038_%28B%29.pdf?sequence=1&isAllowed=y
  10. Jain, A., Samdani, S., Meena, V., Sharma, M.P. (2016). Diphtheria: It is still prevalent!!! Int J Pediatr Otorhinolaryngol 86:68–71. doi: 10.1016/j.ijporl.2016.04.024. Epub 2016 Apr 21. PMID: 27260583. https://www.sciencedirect.com/science/article/abs/pii/S0165587616300684?via%3Dihub
  11. UK Health Security Agency. (2022). Public health control and management of diphtheria in England. Retrieved July 10, 2022, from https://assets.publishing.service.gov.uk/government/uploads/system/uploads/attachment_data/file/1083946/Diphtheria-guidelines-2022-v16.1.pdf

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