Materiały źródłowe

• #1 Diphtheria – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK560911/

  Diphtheria is a toxin-mediated infection primarily caused by Corynebacterium diphtheriae, a member of the Corynebacterium species. […] The clinical manifestations of C diphtheriae infection are diverse and depend on factors such as the anatomical site of infection, the immune status of the host, and the production and systemic distribution of toxins. […] This comprehensive activity provides an in-depth exploration of diphtheria, covering its epidemiology, pathogenesis, clinical features, diagnosis, and management. […] Timely diagnosis plays a pivotal role in achieving favorable clinical outcomes, as initiating antitoxin therapy and appropriate antibiotics early on can significantly impact patient prognosis. […] Diagnosis involves isolating the organism, culturing it, and monitoring toxin production.

• #1 Clinical Guidance for Diphtheria | Diphtheria | CDC

  https://www.cdc.gov/diphtheria/hcp/clinical-guidance/index.html

  Healthcare providers most often diagnose diphtheria based on clinical presentation. […] Preliminary diagnosis is usually made on the basis of clinical presentation. It’s imperative to begin presumptive therapy quickly before confirmatory test results are available. […] Testing begins with culturing the site where diphtheria is suspected (e.g., a pharyngeal or skin wound culture). Collect bacterial culture specimens prior to antibiotic treatment, if possible. […] If C. diphtheriae are identified, further testing is needed to determine whether the strain is toxigenic.

• #1 Clinical manifestations, diagnosis, and treatment of diphtheria – UpToDate

  https://www.uptodate.com/contents/clinical-manifestations-diagnosis-and-treatment-of-diphtheria

  Clinical manifestations, diagnosis, and treatment of diphtheria […] The clinical manifestations, diagnosis, and treatment of diphtheria will be reviewed here. […] DIAGNOSIS […] Approach to diagnosis […] Diagnostic tests […] Culture […] Toxin detection […] Infection with C. diphtheriae typically presents as respiratory or cutaneous disease. […] Respiratory diphtheria is typically caused by toxin-producing strains of C. diphtheriae; rarely, it is caused by toxigenic strains of other Corynebacterium species (C. ulcerans, C. hemolyticum, or C. pseudotuberculosis). […] Symptoms typically begin two to five days after infection. […] The onset of symptoms is typically gradual; the most common presenting symptoms are sore throat, malaise, cervical lymphadenopathy, and low-grade fever.

• #1 Diphtheria – Diagnosis & treatment – Mayo Clinic

  https://www.mayoclinic.org/diseases-conditions/diphtheria/diagnosis-treatment/drc-20351903

  Doctors may suspect diphtheria in a sick child who has a sore throat with a gray membrane covering the tonsils and throat. Growth of C. diphtheriae in a lab culture of material from the throat membrane confirms the diagnosis. Doctors can also take a tissue sample from an infected wound and have it tested in a lab to check for the type of diphtheria that affects the skin (cutaneous diphtheria). […] If a doctor suspects diphtheria, treatment begins immediately, even before the results of bacterial tests are available.

• #1 Clinical manifestations, diagnosis, and treatment of diphtheria – UpToDate

  https://www.uptodate.com/contents/clinical-manifestations-diagnosis-and-treatment-of-diphtheria/print

  The onset of symptoms is typically gradual; the most common presenting symptoms are sore throat, malaise, cervical lymphadenopathy, and low-grade fever. The earliest pharyngeal finding is mild erythema, which can progress to isolated spots of gray and white exudate. In at least one-third of cases, local elaboration of toxin induces the formation of a coalescing pseudomembrane (composed of necrotic fibrin, leukocytes, erythrocytes, epithelial cells, and organisms). This membrane adheres tightly to the underlying tissue and bleeds with scraping.

• #1 Diphtheria – Infectious Disease Advisor

  https://www.infectiousdiseaseadvisor.com/ddi/diphtheria/

  Diphtheria is a potentially fatal disease caused by infection with toxin-producing strains of Corynebacterium diphtheriae, a Gram-positive bacillus. […] Although vaccines offer effective protection against diphtheria and vaccination rates in the United States are high, clinicians need to be aware of the symptoms, diagnosis, and treatment of diphtheria. […] Patients typically present with symptoms 2 to 5 days following C diphtheria infection, although the incubation period can range from 1 to 10 days. […] Diphtheria infection can be confirmed by culture to identify the bacterial species and by the Elek test to confirm the presence of the diphtheria toxoid. […] If a diphtheria diagnosis is confirmed, it must be reported to the CDC. […] According to the CDC, clinicians should not wait for laboratory results before beginning treatment for diphtheria; they should immediately begin antibiotic therapy and administer diphtheria antitoxin (DAT) as soon as possible.

• #1 Clinical manifestations, diagnosis, and treatment of diphtheria – UpToDate

  https://www.uptodate.com/contents/clinical-manifestations-diagnosis-and-treatment-of-diphtheria

  The earliest pharyngeal finding is mild erythema, which can progress to isolated spots of gray and white exudate. […] In at least one-third of cases, local elaboration of toxin induces the formation of a coalescing pseudomembrane (composed of necrotic fibrin, leukocytes, erythrocytes, epithelial cells, and organisms).

• #1

  https://www.who.int/news-room/questions-and-answers/item/diphtheria

  How is diphtheria diagnosed? Clinical diagnosis of diphtheria usually relies on the presence of a greyish membrane covering the throat. Although laboratory investigation of suspected cases is recommended for case confirmation, treatment should be started immediately. […] Diphtheria infection is treated with the administration of a diphtheria antitoxin, administered intravenously or through an intramuscular injection. Antibiotics are also given to eliminate the bacteria and stop toxin production, and to prevent transmission to others.

• #1 Laboratory Testing for Diphtheria | Diphtheria | CDC

  https://www.cdc.gov/diphtheria/php/laboratories/index.html

  Clinical laboratories can use various methods to identify Corynebacterium diphtheriae, but identification alone isn’t enough for diagnosis confirmation. […] CDC uses culture and molecular methods, and a specialized toxin production test to confirm diphtheria diagnoses. […] Confirmatory testing informs clinical management and public health action to prevent further spread. […] Laboratories must follow a series of steps in order to confirm a diphtheria diagnosis: Identifying and isolating C. diphtheriae, Detecting the diphtheria toxin (tox) gene, Showing toxin production. […] Therefore, tests that identify C. diphtheriae or detect the tox gene but don’t confirm toxin production are insufficient to confirm a diphtheria diagnosis. […] Confirmation of toxin production must be conducted via the Elek test. […] Currently, CDC is the only laboratory in the United States that performs the Elek test. […] State and local public health laboratories should submit C. diphtheriae specimens or isolates to CDC for confirmatory testing. This helps ensure appropriate public health action can be taken.

• #1 Diphtheria – Infectious Diseases – Merck Manual Professional Edition

  https://www.merckmanuals.com/professional/infectious-diseases/gram-positive-bacilli/diphtheria

  The laboratory should be notified that C. diphtheriae is suspected, so that special culture media (Loeffler or Tindale) can be used. […] In vitro testing for toxin production (modified Elek test) is done to differentiate toxigenic from nontoxigenic strains. […] Cutaneous diphtheria should be considered when a patient develops skin lesions during an outbreak of respiratory diphtheria. […] Swab or biopsy specimens should be cultured. […] ECG should be done to look for ST-T wave changes, QTc prolongation, and/or 1st-degree heart block related to myocarditis, which often becomes evident as the respiratory symptoms resolve. […] Treat with diphtheria antitoxin and penicillin or erythromycin; document cure by culture.

• #1 Diphtheria – Infectious Diseases – Merck Manual Professional Edition

  https://www.merckmanuals.com/professional/infectious-diseases/gram-positive-bacilli/diphtheria

  Diphtheria is an acute pharyngeal or cutaneous infection caused mainly by toxigenic strains of the gram-positive bacillus Corynebacterium diphtheriae and rarely by other, less common Corynebacterium species. […] Diagnosis is clinical and confirmed by culture. […] Pharyngeal diphtheria needs to be considered in patients with nonspecific findings of pharyngitis, cervical adenopathy, and low-grade fever if they also have systemic toxicity plus hoarseness, palatal paralysis, or stridor. The appearance of the characteristic membrane suggests the diagnosis. […] Gram stain of a specimen from the membrane may reveal gram-positive bacilli with metachromatic (beaded) staining in typical Chinese-character configuration, with club-shaped swelling at one or both ends. […] Material for culture should be obtained from below the membrane, or a portion of the membrane itself should be submitted.

• #1 Diphtheria Workup: Laboratory Studies, Imaging Studies, Other Tests

  https://emedicine.medscape.com/article/782051-workup

  To establish the diagnosis of C diphtheriae, it is vital to both isolate C diphtheriae in culture media and to identify the presence of toxin production. […] Obtain throat and pharyngeal swabs from all close contacts. […] Toxigenicity testing is aimed at determining the presence of toxin production. […] Elek test detects the development of an immunoprecipitin band on a filter paper impregnated with antitoxin and then is laid over an agar culture of the organism being tested. […] Polymerase chain reaction (PCR) assays for detection of DNA sequence encoding the A subunit of tox+ strain are both rapid and sensitive. […] Once diphtheria infection has been established, the Centers for Disease Control and Prevention (CDC) should be contacted, and further testing may be requested. […] Serum antibodies to diphtheria toxin prior to administration of antitoxin: Low levels cannot exclude the possibility of the disease; high levels may protect against severe illness (concentrations of 0.1 to 0.01 IU are thought to confer protection). […] Chest radiograph and soft tissue neck radiography/CT or ultrasonography may show prevertebral soft tissue swelling, enlarged epiglottis, and narrowing of the subglottic region. […] ECG may show ST-T wave changes, variable heart block, and dysrhythmia.

• #1 Challenges of Diphtheria Toxin Detection

  https://www.mdpi.com/2072-6651/16/6/245

  The detection of the toxin is the most important test in the microbiological diagnosis of diphtheria. […] The WHO Manual for the Laboratory Diagnosis of Diphtheria from 1994 mentioned the in vivo subcutaneous test for virulence in guinea pigs as the most reliable method for detection of DT production, but it did not recommend it for inexperienced laboratory staff. […] The current WHO laboratory manual for the diagnosis of diphtheria and other related infections, published in 2021, does not mention in vivo toxin testing due to the availability of an alternative test (reducing animal suffering) such as the Elek test. […] The Elek test (and the modified Elek test) is recommended as the “gold standard” in diphtheria diagnostics. […] Currently, the Elek test is still the basic recommended diagnostic test, enabling the detection of the main pathogenicity factor of C. diphtheriae, which is a highly potent toxin.

• #1 Diphtheria differential diagnosis – wikidoc

  https://www.wikidoc.org/index.php/Diphtheria_differential_diagnosis

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

• #1 Diphtheria Antitoxoid | Test Detail | Quest Diagnostics

  https://testdirectory.questdiagnostics.com/test/test-detail/4865/diphtheria-antitoxoid?p=r&cc=MASTER

  Diphtheria Antitoxoid – Used to evaluate diphtheria immunization response. Antibody levels of ≥0.10 IU/mL are considered protective. For Pre and Post vaccination testing to assess normal immune response, please refer to test code 10680-Diphtheria Antitoxoid, Pre and Post Vaccination. […] Antibody levels ≥0.10 are considered protective. After a primary series of three properly spaced diphtheria toxoid doses in adults or four doses in infants, a protective level of antitoxin (defined as ≥0.10 IU of antitoxin/mL) is reached in more than 95% of immunized persons.

• #1 Diphtheria – Serology | Public Health Ontario

  https://www.publichealthontario.ca/en/Laboratory-Services/Test-Information-Index/Diphtheria-Serology

  Testing for Diphtheria is not done for immunity/acute diagnosis/pre-vaccination screening and is only available only for the rare event of an adverse reaction to Diphtheria vaccine or the possibility of humoral immunodeficiency in the patient. This must be indicated on the test requisition in order for testing to be performed. […] Indicate on the General Test Requisition Form if testing is required due adverse reaction to Diphtheria vaccine, or humoral immunodeficiency in the patient. This must be indicated on the test requisition in order for testing to be performed. […] The results may be used to aid diagnosis of immunodeficiency. Results must be confirmed by clinical findings and other serological tests. […] The results obtained from this assay are not diagnostic proof of protection/immunity against Diphtheria or the presence/absence of immunodeficiency. […] Diphtheria serology testing is performed once per month. […] Turnaround time is up to 28 days from receipt by PHO laboratory. […] Diphtheria serology testing for Anti-Diphtheria Toxoid IgG is by the Enzyme Immunoassay (EIA) method.

• #1 Diphtheria | Nature Reviews Disease Primers

  https://www.nature.com/articles/s41572-019-0131-y

  Diphtheria is generally an acute respiratory infection, characterized by the formation of a pseudomembrane in the throat, but cutaneous infections are possible. […] Clinical diagnosis is confirmed by the isolation and identification of the causative Corynebacterium spp., usually by bacterial culture followed by enzymatic and toxin detection tests. […] The prevalence of toxigenic Corynebacterium spp. highlights the need for proper clinical and epidemiological investigations to quickly identify and treat affected individuals, along with public health measures to prevent and contain the spread of this disease. […] A modified Elek test for detection of toxigenic corynebacteria in the diagnostic laboratory. […] Rapid enzyme immunoassay for determination of toxigenicity among clinical isolates of corynebacteria.

• #1 Diphtheria | Nature Reviews Disease Primers

  https://www.nature.com/articles/s41572-019-0131-y

  Polymerase chain reaction for screening clinical isolates of corynebacteria for the production of diphtheria toxin. […] Identification and molecular discrimination of toxigenic and nontoxigenic diphtheria Corynebacterium strains by combined real-time polymerase chain reaction assays. […] Development, validation and implementation of a quadruplex real-time PCR assay for identification of potentially toxigenic corynebacteria. […] Counter immunoelectrophoresis for rapid testing of toxin producing Corynebacterium diphtheriae. […] Identification of toxinogenesis in Corynebacterium diphtheriae.

• #1 Challenges of Diphtheria Toxin Detection

  https://www.mdpi.com/2072-6651/16/6/245

  Therefore, a rapid, easy to interpret and modern method for the detection of DT-producing isolates is needed, especially considering that the availability of diphtheria antitoxin—which is a main cure and a necessary reagent for current diagnostics methods—is extremally limited. […] The very promising tools are ICS and LFIA for toxin detection, and isothermal amplification methods, such as LAMP, for the detection of tox gene. […] According to the definition for the purposes of epidemiological surveillance, a confirmed diagnosis of diphtheria requires meeting both clinical and laboratory criteria. The laboratory criterion includes the isolation of toxin-producing corynebacteria from clinical material. […] Due to the fact that PCR only allows for the detection of the gene encoding DT but does not provide information on the production of DT, it is necessary to perform the Elek test in all tox-positive isolates to confirm whether the strain is toxigenic.

• #1

  https://www.health.vic.gov.au/infectious-diseases/diphtheria

  Diphtheria is an urgent notifiable condition that must be notified immediately to the department by medical practitioners and pathology services. Exclusion periods apply to both cases and contacts. […] Diphtheria is an acute bacterial infection caused by toxigenic strains of Corynebacterium diphtheriae. […] Case management involves diphtheria antitoxin, antibiotic therapy and infection control. […] Diphtheria is an urgent notifiable condition and must be notified by medical practitioners and pathology services immediately by telephone upon initial diagnosis (presumptive or confirmed). Pathology services must follow up with written notification within 5 days. […] Diagnosis is usually based on observation of the classical greyish-white membrane overlying the tonsils or pharynx. […] Specimens for C. diphtheriae culture should be obtained from the nose and throat, and from any other suspicious lesions. Swabs should be obtained from the pharyngeal membrane, or a portion of the membrane itself could be submitted for culture.

• #1

  https://www.health.vic.gov.au/infectious-diseases/diphtheria

  Selective medium is required to culture C. diphtheriae, so the testing laboratory should be notified that the disease is clinically suspected. All isolates should be sent to a public health reference laboratory for C. diphtheriae toxin detection by polymerase chain reaction (PCR). […] Management of cases involves diphtheria antitoxin, antibiotic therapy and infection control. […] Diphtheria antitoxin should be given if there is strong clinical suspicion, immediately after specimens are taken and without waiting for laboratory confirmation. […] Parenteral antibiotic treatment is usually required initially, and can be either erythromycin or penicillin. These can be substituted with equivalent oral formulations once the patient can swallow comfortably. Antibiotics should be continued to complete a total of 14 days of treatment.

• #1 Diphtheria (for Parents) | Nemours KidsHealth

  https://kidshealth.org/en/parents/diphtheria.html

  Diphtheria is a bacterial infection. It spreads easily and happens quickly, and mainly affects the nose and throat. […] Children and adults with diphtheria are treated in a hospital. After a doctor confirms the diagnosis through a throat culture, the infected person gets a special anti-toxin, given through injections or an IV, to neutralize the diphtheria toxin already circulating in the body, plus antibiotics to kill the remaining diphtheria bacteria. […] When someone is diagnosed with diphtheria, the doctor will notify the local health department and treat everyone in the household who may have been exposed to the bacteria. Treatment includes throat cultures and booster doses of the diphtheria vaccine. They will also get antibiotics as a precaution.

• #1 Diphtheria – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK560911/

  In suspected cases of diphtheria, antitoxin should be administered urgently based on clinical judgment without waiting for laboratory confirmation. […] The antibiotics of choice for treating diphtheria are erythromycin or penicillin G. […] Early initiation of antibiotics is crucial to eliminate the organism promptly, limiting toxin release, expediting patient recovery, and preventing infection spread to close contacts. […] Distinguishing diphtheria from other upper respiratory tract infections with similar presentations is crucial. […] The prognosis of diphtheria is influenced by several factors. […] The primary complications of diphtheria often involve myocarditis and neuritis. […] Timely diagnosis is crucial, involving isolation, antitoxin therapy, and antibiotic treatment.

• #1 Diphtheria: Causes, Symptoms, Treatment & Prevention

  https://my.clevelandclinic.org/health/diseases/17870-diphtheria

  Diphtheria is a contagious infection caused by a bacterium called Corynebacterium diphtheriae. The bacterium releases a toxin that causes a buildup of grey tissue in your throat, leading to problems with swallowing and breathing. […] Diphtheria treatment begins immediately sometimes even before the lab test results are confirmed. Your healthcare provider will prescribe diphtheria antitoxin to stop damage to your organs. Theyll also prescribe antibiotics, typically penicillin or erythromycin, to fight infection. […] Your healthcare provider will make a diagnosis based on symptoms and a lab test. Theyll use a swab to take a sample from the back of your throat or from a sore. This swab then goes to a lab for diagnosis. […] Yes. When treated immediately, diphtheria is managed successfully with antitoxins and antibiotics. Vaccination can prevent diphtheria altogether.

• #1 Diphtheria | Diagnosis and Treatment | CDC

  http://medbox.iiab.me/modules/en-cdc/www.cdc.gov/diphtheria/about/diagnosis-treatment.html

  Getting treatment quickly for diphtheria is important. Doctors usually decide if a person has diphtheria by looking for common signs and symptoms. They can use a swab from the back of the throat and test it for the bacteria that cause diphtheria. A doctor can also take a sample from a skin lesion (like a sore) and try and grow the bacteria to be sure a patient has diphtheria. […] It is important to start treatment right away if a doctor suspects diphtheria and not to wait for laboratory confirmation. […] After the patient finishes taking the antibiotic, the doctor will run tests to make sure the bacteria are not in the patients body anymore.

• #1 Diphtheria: Background, Pathophysiology, Epidemiology

  https://emedicine.medscape.com/article/782051-overview

  The most widely quoted diphtheria mortality rate is 5-10%. It may reach higher than 20% in children younger than 5 years and adults older than 40 years. […] Historically, diphtheria has been primarily a disease of childhood, affecting populations younger than 12 years. […] Recently, however, diphtheria has shifted into the adolescent and adult population, most notably those in ages 40 and older accounting for most new cases. […] Immunization schedules have recently changed requiring a toxoid booster at age 11-12 and every 10 years thereafter.

• #1 Diphtheria | Queensland Health

  https://www.health.qld.gov.au/cdcg/index/diphtheria

  Classical respiratory diphtheria is a medical emergency for airway protection (while using PPE), urgent referral and consideration of DAT. Post-infection administration of Diphtheria antitoxin (DAT) reduces mortality by 76%. […] Antibiotics are required to eradicate the organism, stop further toxin production, and help prevent transmission. Antibiotics should be given immediately AFTER appropriate nose/throat and wound swabs are taken wherever possible. […] While antibiotics are necessary, diphtheria antitoxin (DAT) is considered the mainstay of preventing toxin related complications of respiratory disease. When indicated, DAT should be given promptly. […] Ascertain diphtheria vaccination status, referring to records if available. Patients should be vaccinated (with the age-appropriate formulation) in the convalescent phase of their disease as clinical infection may not induce adequate immunity.

• #1 Diphtheria | Queensland Health

  https://www.health.qld.gov.au/cdcg/index/diphtheria

  All contacts should be advised of the nature of the infection and its mode of transmission. Medium and high-risk contacts as defined in Appendix C should be advised to monitor for symptoms of diphtheria for 5 days from contact and seek medical advice promptly should symptoms appear. […] The most effective preventive measure is widespread vaccination with diphtheria toxoid. Other preventative measures include: maintaining high Australian childhood and adult vaccination coverage rates, including an emphasis on those at high risk, e.g. HCWs and travellers.

• #1

  https://www.health.vic.gov.au/infectious-diseases/diphtheria

  Use standard precautions with additional respiratory precautions for respiratory tract diphtheria, and standard precautions with additional contact precautions for cutaneous diphtheria, until the case is shown to be clear of carriage via two negative cultures taken at least 24 hours apart, collected at least 24 hours after completing antibiotics. The disease is usually not highly contagious after 48 hours of antibiotic therapy. […] Outbreaks of diphtheria require immunising the largest possible proportion of the population involved, emphasising the need for protection of infants and preschool children.

• #1 Diphtheria | Doctor

  https://patient.info/doctor/diphtheria-and-diphtheria-vaccination

  Diphtheria is a toxin-mediated bacterial acute upper respiratory tract infection, but sometimes it infects the skin. […] Definitive diagnosis of diphtheria requires a positive culture from respiratory tract secretions or cutaneous lesions, and a positive toxin assay. […] Diphtheria anti-toxin (produced from horse serum) should be considered urgently for probable and confirmed cases of toxinogenic diphtheria. […] Patients should be immunised in the convalescent stage because clinical infection does not always induce adequate levels of antitoxin. […] Diphtheria cases are mainly from Southeast Asia, South America, Africa and India. […] Maintaining high vaccination coverage is essential to prevent indigenous C. ulcerans and re-emergence of C. diphtheriae. […] Vaccination confers protection against disease by production of antibodies to the diphtheria toxin. […] Overall, there is a 5-10% mortality rate, but it is up to 20% in those younger than 5 years and older than 40 years.

• #1 Diphtheria – Infections – Merck Manual Consumer Version

  https://www.merckmanuals.com/home/infections/bacterial-infections-gram-positive-bacteria/diphtheria

  Diphtheria is caused by a bacterial infection that is now rare in countries where immunization is widespread. […] The diagnosis is based on symptoms, particularly a sore throat and the pseudomembrane, and the results of a culture. […] A doctor suspects diphtheria in a sick person who has a sore throat with a pseudomembrane, particularly if the roof of the mouth is paralyzed and if the person was not vaccinated. The diagnosis is confirmed by sending a sample of material from the person’s throat to a laboratory where bacteria can be grown (cultured). […] Doctors suspect skin diphtheria when people develop sores during an outbreak of respiratory diphtheria. To confirm the diagnosis, doctors take a sample from a sore and send it to a laboratory to be cultured.

• #1 Challenges of Diphtheria Toxin Detection

  https://www.mdpi.com/2072-6651/16/6/245

  Diagnostic laboratories are recommended to submit tox-positive isolates to the National Reference Laboratory to confirm the production DT with the Elek test. […] The challenges in the development of new test for DT detection include, among others, the following: (i) the test should be independent of the availability of diphtheria antitoxin; (ii) it should be easy-to-perform and the results should be easy-to-interpret so that local laboratories would be able to carry out the test even without any experience in diphtheria diagnostics; (iii) it should be rapid; (iv) it might be implemented as a point-of-care test, especially in cases when an outbreak is suspected; and (v) it should be easy to store and maintain activity for long time because diphtheria cases occur very rarely in some countries.

• #1 Challenges of Diphtheria Toxin Detection

  https://www.mdpi.com/2072-6651/16/6/245

  Diphtheria toxin (DT) is the main virulence factor of Corynebacterium diphtheriae, C. ulcerans and C. pseudotuberculosis. […] The detection of the toxin is the most important test in the microbiological diagnosis of diphtheria and other corynebacteria infections. […] Despite substantial progress in the science and diagnostics of infectious diseases, the Elek test is still the basic recommended diagnostic test for DT detection. […] The challenge here is the poor availability of an antitoxin and declining experience even in reference laboratories due to the low prevalence of diphtheria in developed countries. […] The detection of the DT is the most important test in the diagnosis of diphtheria. […] Below, we present various methods for DT detection described in the scientific literature.

• #1 Diagnosis and Epidemiology of Diphtheria | SpringerLink

  https://link.springer.com/protocol/10.1385/0-89603-498-4:191

  Prior to the late 1980s diphtheria was regarded in many countries as one of those rare and forgotten diseases associated with the preimmunization era of the 1940s. […] Despite the success of many immunization programs, there is still much to be learned about this disease that has made a dramatic return in the 1990s, particularly to countries of the former Soviet Union. […] Diphtheria is also endemic in other countries of the world. […] The increase in international travel, migration from Eastern Europe, and also the emergence of new strains of the causative organism, Corynebacterium diphtheriae, causing disease have emphasized the importance of both clinical and laboratory-awareness. […] In addition, current immunization programs within each country should be reviewed, particularly for adults, to ensure that population immunity is adequate to prevent the re-emergence of epidemic disease in the Western world.

• #2 Diphtheria – Infectious Disease Advisor

  https://www.infectiousdiseaseadvisor.com/ddi/diphtheria/

  Diphtheria is a potentially fatal disease caused by infection with toxin-producing strains of Corynebacterium diphtheriae, a Gram-positive bacillus. […] Although vaccines offer effective protection against diphtheria and vaccination rates in the United States are high, clinicians need to be aware of the symptoms, diagnosis, and treatment of diphtheria. […] Patients typically present with symptoms 2 to 5 days following C diphtheria infection, although the incubation period can range from 1 to 10 days. […] Diphtheria infection can be confirmed by culture to identify the bacterial species and by the Elek test to confirm the presence of the diphtheria toxoid. […] If a diphtheria diagnosis is confirmed, it must be reported to the CDC. […] According to the CDC, clinicians should not wait for laboratory results before beginning treatment for diphtheria; they should immediately begin antibiotic therapy and administer diphtheria antitoxin (DAT) as soon as possible.

• #2 Diphtheria – Infectious Diseases – Merck Manual Professional Edition

  https://www.merckmanuals.com/professional/infectious-diseases/gram-positive-bacilli/diphtheria

  Diphtheria is an acute pharyngeal or cutaneous infection caused mainly by toxigenic strains of the gram-positive bacillus Corynebacterium diphtheriae and rarely by other, less common Corynebacterium species. […] Diagnosis is clinical and confirmed by culture. […] Pharyngeal diphtheria needs to be considered in patients with nonspecific findings of pharyngitis, cervical adenopathy, and low-grade fever if they also have systemic toxicity plus hoarseness, palatal paralysis, or stridor. The appearance of the characteristic membrane suggests the diagnosis. […] Gram stain of a specimen from the membrane may reveal gram-positive bacilli with metachromatic (beaded) staining in typical Chinese-character configuration, with club-shaped swelling at one or both ends. […] Material for culture should be obtained from below the membrane, or a portion of the membrane itself should be submitted.

• #2 Clinical manifestations, diagnosis, and treatment of diphtheria – UpToDate

  https://www.uptodate.com/contents/clinical-manifestations-diagnosis-and-treatment-of-diphtheria/print

  The onset of symptoms is typically gradual; the most common presenting symptoms are sore throat, malaise, cervical lymphadenopathy, and low-grade fever. The earliest pharyngeal finding is mild erythema, which can progress to isolated spots of gray and white exudate. In at least one-third of cases, local elaboration of toxin induces the formation of a coalescing pseudomembrane (composed of necrotic fibrin, leukocytes, erythrocytes, epithelial cells, and organisms). This membrane adheres tightly to the underlying tissue and bleeds with scraping.

• #2 Azthena logo with the word Azthena

  https://www.news-medical.net/health/Diphtheria-Diagnosis.aspx

  Diphtheria is usually diagnosed based on a patients clinical presentation. Presumptive treatment is then started while further tests to confirm the diagnosis are performed. The criteria for diagnosing this infection are outlined by the Centers for Disease Control and Prevention (CDC) and include both clinical and laboratory criteria. […] The diagnosis can be confirmed by culturing a swab sample from infected areas. A swab is taken from the throat, and in particular from the tonsillar crypts as well as any discolored or ulcerated areas. […] According to the CDC, the following clinical and laboratory criteria need to be met for a diagnosis of diphtheria to be confirmed: […] Presence of upper respiratory tract infection along with sore throat […] Presence of high fever […] Presence of the grey white membrane or pseudomembrane over the throat, back of the mouth or tonsils […] Presence of corynebacterium diphtheriae in the throat swab samples […] Histological or cellular level presence of the bacteria.

• #2 Clinical manifestations, diagnosis, and treatment of diphtheria – UpToDate

  https://www.uptodate.com/contents/clinical-manifestations-diagnosis-and-treatment-of-diphtheria/print

  Diphtheria is an infectious disease caused by the gram-positive bacillus Corynebacterium diphtheriae. Infection may lead to respiratory disease, cutaneous disease, or an asymptomatic carrier state. The clinical manifestations, diagnosis, and treatment of diphtheria will be reviewed here. […] Infection with C. diphtheriae typically presents as respiratory or cutaneous disease. Systemic manifestations involving the heart (myocarditis), nervous system, and kidneys can also occur. Rarely, diphtheria presents as vaginal, conjunctival, or otic infection. […] Respiratory diphtheria is typically caused by toxin-producing strains of C. diphtheriae; rarely, it is caused by toxigenic strains of other Corynebacterium species (C. ulcerans, C. hemolyticum, or C. pseudotuberculosis). Symptoms typically begin two to five days after infection. In addition to respiratory symptoms, absorption and dissemination of diphtheria toxin can lead to toxin damage of the heart (myocarditis), nervous system, and kidneys.

• #2 Corynebacterium Diphtheriae – Medical Microbiology – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK7971/

  Clinical diagnosis depends upon culture-proven toxigenic Corynebacterium diphtheriae infection of the skin, nose, or throat combined with clinical signs of nasopharyngeal diphtheria (e.g., sore throat, dysphagia, bloody nasal discharge, pseudomembrane). Toxigenicity is identified by a variety of in vitro (e.g., gel immunodiffusion, tissue culture) or in vivo (e.g., rabbit skin test, guinea pig challenge) methods. […] The clinical diagnosis of diphtheria requires bacteriologic laboratory confirmation of toxigenic Corynebacterium diphtheriae in throat or lesion cultures. For primary isolation, a variety of media may be used: Loeffler agar, Mueller-Miller tellurite agar, or Tinsdale tellurite agar. Sterile cotton-tipped applicators are used to swab the pharyngeal tonsils or their beds. Calcium alginate swabs may be inserted through both nares to collect nasopharyngeal samples for culture. Since diphtheritic lesions are often covered with a pseudomembrane, the surface of the lesion may have to be carefully exposed before swabbing with the applicator.

• #2 Challenges of Diphtheria Toxin Detection

  https://www.mdpi.com/2072-6651/16/6/245

  Therefore, a rapid, easy to interpret and modern method for the detection of DT-producing isolates is needed, especially considering that the availability of diphtheria antitoxin—which is a main cure and a necessary reagent for current diagnostics methods—is extremally limited. […] The very promising tools are ICS and LFIA for toxin detection, and isothermal amplification methods, such as LAMP, for the detection of tox gene. […] According to the definition for the purposes of epidemiological surveillance, a confirmed diagnosis of diphtheria requires meeting both clinical and laboratory criteria. The laboratory criterion includes the isolation of toxin-producing corynebacteria from clinical material. […] Due to the fact that PCR only allows for the detection of the gene encoding DT but does not provide information on the production of DT, it is necessary to perform the Elek test in all tox-positive isolates to confirm whether the strain is toxigenic.

• #2 Diphtheria – Infectious Diseases – Merck Manual Professional Edition

  https://www.merckmanuals.com/professional/infectious-diseases/gram-positive-bacilli/diphtheria

  The laboratory should be notified that C. diphtheriae is suspected, so that special culture media (Loeffler or Tindale) can be used. […] In vitro testing for toxin production (modified Elek test) is done to differentiate toxigenic from nontoxigenic strains. […] Cutaneous diphtheria should be considered when a patient develops skin lesions during an outbreak of respiratory diphtheria. […] Swab or biopsy specimens should be cultured. […] ECG should be done to look for ST-T wave changes, QTc prolongation, and/or 1st-degree heart block related to myocarditis, which often becomes evident as the respiratory symptoms resolve. […] Treat with diphtheria antitoxin and penicillin or erythromycin; document cure by culture.

• #2 Diphtheria – Culture, Reference Isolates Identification Confirmation & Toxin Production Confirmation | Public Health Ontario

  https://www.publichealthontario.ca/en/Laboratory-Services/Test-Information-Index/Diphtheria-Culture

  Diphtheria toxin gene detection of isolates by PCR is performed every Tuesday and Thursday at PHOs laboratory, Toronto site. Turnaround time is 3 days after identification confirmation of the isolate. […] Confirmation of diphtheria toxin production (via modified Elek test) of isolate is performed at National Microbiology Laboratory (NML) at Winnipeg, Manitoba. Turnaround time is 9 calendar days from the date the isolate was received at NML. […] Isolates that are positive for diphtheria toxin genes by PCR are submitted to National Microbiology Laboratory for confirmation by real-time PCR and phenotypic detection of expressed diphtheria toxin by Modified Elek test. […] Toxin producing C. diphtheriae or C. ulcerans specimens are reported to the Medical Officer of Health as per Health Protection and Promotion Act.

• #2 Cutaneous diphtheria

  https://dermnetnz.org/topics/cutaneous-diphtheria

  Cutaneous diphtheria typically occurs in tropical areas where C. diphtheria is endemic, including in: […] In developed countries, cutaneous diphtheria most commonly presents in unvaccinated individuals following travel to an endemic area, or has been contracted from domesticated pets or wild animals. […] The diagnosis of cutaneous diphtheria should be considered for a non-healing ulcer typically after recent travel to an endemic area. […] C. diphtheriae or C. ulcerans may be cultured from a bacterial wound swab. […] As laboratory processing for diphtheria may not be routine, it is vital that complete clinical information is provided to alert the laboratory to consider culture for atypical organisms. […] Cutaneous diphtheria infection needs to be identified and treated to prevent spread of disease. Treatment includes: […] Cases are not contagious after 48 hours treatment with appropriate antibiotics. […] The prognosis for uncomplicated cutaneous diphtheria is good, with most cases responding to oral antibiotics and simple wound care measures.

• #2 Diphtheria/Tetanus Antibody Panel, Serum » Incyte Diagnostics

  https://www.incytediagnostics.com/laboratory-services/test-directory/TestDetails/diphtheriatetanus-antibody-panel-serum

  Useful for: […] Assessment of an antibody response to tetanus and diphtheria toxoid vaccines, which should be performed at least 3 weeks after immunization […] This test should not be used to diagnose tetanus infection. […] This assay does not provide diagnostic proof of lack of protection against diphtheria or the presence of absence of immunodeficiency. Results must be confirmed by clinical findings and other serological tests. […] The results obtained from this assay are not diagnostic proof of lack of protection against tetanus or the presence or absence of immunodeficiency.

• #2

  https://www.health.vic.gov.au/infectious-diseases/diphtheria

  Diphtheria is an urgent notifiable condition that must be notified immediately to the department by medical practitioners and pathology services. Exclusion periods apply to both cases and contacts. […] Diphtheria is an acute bacterial infection caused by toxigenic strains of Corynebacterium diphtheriae. […] Case management involves diphtheria antitoxin, antibiotic therapy and infection control. […] Diphtheria is an urgent notifiable condition and must be notified by medical practitioners and pathology services immediately by telephone upon initial diagnosis (presumptive or confirmed). Pathology services must follow up with written notification within 5 days. […] Diagnosis is usually based on observation of the classical greyish-white membrane overlying the tonsils or pharynx. […] Specimens for C. diphtheriae culture should be obtained from the nose and throat, and from any other suspicious lesions. Swabs should be obtained from the pharyngeal membrane, or a portion of the membrane itself could be submitted for culture.

• #2 Diphtheria – Infectious Disease Advisor

  https://www.infectiousdiseaseadvisor.com/ddi/diphtheria/

  Diphtheria antitoxin can be obtained only through the CDC via an investigational new drug protocol. […] According to the CDC, clinicians should administer antimicrobial agents as soon as they suspect diphtheria infection. […] The preferred medications are penicillin or erythromycin. […] Diphtheria antitoxin may cause anaphylaxis in some patients, particularly those with a history of allergic rhinitis, asthma, or urticaria. […] Antibiotic resistance in toxigenic C diphtheriae has not been widely reported. […] Most complications from diphtheria infection are caused by the diphtheria toxin.

• #2

  https://www.health.vic.gov.au/infectious-diseases/diphtheria

  Use standard precautions with additional respiratory precautions for respiratory tract diphtheria, and standard precautions with additional contact precautions for cutaneous diphtheria, until the case is shown to be clear of carriage via two negative cultures taken at least 24 hours apart, collected at least 24 hours after completing antibiotics. The disease is usually not highly contagious after 48 hours of antibiotic therapy. […] Outbreaks of diphtheria require immunising the largest possible proportion of the population involved, emphasising the need for protection of infants and preschool children.

• #2 Diphtheria Symptoms, Treatment, Transmission, Causes & Vaccine

  https://www.medicinenet.com/diphtheria_facts/article.htm

  Doctors diagnose diphtheria by the patient’s history and physical examination; a culture of Corynebacterium from the patient yields a definitive diagnosis although the patient should be treated if diphtheria is even suspected. […] Physicians make a preliminary diagnosis of diphtheria from the patient’s history and physical exam and the presence of a pseudomembrane formation in the throat especially if there is a history of not receiving the vaccination. […] Medical professionals base their confirmation on the isolation of the organism from swab specimens taken from the throat or from skin lesions. However, because diphtheria can be lethal, the CDC recommends immediate treatment if diphtheria is suspected; do not wait for laboratory confirmation.

• #2

  https://healthcarentsickcare.com/blogs/health-articles/how-to-test-for-diphtheria?srsltid=AfmBOoro4JoJapTXsgQblZ0tMsby6Kt2uTsZpli3rUzKOmar6ALgRzyu

  Diphtheria, once a scourge that ravaged communities, still lingers in the shadows, particularly in regions with low vaccination coverage. Its deceptive nature, often masquerading as common ailments, makes early diagnosis crucial. […] When diagnosing diphtheria, laboratory tests play a crucial role in confirming the presence of the Corynebacterium diphtheriae bacteria and its toxin. Here’s an overview of the key lab tests used: […] A positive result from any of these tests, particularly the culture or PCR test, confirms diphtheria diagnosis. Based on the test results, your doctor will determine the appropriate course of treatment and monitor your progress. […] Early diagnosis is crucial for prompt treatment and improved outcomes. […] While throat swabs are the primary diagnostic tool, a blood test may be ordered to confirm the presence of the toxin in severe cases. […] Diphtheria, though a formidable foe, can be kept at bay with knowledge, vigilance, and timely diagnosis. Remember, early detection and treatment are crucial for successful management.

• #2 Diphtheria | Doctor

  https://patient.info/doctor/diphtheria-and-diphtheria-vaccination

  Diphtheria is a toxin-mediated bacterial acute upper respiratory tract infection, but sometimes it infects the skin. […] Definitive diagnosis of diphtheria requires a positive culture from respiratory tract secretions or cutaneous lesions, and a positive toxin assay. […] Diphtheria anti-toxin (produced from horse serum) should be considered urgently for probable and confirmed cases of toxinogenic diphtheria. […] Patients should be immunised in the convalescent stage because clinical infection does not always induce adequate levels of antitoxin. […] Diphtheria cases are mainly from Southeast Asia, South America, Africa and India. […] Maintaining high vaccination coverage is essential to prevent indigenous C. ulcerans and re-emergence of C. diphtheriae. […] Vaccination confers protection against disease by production of antibodies to the diphtheria toxin. […] Overall, there is a 5-10% mortality rate, but it is up to 20% in those younger than 5 years and older than 40 years.

• #3 Diphtheria – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK560911/

  In suspected cases of diphtheria, antitoxin should be administered urgently based on clinical judgment without waiting for laboratory confirmation. […] The antibiotics of choice for treating diphtheria are erythromycin or penicillin G. […] Early initiation of antibiotics is crucial to eliminate the organism promptly, limiting toxin release, expediting patient recovery, and preventing infection spread to close contacts. […] Distinguishing diphtheria from other upper respiratory tract infections with similar presentations is crucial. […] The prognosis of diphtheria is influenced by several factors. […] The primary complications of diphtheria often involve myocarditis and neuritis. […] Timely diagnosis is crucial, involving isolation, antitoxin therapy, and antibiotic treatment.

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