C diphtheria is responsible for both endemic and epidemic diseases, and it was first described in the 5th century BC by Hippocrates. Diphtheria manifests as either an upper respiratory tract or cutaneous infection and is caused by the aerobic gram-positive bacteria, Corynebacterium diphtheria. The infection usually occurs in the spring or winter months. It is communicable for 2-6 weeks without antibiotic treatment.[1, 2] People who are most susceptible to infection are those who are not completely immunized or have low antitoxin antibody levels and have been exposed to a carrier or diseased individual. A carrier is someone whose cultures are positive for the diphtheria species but does not exhibit signs and symptoms. Studies show that as the number of asymptomatic carriers decrease, the number of diphtheria cases consequently decline.[1, 3]
C diphtheria is a nonencapsulated, nonmotile, gram-positive bacillus; this is shown in the image below. Pathogenic strains can result in severe localized upper respiratory infection, localized cutaneous infections, and rarely systemic infection.
View Image | Photomicrograph depicts a number of gram-positive Corynebacterium diphtheriae bacteria, which had been stained using the methylene blue technique. The.... |
Exotoxins are associated with both invasive localized and systemic forms of this disease; however, case reports of invasive disease in absence of the exotoxin release have been documented.[1] Exotoxins are encoded in viral bacteriophages, which are transmitted from bacteria to bacteria. The 3 isolated strains of C diphtheria include gravis, intermedius, and mitis. Intermedius is thought to be responsible for systemic elaboration of the disease, as it is most often associated with the exotoxin. However, all 3 strains are capable of producing toxins.[1, 2]
Corynebacterium ulcerans is a relatively rare species, which more frequently causes cutaneous diphtheria; however, this species may rarely cause respiratory symptoms. Severity of disease is dependent on exotoxin production. C ulcerans has also been linked to zoonotic transmission to humans and has been most frequently seen in agricultural communities associated with livestock.[4, 5]
The use of diphtheria and tetanus toxoids and acellular pertussis (DTaP) in the United States has greatly decreased the incidence of diphtheria. Although childhood DTaP coverage exceeds 80%, acquired immunity wanes over time, requiring a booster to preserve immunity. Although vaccination is not guaranteed to prevent diphtheria, vaccinated persons who go on to develop diphtheria have been reported as having milder and less fatal infections.[6]
Overcrowding, poor health, substandard living conditions, incomplete immunization, and immunocompromised states facilitate susceptibility to diphtheria and are risk factors associated with transmission of this disease.[7] Human carriers are the main reservoir of infection; however, case reports have linked the disease to livestock.[5, 4] Infected patients and asymptomatic carriers can transmit C diphtheria via respiratory droplets, nasopharyngeal secretions, and rarely fomites.[1, 2] In the case of cutaneous disease, contact with wound exudates may result in the transmission of the disease to the skin as well the respiratory tract.[4]
Immunity from exposure or vaccination wanes over time. Inadequate boosting of previously vaccinated individuals may result in increased risk of acquiring the disease from a carrier, even if adequately immunized previously. Additionally, since the advent of widespread vaccination, cases of nontoxigenic strains causing invasive disease have increased.[8]
C diphtheria adheres to mucosal epithelial cells where the exotoxin, released by endosomes, causes a localized inflammatory reaction followed by tissue destruction and necrosis. The toxin is made of two joined proteins.[2] The B fragment binds to a receptor on the surface of the susceptible host cell, which proteolytically cleaves the membrane lipid layer enabling segment A to enter.[1] Molecularly, it is suggested that the cellular susceptibility is also due to diphthamide modification, dependent on human leukocyte antigen (HLA) types predisposing to more severe infection. The diphthamide molecule is present in all eukaryotic organisms and is located on a histidine residue of the translation elongation factor 2 (eEF2). eEF2 is responsible for the modification of this histidine residue and is the target for the diphtheria toxin (DT).
Fragment A inhibits an amino acid transfer from RNA translocase to the ribosomal amino acid chain, thus inhibiting protein synthesis is required for normal host cell functioning.[1] DT causes a catalytic transfer of NAD to diphthamide, which inactivates the elongation factor, resulting in the inactivation eEF2, which results in protein synthesis blockage and subsequent cell death.[9, 2]
Local tissue destruction enables the toxin to be carried lymphatically and hematologically to other parts of the body. Elaboration of the diphtheria toxin may affect distant organs such as the myocardium, kidneys, and nervous system. Nontoxigenic strains tend to produce less severe infections; however, since widespread vaccination, case reports of nontoxigenic strains of C diphtheria causing invasive disease have been documented.[1]
United States
Since the introduction and widespread use of diphtheria toxoid in the 1920s, respiratory diphtheria has been well controlled, with an incidence of approximately 1000 cases reported annually. Before vaccination, at least 200,000 cases occurred annually in the United States.[10]
Diphtheria remained endemic in some states through the 1970s, with reported incidence rates of greater than 1.0 per million population in Alaska, Arizona, Montana, New Mexico, South Dakota, and Washington.[1] Most of these infections were attributed to incomplete vaccination.
In the United States, diphtheria currently occurs sporadically, mostly among the Native American population, homeless people, lower socioeconomic groups, and alcoholics.[7] Immigrants and travelers from regions with ongoing epidemics are also at risk.[7] The most recent data from the CDC show that, between 1996 and 2016, only 13 cases were reported.[6]
International
According to the World Health Organization (WHO), diphtheria epidemics remain a health threat in developing nations.[2] The largest epidemic recorded since widespread implementation of vaccine programs was in 1990-1995, when a diphtheria epidemic emerged in the Russian Federation, rapidly spreading to involve all Newly Independent States (NIS) and Baltic States. This epidemic caused more than 157,000 cases and 5000 deaths according to WHO reports.[11, 12] Disproportionately high rates of death were observed in individuals older than 40 years, and 5,000 deaths were reported. This epidemic accounted for 80% of cases reported worldwide during this time period.[13]
From 1993-2003, a decade long epidemic in Latvia resulted in 1359 reported cases of diphtheria with 101 deaths. The incidence fell from 3.9 cases per 100,000 cases in 2001 to 1.12 cases per 100,000 population in 2003. Most cases were registered in unvaccinated adults.
From 1995-2002, 17 cases of cutaneous diphtheria due to toxigenic strains were reported in the United Kingdom.[13]
Overall rates of infection have decreased in Europe from 2000 to 2009, according to the Diphtheria Surveillance Network. This has been attributed to improved vaccination rates creating herd immunity. However, issues with vaccinations still occur, especially in eastern European countries and Russia, and are thought to contribute to the ongoing outbreaks.[14]
Many case reports in the literature describe epidemics in sub-Saharan Africa, France, India, and the United States.[15, 16]
Before the introduction of vaccine in the 1920s, the incidence of respiratory disease was 100-200 cases per 100,000 population in the United States and has decreased to approximately 0.001 cases per 100,000 population.[10, 1]
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. Immunization patterns have the most influence on mortality patterns. Mortality rates have not changed significantly over the past few decades. Most deaths occur on days 3-4 secondary to asphyxia with a pharyngeal membrane or due to myocarditis. Mortality rates of 30-40% have been reported for bacteremic disease.[10]
No racial predilection for diphtheria has been reported.
No significant differences exist between the incidence of diphtheria in males and females. In certain regions of the world, however, women may have lower immunization rates than males. Female infants and young children account for the majority of deaths in endemic regions.
Historically, diphtheria has been primarily a disease of childhood, affecting populations younger than 12 years. Infants become susceptible to the disease at age 6-12 months after their transplacentally derived immunity wanes.[17] Since the advent of diphtheria vaccination, cases of pediatric disease have declined dramatically. Recently, however, diphtheria has shifted into the adolescent and adult population, most notably in ages 40 and older accounting for most new cases.[12] This is primarily due to incomplete immunization status, including never being immunized, inefficient vaccine or response to vaccination, and not receiving a booster after previous vaccination. According to immunologic studies, one must have an antitoxin level of greater 0.1 IU/mL for adequate immunity.[18] Additionally, adolescents and adults may exhibit an atypical presentation of the disease, thus potentially obscuring the diagnosis.[8]
Immunization schedules have recently changed requiring a toxoid booster at age 11-12 and every 10 years thereafter. The toxoid booster, without tetanus, is approved for pregnant women if their antitoxin titers are less than 0.1 IU/mL.[18]
Onset of symptoms of respiratory diphtheria typically follows an incubation period of 2-5 days (range, 1-10 d).[1, 10] Symptoms initially are general and nonspecific, often resembling a typical viral upper respiratory infection (URI). Respiratory involvement typically begins with sore throat and mild pharyngeal inflammation. Development of a localized or coalescing pseudomembrane can occur in any portion of the respiratory tract. The pseudomembrane is characterized by the formation of a dense, gray debris layer composed of a mixture of dead cells, fibrin, RBCs, WBCs, and organisms; the pseudomembrane is shown in the image below.
View Image | The characteristic thick membrane of diphtheria infection in the posterior pharynx. |
Removal of the membrane reveals a bleeding, edematous mucosa. The distribution of the membrane varies from local (eg, tonsillar, pharyngeal) to widely covering the entire tracheobronchial tree. The membrane is intensely infectious, and droplet and contact precautions must be followed when examining or caring for infected patients. A combination of cervical adenopathy and swollen mucosa imparts a "bull's neck" appearance to many of the infected patients; this is shown in the image below. The most frequent cause of death is airway obstruction or suffocation following aspiration of the pseudomembrane.[17]
View Image | Cervical edema and cervical lymphadenopathy from diphtheria infection produce a bull's neck appearance in this child. Source: Public Domain www.immuni.... |
Cutaneous diphtheria is a disease characterized by indolent, nonhealing ulcers covered with a gray membrane. The ulcers are often co-infected with Staphylococcus aureus and group A streptococci. This form of the disease is seen with increasing frequency in poor inner-city dwellers and alcoholics. The lesions of cutaneous diphtheria are infectious, and bacteria from cutaneous lesions have been found to cause pharyngeal infections and thus serve as a reservoir for infection.
Patients with diphtheria may present with the following complaints:
Respiratory diphtheria may quickly progress to respiratory failure due to airway obstruction or aspiration of pseudomembrane into the tracheobronchial tree.
Cutaneous diphtheria often develops at a site of previous trauma or a primary dermatologic disease. It follows an indolent course, typically lasting weeks to months. Occasionally, it may cause respiratory diphtheria.[17]
General: Patient has a low-grade fever but is toxic in appearance, and also may have a swollen neck.
Pharyngeal diphtheria:
Cardiac toxicity typically occurs after 1-2 weeks of illness following improvement in the pharyngeal phase of the disease. It may manifest as follows:
Neurologic toxicity is proportional to the severity of the pharyngeal infection. Most patients with severe disease develop neuropathy. Deficits include the following:
The following factors may predispose to diphtheria infection:
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.[2]
Gram stain shows club-shaped, nonencapsulated, nonmotile bacilli found in clusters.
Immunofluorescent staining of 4-hour cultures or methylene blue–stained specimen may sometimes allow for a speedy identification.
Inoculation of tellurite or Loeffler media with swabs taken from the nose, pseudomembrane, tonsillar crypts, any ulcerations, or discolorations. Identification is accomplished through observation of colony morphology, microscopic appearance, and fermentation reactions. Any diphtheria bacilli isolated must be tested for toxin production.
Obtain throat and pharyngeal swabs from all close contacts.[10]
Toxigenicity testing is aimed to determine 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.[11]
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.
CBC may show moderate leukocytosis.
Urinalysis (UA) may demonstrate transient proteinuria.
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).[10]
Serum troponin I levels seem to correlate with the severity of myocarditis.[23]
Chest radiograph and soft tissue neck radiography/CT or ultrasonography may show prevertebral soft tissue swelling, enlarged epiglottis, and narrowing of the subglottic region.
Echocardiography may demonstrate valvular vegetations; however, this systemic manifestation of diphtheria is rare.[23, 24]
The following procedures may be necessary:
Careful assessment of airway patency and cardiovascular stability. Patients should be transported to the nearest hospital.
Treatment of diphtheria should be initiated even before confirmatory tests are completed due to the high potential for mortality and morbidity.
Isolate all cases promptly and use universal and droplet precautions to limit the number of possible contacts.
Secure definite airway for patients with impending respiratory compromise or the presence of laryngeal membrane. Early airway management allows access for mechanical removal of tracheobronchial membranes and prevents the risk of sudden asphyxia through aspiration. Consider involving ENT or operating room personnel for intubation and securing of airway if there is suspicion for loss of the airway or respiratory failure.
Maintain close monitoring of cardiac activity for early detection of rhythm abnormalities. Initiate electrical pacing for clinically significant conduction disturbance and provide pharmacologic intervention for arrhythmias or for heart failure.
Provide 2 large-bore IVs for patients with a toxic appearance; provide invasive monitoring and aggressive resuscitation for patients with septicemia.
Initiate prompt antibiotic coverage (erythromycin or penicillin) for eradication of organisms, thus limiting the amount of toxin production. Antibiotics hasten recovery and prevent the spread of the disease to other individuals.
Neutralize the toxin as soon as diphtheria is suspected. Diphtheria antitoxin is a horse-derived hyperimmune antiserum that neutralizes circulating toxin prior to its entry into the cells. It prevents the progression of symptoms. The dose and route of administration (IV vs IM) are dependent on the severity of the disease. This antitoxin must be obtained directly from the Centers for Disease Control and Prevention (CDC) through an Investigational New Drug (IND) protocol. The patient must be tested for sensitivity to the antitoxin before it is given. Antitoxin is only available in the United States. For more information regarding acquisition, see the CDC website for diphtheria antitoxin.
Diphtheria disease does not confer immunity; thus, initiation or completion of immunization with diphtheria toxoid is necessary.
Obtain throat and nasal swabs from persons in close contact with the suspected diphtheria victim; administer age-appropriate diphtheria booster.
Initiate antibiotic therapy with erythromycin or penicillin for chemoprophylaxis in a patient with suspected exposure. Throat cultures should be repeated in 2 weeks after treatment.
The following consultations may be necessary:
The widespread use of the diphtheria, tetanus toxoids, and acellular pertussis (DTaP) vaccine in childhood has significantly decreased the incidence of diphtheria. However, childhood immunity wanes, requiring an updated booster vaccine. The CDC recommends either DTaP, Tdap, or DT at least every 10 years to maintain immunity.[6]
Patients with active disease as well as all close contacts should be treated with antibiotics. Treatment is most effective in the early stages of disease and decreases the transmissibility and improves the course of diphtheria. Additionally, close contacts, such as family members, household contacts, and potential carriers, must receive chemoprophylaxis regardless of immunization status or age. This entails treatment with erythromycin or penicillin for 14 days and post treatment cultures to confirm eradication.[3]
The CDC has approved macrolides such as erythromycin as first-line agents for patients older than 6 months of age. However, macrolide therapy has been associated with an increase in pyloric stenosis in children younger than 6 months, especially treatment with erythromycin. Intramuscular penicillin is recommended for patients who will be noncompliant or intolerant to an erythromycin course.
The horse serum antitoxin is given to anyone suspected to have diphtheria and can be administered without confirmation from cultures, as it is most efficacious early during the course of the disease.
Diphtheria antitoxin can be obtained only from the CDC. For more information regarding acquisition, see the CDC website for diphtheria antitoxin.
Clinical Context: Neutralizes toxin before it enters cells. Dose given depends on site of infection and length of time patient is symptomatic. In United States, diphtheria antitoxin (DAT) is available from the CDC. Contact a diphtheria duty officer through CDC’s Emergency Operations Center at 770-488-7100. Report all suspected cases of diphtheria to local and state health departments.
Diphtheria antitoxin was first used in the United States in 1891, derived from a horse serum, it neutralizes unbound exotoxin. It is to be administered as soon as diphtheria suspected. It can only be obtained from the CDC and is not available internationally. Administer immunization toxoid booster, as the antitoxin does not influence immunity.
Clinical Context: Inhibits bacterial growth, possibly by blocking dissociation of peptidyl tRNA from ribosomes causing RNA-dependent protein synthesis to arrest. For treatment of staphylococcal and streptococcal infections.
Age, weight, and severity of infection determine proper dosage in children. When bid dosing is desired, one half the total daily dose may be taken q12h. Double the dose for more severe infections.
Has the added advantage of being a good anti-inflammatory agent by inhibiting migration of polymorphonuclear leukocytes.
Erythromycin and penicillin are both recommended for the treatment of diphtheria. Some studies suggest that erythromycin may be better at eradication of the carrier state. Penicillin is recommended in household contacts who may not comply with the duration of erythromycin treatment. An increased incidence of pyloric stenosis is associated with administration of erythromycin to infants younger than 6 months. It is believed that azithromycin may be a better macrolide treatment in this population, though there are a few case reports describing pyloric stenosis in infants treated with azithromycin for pertussis infections.
The treatment of endocarditis requires the addition of an aminoglycoside.
Clinical Context: Interferes with synthesis of cell wall mucopeptides during active multiplication, which results in bactericidal activity. Effective treatment for systemic diphtheria.
Penicillin may be used for treatment, prophylaxis, and eradication of diphtheria in carriers. However, resistant strains and transmission from penicillin-treated carriers has been reported.
Complete age-appropriate immunization schedule.
Treat all household and other close contacts with antibiotics as mentioned above. All suspected and confirmed carriers should be treated with erythromycin or penicillin for 14 days.
Follow-up pharyngeal cultures must be obtained post treatment, confirming eradication of the bacterium.[3]
Provide supportive care, continuation of antibiotic treatment, and antipyretics for fever.
Closely observe for development of primary or secondary bacterial pneumonia.
Perform serial ECGs to detect cardiac abnormalities.
Provide physical therapy for patients with neurologic dysfunction.
Patients with endocarditis may require valve replacement, especially with previous prosthetic valves. However, some evidence suggests that antibiotic therapy with a beta-lactam with or without an aminoglycoside may be adequate in treating endocarditis with either a native or prosthetic valve.[20]
Respiratory isolation may be indicated.
Monitor for serum sickness or hypersensitivity reactions in patients treated with DAT.
The following medications may be necessary:
Intensive care unit admission is recommended for patients with impending respiratory compromise.
Isolation may be indicated.
The Global Pertussis Initiative formed in 2001 is the task force working towards global immunizations and disease prevention in infants, adolescents, and adults for diphtheria, pertussis, and tetanus.
The 4 forms of the diphtheria toxoid are as follows: DTaP, Tdap, DT, and Td. The childhood vaccination is called DTaP. Adult vaccination form is Tdap. These toxoid vaccinations are combined with acellular pertussis and tetanus vaccine.[25]
DTap is given at 2 months, 4 months, 6 months, 15-18 months, and 4-6 years. The uppercase D denotes the full strength of tetanus toxoid (7-8 Lf units).[26]
DT does not contain pertussis and is given to children who have had previous adverse reactions to the acellular pertussis incorporated vaccine.
Td is a vaccine for adolescents and adults given as a booster every 10 years or when an exposure has occurred. The lowercase d denotes reduced strength diphtheria toxoid (2.0-2.5 Lf units). It is given to those older than 7 years.[27]
Tdap is recommended for adolescents aged 11-12 years or in place of one Td booster in older adolescents and adults aged 19 years and older.[28] In 2012, the CDC recommended patients 65 years and older receive Tdap if they have not received it previously. Boostrix is Tdap approved for adolescents aged 10 years and older, and Adacel is Tdap approved for those aged 11-64 years. For those 65 and older, the CDC recommends Boostrix. However, either Boostrix or Adacel may be used depending on availability.
The CDC also recommends that pregnant patients greater than 20 weeks’ gestation be given Tdap during pregnancy or shortly after delivery.[29] CDC’s Advisory Committee for Immunization Practices recently recommended that pregnant patients greater than 20 weeks’ gestation receive Tdap regardless of previous Tdap history.[30] This allows maternal antibodies to pass on to the fetus, giving protection for the few months of life.
These immunization schedules have been modified due to trends of pertussis increasing in the adolescent and adult populations. Therefore, Tdap Boostrix, and Adacel are now recommended in the immunization schedule for prevention of endemics associated with pertussis and diphtheria.[31, 29, 28]
Contact/respiratory isolation is indicated for prevention and deterrence of spreading the infection.
See the list below:
Cardiac involvement is associated with a very a poor prognosis, particularly AV and left bundle-branch blocks (mortality rate 60-90%).
Bacteremic disease carries a mortality rate of 30-40%.
High mortality rate is seen with invasive disease.
High mortality rates are seen in individuals younger than 5 years and in those older than 40 years.
Widespread awareness of the need for universal immunization is indicated.
Stress the importance of seeking medical attention in all cases of contact with suspected diphtheria cases.