| disease | Diphtheria |
| alias | Diphtheria |
Diphtheria is an acute infectious disease caused by the diphtheria bacillus. Its clinical features include the formation of pseudomembranes in the throat, larynx, nose, and other areas, along with systemic toxic symptoms such as fever, weakness, nausea, vomiting, and headache. Severe cases may lead to complications like myocarditis and nerve paralysis.
bubble_chart Epidemiology
(1) Source of infection Patients and carriers are the sources of infection for this disease. The infectivity begins at the end of the incubation period. Atypical, mild, nasal diphtheria, and cutaneous diphtheria patients play a significant role in the spread of diphtheria.
Carriers: They can be divided into convalescent carriers and healthy carriers. The duration of carriage in convalescent carriers is related to the following factors: ① Treatment: When treated with antitoxin alone, 3% of patients may become long-term carriers (over 3 months). For those treated with both antitoxin and antibiotics, the vast majority (90%) clear the bacteria within 4 days, and the remainder within 12 days, with rare cases still carrying the bacteria after 3 months. ② Type of disease: Pharyngeal diphtheria clears faster than nasal diphtheria. ③ Those with concurrent streptococcal infections, chronic tonsillitis, or pharyngitis clear the bacteria more slowly.
Healthy carriers: Previously, they generally accounted for 1–2% of the population, but during epidemics, this can rise to 10–20%. They are often overlooked and become important sources of infection.
(2) Routes of transmission The disease is mainly spread through respiratory droplets, but can also be transmitted indirectly via toys, clothing, utensils, etc. Outbreaks can occur through contaminated milk or food. Occasionally, infection may occur through broken skin or mucous membranes. Post-surgical procedures (e.g., tonsillectomy) are particularly prone to infection.
(3) Epidemiological features Diphtheria occurs worldwide, with higher incidence in temperate regions and lower in tropical areas. Cases can occur year-round but are more common in autumn, winter, and early spring. The disease is usually sporadic but may occasionally form epidemics or outbreaks.(4) Population susceptibility The population is generally susceptible to diphtheria. Historically, 50% of cases were in children under 5 years old, later shifting to school-aged children, but in recent years, most patients have been adults. In Sweden, 50–70% of adults lacked immunity to diphtheria, leading to a significant outbreak in 1984–1985. Russia has experienced diphtheria outbreaks since 1990, reporting 47,802 cases by 1994, affecting both children and adults with an average case fatality rate of 3.65%. This was the largest outbreak in developed countries since the 1960s. The disease spread to Ukraine in 1991, and by 1993–1994, 12 countries in the Commonwealth of Independent States had reported diphtheria outbreaks. Investigations revealed low vaccination completion rates among children and low reimmunization coverage among adults as contributing factors, prompting corrective measures. In China, diphtheria is now rare, but in localized outbreaks (e.g., Fuyang region), 85.71% of cases were in individuals over 15 years old. This is due to widespread childhood immunization programs, which confer strong immunity, whereas adults, with minimal diphtheria incidence in recent years, have had few opportunities for natural or artificial immunity, resulting in lower immune levels. Infants under 6 months have maternal immunity, reducing disease incidence, and infection confers lasting immunity.
The diphtheria bacillus (Corynebacterium diphtheriae) exhibits significant polymorphism, appearing rod-shaped or slightly curved, with one or both ends slightly enlarged, and often showing metachromatic granules at the ends. Based on morphological generation and transformation characteristics, colony morphology, and virulence, diphtheria bacilli can be classified into gravis, intermedius, and mitis types, with their frequency of occurrence varying across regions and time periods. The diphtheria bacillus has weak invasiveness but produces a potent exotoxin, which is the primary pathogenic factor. The production of exotoxin by the diphtheria bacillus is associated with the lysogenic β-phage it carries, which harbors the tox gene (TOX+). During the lytic phase, the circular DNA of this phage integrates into the host bacterium's genetic material, enabling the host cell to synthesize the toxin polypeptide. It is known that phages entering the lytic cycle destroy the host cell and release new β-phages. Some diphtheria bacilli lack the lysogenic phage and thus do not produce exotoxin. Such diphtheria bacilli can be converted into toxin-producing strains through lysogenization (infection with the lysogenic TOX+ phage). This phenomenon can also occur naturally, though it is rare in Western countries. The virulence of diphtheria bacilli can be tested in vitro using Elek's test. Pseudodiphtheria bacilli and diphtheroid bacilli resemble diphtheria bacilli morphologically and are found in the nasopharynx, but they do not produce exotoxin or cause disease. Virulence tests can be used to differentiate them.
bubble_chart Pathological Changes
The diphtheria bacillus proliferates in the superficial tissues of the upper respiratory tract (usually the pharynx) or the surface skin of susceptible individuals, secreting exotoxin. The exotoxin infiltrates local and surrounding tissues, causing tissue necrosis and acute pseudomembranous inflammation. The fluid exuded from blood vessels contains easily coagulable fibrin, which binds inflammatory cells, necrotic mucosal tissue, and diphtheria bacilli together to form a pseudomembrane. The pseudomembrane appears grayish-white with relatively neat edges and adheres tightly to the submucosal tissue, making it difficult to remove. In a few patients, the lesions may invade deeper tissues, forming ulcerated surfaces. The mucosa of the larynx, trachea, and bronchi is covered with ciliated epithelium, so the pseudomembrane formed there adheres less tightly and can be expelled more easily through a tracheostomy.
After being absorbed locally, diphtheria exotoxin spreads throughout the body via the lymphatic and circulatory systems, binding to cells and causing lesions. The myocardium and peripheral nerves are the most sensitive, while the kidneys and adrenal cortex also show significant lesions. The amount of exotoxin absorbed depends on the location and extent of the pseudomembrane. The pharynx absorbs the most, followed by the tonsils, with the larynx and trachea absorbing the least. The more extensive the pseudomembrane, the greater the amount of toxin absorbed. Initially, the binding between the toxin and tissues is loose, but over time, it becomes more firm and less easily neutralized by antitoxin. The diphtheria bacillus generally remains in the local lesion and does not enter the bloodstream, though it may occasionally reach local lymph nodes.
In the early stages, the myocardium shows edema, cloudy swelling, and fatty degeneration, followed by multiple focal necroses, cellular infiltration, and muscle fiber rupture. The cardiac conduction system may also be affected. Peripheral nerves exhibit toxic neuritis, with nerve myelin showing fatty degeneration and subsequent axonal rupture. The nerves of the eyes, palate, pharynx, larynx, and heart are most commonly damaged. The kidneys display cloudy swelling and shedding of renal tubular epithelial cells. The liver shows fatty infiltration and hepatocyte necrosis. The adrenal glands are congested and swollen, with occasional small hemorrhages.
bubble_chart Clinical Manifestations
Diphtheria can be divided into four types, with the incidence rates in descending order being pharyngeal diphtheria, laryngeal diphtheria, nasal diphtheria, and diphtheria in other locations. Pharyngeal diphtheria is more common in adults and older children, while other types of diphtheria are more frequently seen in young children.
(1) Pharyngeal diphtheria
1. Mild type: Fever and systemic symptoms are mild, with slight redness and swelling of the tonsils, on which there are dot-like or small patches of pseudomembrane. Symptoms may disappear naturally after a few days. It can easily be misdiagnosed as acute tonsillitis. Caution should be exercised during diphtheria outbreaks.
2. General type: Gradual onset, with lack of strength, poor appetite, nausea, vomiting, headache, mild to moderate fever, and sore throat. The tonsils show grade II redness and swelling, with large patches of milky white or grayish-white pseudomembrane visible on them, though the range does not extend beyond the tonsils. Sometimes the pseudomembrane may appear yellowish, and if mixed with blood, it can turn dark black. The pseudomembrane is initially thin with relatively neat edges and is difficult to remove. If forcibly wiped off, it may cause slight bleeding, and a new pseudomembrane will form within 24 hours.
3. Severe type: Significant edema and congestion of the tonsils and pharynx. The pseudomembrane spreads into large patches within 12–24 hours. In addition to the tonsils, it may also affect the palatine arches, palate, uvula, posterior pharyngeal wall, and nasopharynx, and may even extend to the oral mucosa. The mouth emits a foul odor, and the cervical lymph nodes are swollen, possibly leading to periadentitis, with neck swelling resembling a "bull neck." Pharyngeal pain in pharyngeal diphtheria is mostly not prominent. Severe systemic toxic symptoms may include high fever or hypothermia, dysphoria, restlessness, rapid breathing, pale complexion, vomiting, thready and rapid pulse, low blood pressure, or even cardiac enlargement, arrhythmia, bleeding, thrombocytopenia, and other critical symptoms.
(2) Laryngeal and tracheobronchial diphtheria: Mostly caused by the spread of pharyngeal diphtheria to the larynx, but it can also be primary. More common in children aged 1–5. The onset is relatively slow, accompanied by fever, a "barking" cough, hoarseness, or even aphonia. At the same time, due to the presence of pseudomembrane, edema, and spasms in the larynx, symptoms of respiratory obstruction occur. A stridor may be heard during inhalation, and in severe cases, the "three depressions sign" may be visible during inhalation. The patient appears panicked and cyanotic. Laryngoscopy reveals redness, swelling, and pseudomembrane in the larynx. The pseudomembrane may sometimes extend to the trachea and bronchi, and in severe cases, even the bronchioles may develop pseudomembranes.
(3) Nasal diphtheria: Rare. Refers to anterior nasal diphtheria, while posterior nasal diphtheria is part of pharyngeal diphtheria. Nasal diphtheria can occur alone or coexist with laryngeal or pharyngeal diphtheria. More common in infants and young children, with primary nasal cases being more frequent. The lesion range is small, and systemic symptoms are mild, mainly manifesting as serosanguinous nasal discharge, which later turns into thick purulent discharge, sometimes accompanied by epistaxis, often unilateral. The skin around the nostrils becomes red, eroded, and crusted, and white pseudomembrane may be seen in the nasal vestibule or septum. Untreated cases often become chronic.
(4) Cutaneous or wound diphtheria: Uncommon. Caused by direct or indirect infection of the skin or mucosa. Although symptoms are not severe, the course is prolonged, and it is prone to spreading diphtheria.
(5) Others: Diphtheria may occasionally occur in the external genitalia, umbilicus, esophagus, middle ear, conjunctiva, etc. Local inflammation and pseudomembrane are present, often accompanied by secondary infections. Systemic symptoms are mild. Chronic diphtheria has been reported domestically, with a course of 1–3 months. Although such cases are rare, they are epidemiologically significant. Bingchuan
bubble_chart Auxiliary Examination
The total white blood cell count is generally between 10,000 and 20,000, with an increased percentage of neutrophils. Diphtheria bacilli can be found in cultures and smear tests of nasal and pharyngeal swabs, and the virulence test is positive.
The diagnosis of diphtheria primarily relies on medical history and clinical symptoms. Most patients have not received diphtheria vaccination and have a history of contact with diphtheria patients. Clinical manifestations include a pseudomembrane that is difficult to separate from the underlying tissue. For patients with pseudomembranes in the nose or throat, a smear can be performed. If bacteria resembling diphtheria bacilli are found, a preliminary diagnosis of diphtheria can be made. If diphtheria bacilli are cultured, the diagnosis can be largely confirmed. If the culture is positive but clinical suspicion remains, a bacterial virulence test should be conducted to aid in differentiation. Early treatment is extremely important. For cases where clinical symptoms strongly suggest diphtheria, antitoxin therapy can be initiated immediately without waiting for culture results. A negative culture does not completely rule out diphtheria.
bubble_chart Treatment Measures
1) General Treatment Patients should rest in bed and reduce activity, generally for no less than 3 weeks, extending to 4–6 weeks for those with extensive pseudomembranes. Attention should be paid to oral and nasal hygiene.
2) Antibiotic Treatment Antibiotics can inhibit the growth of *Corynebacterium diphtheriae* and thereby prevent toxin production. Penicillin is commonly used for about 7–10 days, until symptoms disappear and cultures for *C. diphtheriae* turn negative. For patients allergic to penicillin or those whose cultures remain positive after 1 week of penicillin treatment, erythromycin may be substituted at a dose of 40 mg/(kg·d), administered orally or intravenously in four divided doses, with the same treatment duration. Amoxicillin, rifampin, etc., may also be effective.
3) Antitoxin Treatment Antitoxin can neutralize free toxins but not bound toxins. It is most effective when administered within the first 3 days of the illness, with significantly reduced efficacy thereafter, so early use is crucial. The dose depends on the extent and location of the pseudomembrane and the timing of treatment. For pharyngeal diphtheria with pseudomembrane confined to the tonsils, 20,000–40,000 units (u) are given; for extensive pseudomembranes with severe toxic symptoms, 40,000–100,000 u; for laryngeal and nasal diphtheria, 10,000–30,000 u. If treatment begins after 3 days of illness, the dose is doubled. The antitoxin can be administered intramuscularly or diluted for intravenous infusion, all at once. If lesions continue to expand after 24 hours, the same dose may be repeated intramuscularly. Before administering antitoxin, allergy history should be checked, and a skin sensitivity test performed. It should only be used if the test is negative; for positive cases, a desensitization protocol should be followed.
4) Treatment of Myocarditis Patients should rest in bed, and sedatives may be given for dysphoria. Prednisone 20–40 mg/day may be used, divided into four oral doses, with gradual tapering as symptoms improve. For severe cases, adenosine triphosphate (ATP) 20 mg and coenzyme A 50 u may be dissolved in 50–100 ml of 5–10% glucose solution for intravenous infusion.
5) Treatment of Nerve Paralysis For patients with dysphagia, nasogastric feeding should be used.
6) Treatment of Laryngeal Obstruction For grade I laryngeal obstruction, close monitoring is required, with readiness for tracheotomy. If dyspnea worsens and retractions appear, tracheotomy should be performed immediately, and the pseudomembrane removed with forceps or dissolved by instilling trypsin or chymotrypsin.
7) Management of Diphtheria Carriers First, perform a virulence test for *C. diphtheriae*. Positive carriers should be isolated and treated with penicillin or erythromycin at the same doses as above; antitoxin is unnecessary. Isolation may be lifted after three consecutive negative cultures. For persistent carriers, tonsillectomy may be considered. For convalescent diphtheria carriers requiring tonsillectomy, it must be performed 3 months after recovery, when the heart is completely normal. {|106|}
Infants aged 3, 4, and 5 months receive one dose of the diphtheria, pertussis, and tetanus (DPT) triple vaccine each month, totaling 3 doses for primary immunization. A booster dose is administered between 1.5 and 2 years of age. At 7 and 15 years of age, refined diphtheria and tetanus (DT) toxoid is administered once each to enhance the long-term immunity against diphtheria, protecting older children and adults from the disease. Adults should also receive booster immunizations when necessary.
Diphtheria patients should be promptly isolated and actively treated. Isolation should continue until systemic and local symptoms disappear, and cultures from the nasopharynx or other lesions are negative twice consecutively. Isolation should not be lifted earlier than 7 days after treatment. The patient's secretions and utensils must be strictly disinfected. Respiratory secretions should be treated with double the amount of 5% cresol soap (lysol) or phenol for one hour. Contaminated clothing and utensils should be boiled for 15 minutes, and items that cannot be boiled should be soaked in 5% cresol soap or phenol for one hour. After the patient leaves, the room should be sprayed with the aforementioned disinfectant and then cleaned.
Contacts in group childcare and adult institutions should be observed for 7 days, with nasopharyngeal swab cultures and diphtheria bacillus toxin tests performed. Close adult contacts should also undergo these tests. ① Those with both positive cultures and toxin tests should be treated as diphtheria cases, isolated for observation, and treated with penicillin. Antitoxin should be administered immediately if symptoms appear. ② Those with positive cultures but negative toxin tests should be treated as diphtheria cases. ③ Those with both negative cultures and toxin tests may be released from observation. ④ Those with negative cultures but positive toxin tests should be given preventive vaccination immediately.
Although diphtheria toxin can affect cells throughout the body, the heart, nervous system, and kidneys are the most significantly impacted. Severe diphtheria can lead to complications such as myocarditis or peripheral nerve paralysis, and occasionally toxic nephritis may occur.
(1) Cardiovascular System
1. Peripheral circulatory failure manifests as nausea, vomiting, pale complexion, cold extremities, weak pulse, and decreased blood pressure. If myocardial damage occurs simultaneously, the symptoms of circulatory failure may worsen.
2. Myocarditis usually appears in the second week of the disease course, presenting as weakness, pale complexion, difficulty breathing, enlarged heart, faint heart sounds, tachycardia or bradycardia, arrhythmia, and hepatomegaly. Electrocardiograms often show low voltage, ST segment and T wave changes, bundle branch or atrioventricular block, or other arrhythmias. Patients may die from heart failure, so close observation and prompt treatment are essential.
Some classify diphtheria myocarditis into early-stage (days 3–5) and advanced-stage (days 5–14) types. The early stage is caused by severe toxemia and may lead to sudden death within minutes to hours. The advanced stage results from myocardial lesions affecting peripheral circulation, often presenting with extreme pallor followed by cyanosis, abdominal pain, weak and slow pulse, indistinct or absent first heart sound, irregular heart rhythm, and decreased blood pressure.
(2) Peripheral Nerve Paralysis This manifests as flaccid paralysis, typically occurring in weeks 3–4 of the disease course. Palatal paralysis is the most common, causing a slight nasal tone in speech, choking on liquids through the nose, and loss of the uvular reflex. Eye muscle paralysis may also occur, leading to strabismus, eyelid drooping, and dilated pupils. Facial nerve paralysis can cause a crooked mouth. Paralysis of voluntary muscles in the limbs is rare. Cerebrospinal fluid usually shows no abnormalities.
(3) Toxic Nephritis This is rare, primarily presenting as reduced urine output, leukocytes, and casts in the urine, but generally no hematuria.
Diphtheria can lead to secondary bacterial infections such as cervical lymphadenitis, perilynphadenitis, otitis media, and pneumonia. Occasionally, peritonsillar abscesses may develop, requiring incision and drainage only after sufficient antitoxin has been administered.
(1) Diphtheria needs to be differentiated from the following diseases:
1. Acute tonsillitis: Sudden onset, high fever, red and swollen tonsils, significant sore throat; secretions are thin, light in color, limited to the tonsils, and easily wiped away.
2. Thrush: Low-grade fever, white patchy lesions attached to the oral mucosa, which may spread to the throat. The white membrane is loose and easily peeled off. Although the lesions can be extensive, toxic symptoms are not prominent.
3. Ulceromembranous pharyngitis: Necrotic ulcers and pseudomembranes in the throat, often accompanied by gingivitis, easy bleeding, and foul odor in the mouth. Smear from a throat swab may reveal fusiform bacilli and spirochetes.
4. Infectious mononucleosis: White membranes on the tonsils that resolve slowly. Smears and cultures show no diphtheria bacilli, and diphtheria antitoxin treatment is ineffective. Abnormal lymphocytes are present in peripheral blood, and the heterophil agglutination test may be positive, with specific antibodies also positive.
(2) Laryngeal diphtheria needs to be differentiated from the following diseases:
1. Acute laryngitis: Most cases of acute laryngeal obstruction in children are caused by acute laryngitis, measles complicated by laryngitis, and laryngeal diphtheria. Measles complicated by laryngitis has a history of measles; acute laryngitis has a sudden onset with abrupt respiratory distress. Since primary laryngitis patients have no pseudomembranes in the throat, laryngeal obstruction is difficult to confirm. If a white membrane is expelled from a tracheostomy, diphtheria should be considered.
2. Tracheal foreign body: History of foreign body inhalation, with severe coughing at the time of inhalation, followed by paroxysmal coughing. No pseudomembrane is found, and localized emphysema or atelectasis is often visible on chest X-ray.
(3) Nasal diphtheria needs to be differentiated from the following diseases:
1. Nasal foreign body: Usually unilateral, examination reveals a foreign body in the nasal cavity without a pseudomembrane.
2. Congenital syphilis: Often accompanied by other syphilitic symptoms, ulcers in the nasal cavity without white membranes. Serum Wassermann reaction is positive.
