tetanus



OVERVIEW

Definition.

Diphtheria belongs to China’s category B management of infectious diseases, is an acute respiratory infectious disease caused by Corynebacterium diphtheriae [1]. It is mainly manifested as pharyngeal, laryngeal and nasal mucosal congestion with localized adherence of grayish-white pseudomembrane, which may lead to myocarditis, peripheral nerve paralysis and other complications in severe cases [2-4].

Corynebacterium diphtheriae is highly resistant to cold and dryness; it can survive on clothing, sheets, and toys for days to weeks; it is sensitive to commonly used disinfectants and ultraviolet light, and can be inactivated by boiling for 1 minute or heating at 56°C for 10 minutes [1,4].

Morbidity

Diphtheria is widespread throughout the world; due to universal vaccination against diphtheria, the incidence of diphtheria is now significantly reduced and epidemics or outbreaks are rare [5].

The disease can be seen throughout the year, most frequently in fall and winter, and least frequently in summer.

In our country, one case of diphtheria was reported in 2006 and no cases of diphtheria were reported from 2007 to 2019, but two cases were reported in 2020 and one in July 2022 [4].

Etiology

Causes of the disease

The disease is caused by Corynebacterium diphtheriae infection, and there are three basic conditions that lead to epidemics.

Patients and carriers of diphtheria are the main source of infection of the disease.

The incubation period of the disease (the period between the entry of the virus into the body and the appearance of symptoms) is 1-7 days, mostly 2-4 days, and it is infectious at the end of the incubation period, and it is most infectious in the first week of the disease [1].

It is mostly transmitted through droplet transmission, but can also be transmitted indirectly through direct contact with contaminated hands, toys, stationery, clothing and blankets, and can occasionally be infected through broken skin and mucous membranes.

The population is generally susceptible, but children have the highest susceptibility, and can obtain persistent immunity after the disease.

Before vaccination, the prevalence of the disease is highest in children aged 1 to 5 years [4].

Pathogenesis

Corynebacterium diphtheriae is weakly invasive, generally only adheres to the surface of the respiratory mucosa to reproduce, and often does not invade deep tissues or enter the bloodstream.

The main pathogenic factor of Corynebacterium diphtheriae is the release of exotoxin, which can cause tissue inflammatory necrosis, a large number of inflammatory cells infiltration, fibrin exudation, and local formation of characteristic diphtheria pseudomembrane.

After local absorption, diphtheria toxin can reach all organs of the body with blood, causing systemic toxic symptoms and multiple organ lesions, among which toxic myocarditis and neuritis are the most common.

Symptoms

Main symptoms

According to the different parts of the lesion and the severity of the poisoning symptoms, it can be categorized into the following 4 types.

Pharyngeal diphtheria

Pharyngeal diphtheria is the most common, accounting for about 80% of diphtheria, and can be categorized into the following four types according to the severity of the disease.

There is only slight fever and sore throat, and systemic symptoms such as fatigue are mild.

Pseudomembranes are mostly confined to the tonsils in the form of dots or small patches, sometimes without pseudomembrane formation.

There may be sore throat, mild to moderate fever, loss of appetite, nausea, vomiting, and malaise.

Enlarged tonsils can be seen, large grayish-white pseudomembrane on tonsils, which can involve the posterior pharyngeal wall, pseudomembrane is not easy to peel off, and forcible peeling is easy to cause bleeding.

Systemic toxicity symptoms are obvious, there may be moderate to high fever, pallor, malaise is obvious, and in severe cases, hypotension may occur.

Edema and congestion of tonsils and pharynx can be seen, and the pseudomembrane can spread to the larynx and nasopharynx, and even the oral mucosa, which is pale gray or even black, mostly accompanied by halitosis.

The onset of the disease is rapid and the disease progresses quickly.

Tonsils and pharynx are highly swollen, which can affect breathing and swallowing, at this time, the pseudomembrane is large, black, local necrosis is obvious, mostly accompanied by rotten bad breath odor.

When the toxin diffuses to the soft tissues of the neck, it can cause the characteristic neck swelling, called “cow’s neck”.

Systemic poisoning symptoms are serious, can lead to severe myocarditis and severe peripheral neuritis. The morbidity and mortality rate is very high, often within 6-10 days [1].

Laryngeal diphtheria

Mostly spread from pharyngeal diphtheria, which may manifest as hoarseness or even loss of voice.

Laryngeal diphtheria often causes partial obstruction of the airway due to laryngeal edema and pseudomembrane formation, which produces asphyxia, and may present with shortness of breath, dyspnea, and the triple concavity sign (marked depression of the suprasternal fossa, supraclavicular fossa, and intercostal space during inspiration).

Nasal diphtheria

Mostly from pharyngeal diphtheria. It is characterized by nasal congestion, purulent or bloody nasal discharge, reddening, erosion and crusting of the skin around the nostrils, and white pseudomembrane on the nasal vestibule or nasal septum.

Other parts of diphtheria

Diphtheria may occasionally occur in the conjunctiva of the eye, external ear canal, and skin lesions [6-7]. There may be localized redness and swelling, pseudomembrane formation, and mild systemic symptoms, but it is important in disease transmission.

Complications.

The most common complications associated with diphtheria are myocarditis and peripheral nerve palsy.

Myocarditis

Myocarditis is characterized by pallor, tachycardia or bradycardia, rhythmic disturbances, cardiac enlargement, electrocardiographic abnormalities, elevated cardiac enzymes and troponin, and in severe cases, heart failure or peripheral circulatory failure, which is an important cause of death [5,8-9].

Peripheral nerve paralysis

Most commonly seen in patients with heavy diphtheria [10], with soft palate paralysis is the most common, there may be slurred speech, nasal sound, choking when drinking water; followed by ocular muscle paralysis, which may be manifested as strabismus, eyelid ptosis, pupil dilatation, etc.; the presence of facial nerve paralysis may be manifested as crooked corners of the mouth, nasolabial sulcus becomes shallow, etc.

Toxic nephropathy

Rare, mainly manifested by decreased urine output, urine routine may have white blood cells and tubular appearance.

Secondary infection

It can be secondary to other bacterial infections, which may manifest as pneumonia, purulent lymphadenitis, otitis media, sinusitis, etc.

Consultation

Department of Medicine

Department of Infectious Diseases

History of close contact with diphtheria patients, fever, sore throat, bloody nose, tonsils, pharynx, nose covered with gray pseudomembrane, etc. It is recommended to consult a doctor promptly.

Pediatrics

Pediatricians are advised to consult a pediatrician when the above symptoms occur.

Preparation for medical treatment

Preparation for consultation: registration, preparation of documents, common problems

Tips for seeking medical treatment

Patients with high fever can be cooled down physically by wiping their armpits with a wet towel or applying a compress to the forehead before going to the doctor.

Parents need to provide the doctor with the symptoms of the child if the infant is unable to describe his/her own symptoms.

Preparation Checklist

Especially need to pay attention to the time of symptom onset, special performance, etc.

Is there a fever? How long has the fever been present? What is the highest temperature?

Is there fatigue, loss of appetite, nausea, vomiting?

Is there a sore throat, bad breath?

Is there hoarseness, loss of voice?

Is there nasal congestion, purulent or bloody nasal discharge?

When did the above symptoms appear?

Is there any history of close contact with diphtheria patients?

Is there any history of traveling in a diphtheria-endemic area?

Have you been immunized against diphtheria?

Test results from the last 2 weeks, which can be brought to the doctor’s office.

Laboratory tests: blood test, urine test, bacterial smear, bacterial culture, etc.

Diagnosis

Diagnosis is based on

Medical history

Close contact with diphtheria patient or history of traveling in diphtheria endemic area, no diphtheria vaccination.

Clinical manifestations

There may be fever, sore throat, grayish-white pseudomembrane adhering to the pharynx, nose, and throat, generalized malaise, and enlarged lymph nodes [1].

Laboratory tests

The white blood cell count may be mildly to moderately elevated, with predominantly increased neutrophils, and thrombocytopenia may be present in severe cases.

Leukocytes and urinary protein can be seen in the urine of some patients.

A double serum taken at the beginning of the disease and during the recovery period to detect specific antibodies, showing a fourfold or more increase helps in the diagnosis of the disease [11].

Bacterial smear

Bacterial culture

When there is a high clinical suspicion of Corynebacterium diphtheriae infection, culture is performed with a special medium, and the diagnosis can be made with a positive culture result.

Diphtheria toxin test

Pseudomembranes or secretion smears are taken and diphtheria exotoxin is detected by fluorescent antibody method.

Polymerase Chain Reaction (PCR)

PCR can detect the diphtheria toxin gene fragment. A positive test indicates the presence of the toxin gene, but further bacterial culture is needed to confirm the diagnosis. A negative test helps to rule out diphtheria infection.

Imaging

Cardiac ultrasonography in patients with myocarditis shows an enlarged heart.

Diagnostic criteria

The disease is diagnosed when there are typical clinical signs, such as fever, sore throat, and a grayish-white pseudomembrane adhering to the pharynx, and when Corynebacterium diphtheriae is cultured from respiratory secretions or mucosal lesions, or when a positive test for diphtheria toxin is performed.

Differential diagnosis

Different parts of diphtheria need to be differentiated from different diseases, and the differential diagnosis of the disease needs to be carried out by specialized doctors.

Pharyngeal diphtheria needs to be differentiated from acute suppurative tonsillitis, thrush, and infectious mononucleosis.

Laryngeal diphtheria needs to be differentiated from acute laryngitis, angioneurotic laryngeal edema, foreign bodies in the trachea.

Nasal diphtheria should be differentiated from foreign bodies in the nasal cavity, nasal septal ulcers, and congenital syphilis causing ulcers in the nasal cavity.

Acute purulent tonsillitis

Acute purulent tonsillitis may have high fever, pharyngeal pain, and a thin yellowish-white purulent secretion on the surface of the tonsils, but it does not extend beyond the tonsils and can be easily swabbed off, so it can be differentiated from pharyngeal diphtheria.

Foreign body in trachea

May manifest as choking cough, but there is no pseudomembrane formation in the larynx, tracheoscopy can be performed to clarify the diagnosis, and can be differentiated from laryngeal diphtheria.

Foreign body in nasal cavity

Foreign bodies are often one-sided, and it is easier to detect the presence of foreign bodies in the nasal cavity without pseudomembrane formation in the nose, which can be differentiated from nasal diphtheria.

Treatment

Therapeutic goal: to reduce symptoms, prevent and minimize complications.

Treatment principle: Pathogenic treatment, including diphtheria antitoxin and antibiotic application.

General treatment

Patients need to be hospitalized and isolated, with 2 weeks of bed rest for mild cases and 4 weeks for severe cases, and absolute bed rest for those complicated by myocarditis.

Adequate calories should be given, and the diet should be fluid.

The living environment should be maintained with fresh air and sufficient sunlight, and relative humidity should be maintained to avoid dryness.

Pathogen treatment

Diphtheria antitoxin

Diphtheria antitoxin neutralizes diphtheria toxin and needs to be administered as early as possible and in adequate doses [1,4].

The dose administered depends on the site, extent and severity of the lesion and the timing of treatment.

It should be noted that the antitoxin is extracted from the diphtheria immune serum of horses, which is a heterologous protein, and a history of allergy must be taken and skin sensitization tests must be performed and negative before the drug is administered [11].

Antibiotics.

Antibiotics inhibit the growth of Corynebacterium diphtheriae, thus stopping the production of the toxin, but they do not substitute for antitoxin.

Penicillin is preferred, penicillin allergy can be changed to erythromycin, clindamycin, azithromycin and rifampicin can also be used in the treatment of this disease.

Complications

If myocarditis is complication, treatment such as myocardial nutrition, e.g. infusion of coenzyme A, etc. is needed.

Complicated peripheral nerve paralysis, need to be under the guidance of the doctor nutritional nerve treatment. For pharyngeal muscle paralysis and choking can not eat, can be given nasal diet. For respiratory paralysis, tracheotomy is feasible and ventilator-assisted treatment is adopted. For paralyzed limb muscles, acupuncture or physiotherapy is feasible.

Prognosis

Cure

The overall prognosis of diphtheria has improved significantly after the application of treatment with antitoxins and antibiotics, and the morbidity and mortality rates have been reduced to less than 5% [2].

The younger the age, the more severe the symptoms, the presence of laryngeal obstruction and the development of complications, the poorer the prognosis; having received vaccination and early and adequate antitoxin and antibiotic treatment improves the prognosis [11].

Those who are injected with antitoxin serum on the first day of illness have a low case fatality rate, which will be significantly higher if delayed beyond 48-72 hours, and those with severe myocarditis with conduction block have a poor prognosis and risk of sudden death.

Harmfulness

Fever, malaise, loss of appetite, enlarged lymph nodes, dyspnea, etc. can occur after infection, affecting patients’ work and life.

Serious patients are at risk of death.

Daily

Daily management

Mainly fluid diet, give enough calories.

Bed rest is required, 2 weeks for mild cases and 4 weeks for severe cases.

Keep the living environment with fresh air and sufficient sunlight, maintain relative humidity to avoid dryness, and pay attention to oral and nasal hygiene.

Prevention

Control the source of infection

Patients need to be isolated in time, and the isolation can be lifted after 2 consecutive negative throat swab cultures for Corynebacterium diphtheriae.

Carriers need to be isolated for 7 days and treated with antibiotics, and the isolation can be lifted after 3 consecutive negative cultures.

Cutting off the transmission pathway

Nasopharyngeal secretions and objects touched by the patient, such as bedding, must be strictly disinfected.

The patient’s living space can be sprayed with disinfectant and ventilated.

Protecting susceptible people

Newborns should be vaccinated against diphtheria toxoid-tetanus toxoid-pertussis vaccine triple vaccine for 3 months after birth, and then injected intramuscularly 3 times at 4, 5 and 18-24 months of age, respectively, and can be booster injected once at the age of 6 years [1].

It is advisable to give both diphtheria toxoid and antitoxin injections to susceptible or close contacts during epidemics.