Diphtheria – Applied aspect

Dr Sunila BHMS,MD(Hom)

DIPHTHERIA
Diphtheria is an acute communicable disease caused by Coryne bacterium diphtheriae. It usually occurs in children and results in the formation of a yellowish-grey pseudomembrane in the mucosa of nasopharynx, oropharynx, tonsils, larynx and trachea. C.diphtheriae elaborates an exotoxin that causes necrosis of the epithelium which is associated with abundant fibrinopurulent exudates resulting in the formation of pseudomembrane. Absorption of exotoxin in the blood may lead to more distant injurious effects such as myocardial necrosis, polyneuritis, parenchymal necrosis of the liver, kidney and adrenals. The constitutional symptoms such as fever, chills, malaise, obstruction of air ways and dyspnoea are quite marked.

Coryne bacterium diphtheriae
Coryne bacterium diphtheriae are gram positive rods 3×3μm in size, pleomorphic, non-motile, non-sporing, non-capsulate, generally aerobic and facultatively anaerobic. These bacilli exhibit characteristic arrangement in smear preparations. Adjacent bacteria lie at various angles to each other giving ‘V’ or ‘L’ appearances which collectively resemble arrangement of Chinese letters or cuneiform writing. This arrangement is because of incomplete separation of daughter cells at the moment of division.

C.diphtheriae is classified into three main types based on the colony morphology on tellurite medium, bio chemical reactions and hemolytic property.

• Gravis
• Intermedius
• Mitis

Virulent strains produce an exotoxin which is responsible for producing remote effects. Around 90-95% of the gravis and intermedius strains are toxigenic while only 80-85% of mitis are so. The toxin is a labile protein of molecular wt 62,000 and it is inactive when released by the bacterium.

Epidemiology:
The disease has been almost wiped out from developed countries, but in India it is still prevalent. Diphtheria is more common in children. In unvaccinated population, children below 2-15 years of age are at the highest risk. Disease is spread by droplets, contaminated vessels shared by children or by direct inoculation into skin abrasions or eyes. The organism is harbored by carriers and cases. Unimmunized children in a partially immunized community are highly susceptible. Untreated cases are infective for more than two weeks. During outbreaks susceptible individuals can be identified by the Schick intra-dermal test.

Schick test: This test was introduced by Schick in 1913 and is performed to assess the immunity against diphtheria in children above 2 months of age.

The test comprises of injecting intradermally 0.2 ml of diphtheria toxin which 1/50μLD of toxin in the left forearm. Similar dose of heat inactivated toxin is injected in the right forearm. Readings are taken after 24-48 hours and then after 5-7 days of inoculation. The following types of reactions may be observed:

• In negative reaction there is no reaction of any kind in either forearm. This indicates the person is immune to diphtheria.
• In positive reaction an erythematous reaction appears in the test arm within 24-36 hours, (1-3cm diameter) and persists for 7 days whereas there is no reaction on the control arm. This status is indicative of susceptibility of the individual to diphtheria.
• Pseudo reaction develops in both the arms in less than 24 hours. Usually fades away in 4 days. This is also indicative of immunity to diphtheria.
• In combined reaction both the arms show reaction during first 24 hours, after which in test arm, reaction continues to develop whereas in control arm it fades. This reaction is indicative of susceptibility to diphtheria. 

Pathogenesis and pathology

• The organisms enter through the respiratory passages, eyes, middle ear, genitalia and skin.
• Incubation period        – 3-4 days
• But it may vary from 2-7 days

The exotoxin causes tissue necrosis, which favors further growth of the organism and toxin production. The epithelium degenerates and serofibrinous exudate develops which contains inflammatory cells and fibrin. The coagulation of these exudates on the ulcerated, necrotic surface creates a bluish white membrane over the involved area. The membrane is adherent and when removed forcibly it leaves a raw bleeding surface. Site of predilection for the primary lesions is the respiratory tract. Other sites of infection are nose, ears, conjunctiva, genitalia and skin.

• Around the membrane, there may be necrosis, ulceration or haemorrhage. Sometimes the membrane may not be evident, but the pharynx may show hyperemia and oedema.
• Regional lymph nodes are markedly enlarged. The toxin is absorbed from the primary site and it causes damage to the myocardium, kidneys, adrenal gland and the cranial and the peripheral nerves.
• Myocardium shows cloudy swelling, fatty change, mild haemorrhage and round cell infiltration. This may lead to cardiomegaly and conduction disturbances.
• Kidney shows cloudy swelling of the tubular epithelium and interstitial nephritis. 
• The adrenal glands are enlarged with haemorrhage in the cortex. 
• Liver cells sow degenerative changes with scattered area of focal necrosis; peripheral cells may show degeneration of the myelin sheath and axis cylinders, motor fibres being more affected.
• The posterior column of the spinal cord may be involved.
• Rarely cerebral haemorrhage, meningitis and encephalitis have been described.
• Respiratory obstruction by the membrane or toxic myocarditis may lead to death.

Clinical features:
These depend on the primary site of involvement, duration of the illness, systemic effect of the toxin and resistance of the heart.

The disease starts with sore throat, low grade fever, head ache, malaise, vague aches and pains, and catarrhal symptoms. As the disease progresses, tachycardia, nausea, vomiting, pallor and weakness follows.

Pharyngeal Diphtheria:
It is the most common form and the membrane is present over the tonsils and the pharynx. Gross cervical lymphadenopathy (described as bull neck) is evident and respiratory obstruction may develop, especially in children. In severe cases circulatory collapse occurs. Local effects of the toxin lead to paralysis of the palate and pharynx.

The term ‘malignant diphtheria’ is given to condition characterized by marked oedema of the sub mandibular areas and anterior part of the neck. There is moderate leukocytosis (14,000-16,000/cumm) with polymorphs forming 60-80% 

Laryngeal Diphtheria:
This forms 25% of the cases. It produces respiratory obstruction early, which may be fatal. (Inflammation and necrosis of subjacent tissues permit dislodgement and aspiration of the membrane, result in acute respiratory obstruction.

The clinical features include barking cough, hoarseness, dyspnoea, stridor and cyanosis. Infants with laryngeal diphtheria may refuse to suck the breast due to choking.

Nasal Diphtheria:
It occurs in 2-3% cases. The membrane is limited to the septum or turbinate and is usually unilateral. The condition may present with a foul smelling serosanguinous nasal discharge or frank epistaxis.

Cutaneous Diphtheria:
Coryne bacterium diphtheria cannot penetrate the intact skin and it gains entry through wounds, burns or abrasions. It causes ulceration. The typical ulcer usually punched out and 0.5 cm or more in size. In the early stage the ulcer is covered by a grayish yellow or brownish membrane.

There may be coexistent pharyngeal diphtheria in 20% of the cases.

Other sites of lesion are the conjunctiva, vulva, vagina, uterine cervix, bladder, urethra, penis, middle ear, buccal mucus membrane and oesophagus. 

Complications: Mechanical obstruction of the air way by the spreading membrane is a dreaded complication.

• The other complications are due to the systemic effects of the toxin. The incidence and severity of toxic manifestations increase in proportion to the extent of the membrane.
• Toxic complications are more pronounced in the heart and motor nerves. Though 60% of the patients have pathological lesions in the heart, only 10-12% manifest clinically.
• Myocarditis should be suspected if there is variation in the intensity of heart sounds, systolic murmurs, conduction defects, atrial fibrillation, ventricular ectopic beats or ventricular tachycardia. Sudden death may occur due to ventricular fibrillation. Congestive failure and cardiac dilation are less common. In infants and young children vomiting may be an early symptom of cardiac involvement.
• Toxic peripheral neuritis: develops 2-6 weeks after the primary lesion. Third, sixth, seventh, ninth and tenth cranial nerves are commonly affected.
• Palatal and pharyngeal paralysis may occur as early as the third day. 
• External ophthalmoplegia and paralysis of accommodation are frequent.
• Motor weakness may involve the limbs or respiratory muscles.
• Ascending polyneuritic type of lesions may follow 2-3 months after the acute attack of diphtheria.

Diagnosis:
The diagnosis of diphtheria is essentially clinical. Confirmation of diagnosis depends on the demonstration of the oranges in the stained smears made from the membrane and by the culture using Loeffler’s medium. Fluorescent anti toxin staining provides a method for rapid diagnosis. Toxigenicity can be assessed by genuine pig inoculation, passive agar gel diffusion (Elekplate method) or counter immuno electrophoresis. 

Differential Diagnosis:
Acute follicular tonsillitis: In follicular tonsillitis the exudates is confined to the tonsils, it is yellowish and can be wiped off without being adherent. Fever is high in acute tonsillitis where as it is only mild in diphtheria. Regional lymphadenopathy is more marked in diphtheria than in acute tonsillitis.

Agranulocytosis and 3. Acute leukaemia: in these there is no true membrane. The tonsils are red, enlarged and necrotic or hemorrhagic. Hematological examination establishes the diagnosis.

Prevention
It includes general active immunization and management of contacts. Active immunization is done with diphtheria, pertussis, and tetanus (DPT) vaccine which is also known as triple antigen. The first dose should be given at 2 months and thereafter two more doses at 4 weeks intervals. Booster doses should be given at the second and fifth year.

References

• Text book of pathology- Harsh Mohan
• Microbiology for dental students- Rajesh Bhatia; RL ichhpujani
• Text book of medicine- Krishnadas
• Harrison’s principles of internal medicine
• Muir’s text book of pathology
• Pathology illustrated/ Govan/ Mac Farlane/ Callander
• Pathologic basis of disease- Robbins, Cotran, Kumar