1. D iphtheria Sorokhan V.D., MD, PhD Bukovinian State Medical University Department of infectious diseases and epidemiology 2. Definition C . diphtheriae infection is typically characterized by a local inflammation, usually in the upper respiratory tract, associated with toxin-mediated cardiac and neural disease. 3. Etiology Corynebacteria are gram-positive, catalase-positive, aerobic or facultatively anaerobic, generally nonmotile rods. 4. Pathophysiology The toxin is a single polypeptide with an active (A) domain, a binding (B) domain, and a hydrophobic segment known as the T domain, which helps release the active part of the polypeptide into the cytoplasm. T he toxin is responsible for many of the clinical manifestations of the disease. 5. Pathophysiology In most cases, C diphtheriae infection grows locally and elicits toxin rather than spreading hematogenously. The characteristic membrane of diphtheria is thick, leathery, grayish-blue or white and composed of bacteria, necrotic epithelium, macrophages, and fibrin. The membrane firmly adheres to the underlying mucosa; forceful removal of this membrane causes bleeding. The membrane can spread down the bronchial tree, causing respiratory tract obstruction and dyspnea. 6. Epidemiology Humans are the only known reservoir for the disease. The primary modes of dissemination are by airborne respiratory droplets, direct contact with droplets, or infected skin lesions. Asymptomatic respiratory carrier states are believed to be important in perpetuating both endemic and epidemic disease. Immunization reduces the likelihood of carrier status. 7. Pathology At autopsy, the heart is pale brown, soft, and enlarged, with a characteristic streaky appearance. Neutral fat accumulations are observed in approximately 50% of patients, with extensive hyaline degeneration and necrosis with inflammatory changes. The coronary vessels, valves, endocardial surfaces, and epicardial surfaces are unaffected. In fatal cases, the kidneys demonstrate interstitial edema and necrosis at autopsy. 8. Mortality/Morbidity Mortality rates are highest at the extremes of age and in insufficiently immunized persons. However, even partial immunization confers a reduced risk of severe disease. Death usually occurs within the first week, either from asphyxia or heart disease. 9. History Following an incubation period of 2-4 days, patients typically report upper respiratory tract symptoms (eg, nasal discharge, sore throat). The posterior pharynx and tonsillar pillars are most often involved. Onset is often sudden, with low-grade fevers, malaise, and membrane development on one or both tonsils, with extension to other parts of the respiratory system. The toxic effect in the myocardium characteristically occurs within 1-2 weeks following onset of infection, often when the upper respiratory tract symptoms are improving. Manifestations are due to arrhythmias and congestive heart failure (CHF). 10. History Neurological symptoms can occur immediately or after several weeks. Bulbar symptoms generally occur within the first 2 weeks after disease onset and can range from mild symptoms (eg, difficulty swallowing) to bilateral symmetric paresis of the palatal and ocular muscles. The bulbar symptoms may remit or progress to paralysis of the proximal and then distal skeletal muscles over the next 30-90 days. Although recovery can be very slow, patients generally regain complete neurologic function. Secondary complications include aspiration from bulbar paralysis and bronchopneumonia from respiratory muscle dysfunction. 11. Physical The membrane usually is grayish-white, although it can become blackish or greenish with necrosis. 12. Physical Respiratory signs : The extent of disease correlates with the severity of symptoms. Extension of the membrane to the posterior pharyngeal wall, soft palate, or nasopharynx is associated with profound malaise, weakness, cervical adenopathy, and swelling, which can distort the airway and cause stridor. 13. Physical Cardiac signs : Subtle evidence of myocarditis may occur in many patients, but 10-25% of patients develop clinical cardiac dysfunction. 14. Physical Nervous system signs : Signs of cranial nerve dysfunction can occur within a few days of disease onset, with paralysis of the soft palate and posterior pharyngeal wall causing dysphagia and regurgitation. Although the motor component is usually affected most severely, both sensory and motor nerves are affected by the peripheral neuritis that occurs later. The symptoms start in the proximal muscle groups of the extremities and spread distally. 15. Physical Skin signs : C . diphtheriae can cause skin infections with nonhealing ulcers. A vesicle or pustule develops initially and progresses to one or more punched-out lesions that measure from a few millimeters to several centimeters, with curved elevated margins. The lesions are initially painful and may be covered with eschar. After a few weeks, the lesions become painless and often have a serosanguineous exudate. 16. Differential Diagnoses Amyloidosis, Bacterial p haryngitis, Candidiasis , Viral p haryngitis, Dilated c ardiomyopathy, Bacterial p neumonia, Infectious m ononucleosis , Upper r espiratory i nfection , Infective e ndocarditis , Peritonsillar a bscess 17. Workup The diagnoses of C . diphtheriae infection can be confirmed definitively by culture on blood agar or selective tellurite media, which inhibits the growth of normal oral flora; C . diphtheriae develops a black colony with a characteristic gray-brown halo. Traditionally, toxin production was demonstrated by injecting toxin material into mice and watching to see if they died. 18. Medication For C . diphtheriae infection, the therapy is antitoxin and antibiotic treatment. Many antibiotics are effective, including penicillin, erythromycin, clindamycin, rifampin, and tetracycline. 19. Diphtheria antitoxin (DAT) Dose given depends on site of infection and length of time patient is symptomatic : Laryngeal or pharyngeal disease of 3 d duration or any patient with neck swelling: 80,000-100,000 U IV . May be given IM for mild-to-moderate disease Test all patients with a 1:10-1:100 dilution of DAT SC; if an immediate reaction occurs, administer epinephrine; hypersensitivity to horse serum not contraindication to antitoxin injection; desensitize subjects with increasing doses of diluted DAT 20. Antibiotics Erythromycin - 500 mg PO/IV q6h for 14 d if tolerated . Vancomycin - 1 g IV infused over 1 h q12h . Rifampin - 600 mg PO qd or divided bid . 21. Prevention C hildhood immunization is the prevention method of choice. Diphtheria/tetanus/pertussis (DTP) vaccine, given at ages 2, 4, and 6 months; at age 15-18 months; and at least 5 years later (age 4-6 y) is the immunization regimen recommended. 22. Tests for self-control Which statement about diphtheria is correct? diphtheria is a lower respiratory tract illness diphtheria is characterized by sore throat, high fever , and an adherent membrane on the tonsils , pharynx , and/or nasal cavity a milder form of diphtheria can be restricted to the skin diphtheria is an acute toxin-mediated disease caused by nondiphtherial corynebacteria 23. Tests for self-control Corynebacterium diphtheriae are: gram-negative, catalase-negative, aerobic or facultatively anaerobic, generally nonmotile rods gram-positive, catalase-negative, anaerobic or facultatively anaerobic, generally motile rods gram-negative, catalase-positive, anaerobic or facultatively anaerobic, generally motile rods gram-positive, catalase-positive, aerobic or facultatively anaerobic, generally nonmotile rods 24. Tests for self-control Diphtheria is: anthroponosis zoonosis anthropozoonosis 25. Tests for self-control Corynebacterium diphtheriae are transmitted by: sexual route transmissive route air-borne route parenteral route food-borne route 26. Tests for self-control Corynebacterium diphtheriae gain entry to the body through upper respiratory tract skin genital tract eyes all mentioned above 27. Tests for self-control Which statement about characteristic membrane of diphtheria is correct? membrane is thin, leathery, grayish-blue or white membrane of diphtheria is composed of virus, necrotic epithelium, macrophages, and fibrin the membrane softly adheres to the underlying mucosa forceful removal of this membrane causes bleeding the membrane can not spread down the bronchial tree, causing respiratory tract obstruction and dyspnea 28. Tests for self-control The toxin-induced manifestations of diphtheria involve mainly: heart, brain, liver heart, kidneys, peripheral nerves heart, liver, peripheral nerves all mentioned above 29. Tests for self-control The incubation period of diphtheria is: 1-2 days 2-4 days 3-6 days 4-8 days 30. Tests for self-control Which statement about respiratory signs of diphtheria is correct? patients typically report lower respiratory tract symptoms (eg, cough) the posterior pharynx and tonsillar pillars are seldom involved onset is often gradual, with low-grade fevers, malaise, and membrane development on one or both tonsils, with extension to other parts of the respiratory system the membrane usually is grayish-white, although it can become blackish or greenish with necrosis 31. Tests for self-control Which statement about respiratory signs of diphtheria is incorrect? nasal infection may present as serosanguineous or seropurulent drainage with tonsillar and pharyngeal infection, exudates coalesce to form the characteristic pseudomembrane of diphtheria t he extent of disease does not correlate with the severity of symptoms. edema and membrane formation require intubation