- Slides: 59
DIPHTHERIA – is an acute infectious disease caused by the toxicogenic strains of Corynobacterium diphteriae, anthroponosis, characterizes by a development of fibrinous inflammation in the place of entry and remote effects resulting from toxin, which affects the heart, kidney and peripheral nerves. Diphthera (greek) – means “membrane” or “leathery skin”
Historical reference: As the disease came to Europe from the East, it has long been called the “Egyptian plague” or “Syrian ulcer”. Some manifestations of the disease in the initial stage of its development called also “throat angina” (pectoris) or “throat plague”. In the 18 th century the disease began to be called “croup”. A detailed description of the clinical disease was given in 1826 by French physician Pierre Bretonne. He first pointed relationship of lesions of the larynx with croup (its inflammatory narrowing) and called the disease “diphtherit”. Later in 1846 internist Trousseau suggested the term “diphtheria”, which applies now
1883 - Klebs E. T. discovered the pathogen in diphtheric films and described it; 1884 - Loeffler E. identified the causative agent in culture and described its properties; 1888 - Roux Е. P. P. , Yersin А. E. , Behring E. А. secreted exotoxin and antitoxin (beginning of specific therapy of diphtheria) 1923 - Glen and Ramon Gaston secreted anatoxin (it was beginning of massive immunization against diphtheria) LOEFFLER E. BRETANNO TRUSSO
ETIOLOGY Corynobabacterium (Greek, korune, “club” or “mace”, bacterion, “small rod”) consists of a diverse group of bacteria including animal and plant pathogens, as well as saprophytes. Some Corynobacteria are part of the normal flora of humans. Corynobabacterium diphteriae (C. d. ) - Gram (+) thin rod; - club-shaped (metachromatic grains of volutin on the end of rod); - Nonmotile, nonsporulating; - Has no capsule; - Selective aerobe; - Large (1 -12 × 0. 3 -0. 8 microns);
ETIOLOGY - Has fibrias, facilitating an adhesion; - Divided by “flicks” in medium and is seen in as short chain (V or Y configuration) or resembling Chinese “letter”; - Grow on complex nutrient media containing serum (Leffler broth) or blood agar with tellurite (Klauber medium); - Optimal temperature for cultivation is 37ºС; - Stable to low temperatures; sensitive to boiling, desinfectans (can be inactivated in 1 -2 min); - Can survive in room temperature, in water, in milk 1 -3 weeks
ETIOLOGY -There are 3 biovars of C. diphtheriae: (biotypes are differentiated by colonial morphology, fermentation reaction, enzymatic abilities and severity of the disease) - GRAVIS (R-form) - causes the most severe forms of the disease; - MITIS (S-form) - causes disease in a mild form - INTERMEDIUS - intermediate form between the above two
ETIOLOGY - Produces exotoxin Toxigenicity is depended on the presence of the tox+ gene, carried by a lysogenic bacteriophage; Cases of non-toxigenic strain of C. d. have been documented. - Produces aggressive enzymes – different active bioligical substances (hyaluronidase, neurominidase, fibrinоlysin, hemolysin, necrotiс and hydropic factors) that promote the action of the diphterial toxin and spreding of C. b.
DIFTERIAL TOXIN - is polypeptide composed of 2 joined segments (A and B); - A - is actually a toxin that inactivates RNA translocase and inhibits protein synthesis in the cell with a subsequent death; - B - recognizes the target-cells, binds to their receptors and facilitate the entry part A; -Toxin is in unbound condition in the blood during 10 min and next 30 -40 min fixed on the surface of the target cells; - Then diphterial toxin penetrates the cells, it couldnʹt be bound by antitoxin ( that why should be early administration of the antitoxin!!!). Donʹt be slow in case of diphteria! The diphterial toxin is on the 3 -d place by action (1 -st – botulism, 2 -d – tetanus).
Mode of action of the diphtheria toxin
Virulence intradermal tests in rabbit. Two days after inoculation a few positive reactions are shown on a rabbit`s skin but most are negative
By intensity: 1. Sick persons 2. Convalescents 3. Bacteriocarrier EPIDEMIOLOGY Source of infection: By epidemiologic significance: 1. Bacteriocarrier 2. Convalescents 3. Sick persons Sanation of convalescents are completed in 15 - 20 days, but sometimes 90 days. The frequency of a carrier state in population is 1 -10 %
Mode of transmission: - Aerogenic mechanism (C. d. spreads via respiratory droplets, contact with nasopharingeal secretions) - contact and alimentary mode (less often) - Peak of incidence - in autumn-winter period - Periodicity of outbreaks is every 5 - 7 years - No racial, sex predilection - Before immunization was introduced, D. was a primarily infection of children affecting populations younger than 12 years. - But now, D. shifted into the adult population. This trend is increased due to uncomplite immune status or total inhibition of it (alcohol or immunocompromised drugs). -D. is a controllable disease now, but the scheduled vaccination of children led to increased morbidity of the diseases among the adults!!!
In active vaccination the incidence has decreased significantly
Increased risk for diphtheria infection includes the following factors: 1. Incomplete or absent immunization (in adult population). In some cases immunity does not prevent infection but lessens the severity of the disease; 2. Low public immunity; 3. Travel to endemic areas with current epidemics; 4. Immunocompromised state; 5. Low socioeconomic status, large-scale population movements, poor healthcare system infrastructure and overcrowding
PATHOGENESIS 1. In place of the penetration ( mucous membranes or skin) bacteria intensively multiplies and produces exotoxin that is accompanied by hyperemia, edema and vascular congestion with increased permeability of small blood vessels and epithelial necrosis; This leads to local damage 2. Fibrinogen of serum leaves the capillaries, reacts with thromboplastin of the necrotic epithelium) a transforms into the insoluble fibrin (diphteric membranes); - Fibrin tightly holding a fibrinous film on the surface of the mucosa. - Membranes increase and thicken up to 5 – 6 days of illness !!!
- Membrane is thick, leathery, grey-white and composed of bacteria, necrotic epithelium, phagocytes and fibrin; - It is firmly adherent to the underlying tissues, bleeding follows its forsible removing. - Has tendency to extend to another organs. - Can detach in 5 -6 days. 3. C. d. remains under the film, but exotoxin invades the regional lymph nodes and subcutaneous tissue (lymphadenitis and edema of the subcutaneous layer) and bloodstream, fixes on the target cells with their subsequent toxic and allergic lesions:
- the heart – the myocardium and conducting system; - nervous system - demyelination of nerve fibers (paresis, paralysis and lesion of the peripheral sympathetic ganglia); - adrenal glands - hemorrhage, tissue necrosis; - kidneys – symptoms of nephrosis
The target organs for C. diphtheria
4. Cord - factor С. d. takes certain role in pathogenesis of diphtheria, inhibits phosphorylation and tissue respiration 5. Recovery after the toxic damage is in 4 - 5 weeks to 6 months if the patient survives 6. Disease forms antitoxic and antibacterial immunity but short-term. The disease can repeat!
CLASSIFICATION of DIPHTHERIA : 1. Localization of the process: - Stomatopharyngeal diphtheria A 36. 0 - Nasal diphtheria A 36. 1 - Laryngeal diphtheria A 36. 2 - Cutaneous diphtheria A 36. 3 - diphtheria of other localization A 36 8 - diphtheria hypothetical (unspecified) A 36. 9
2. Spreading of the process: - Localized (if membranes are localized at the tonsils) - Diffuse (if membranes extend into contiguous regions) - Combined (if membranes are localized on the different anatomic regions) 3. Degree of severity: - Bacteriocarrier -Subclinical -Mild -Moderate -Severe -Hypertoxic 4. Character of local inflammation: - catarral - insular-like ( «island» ) - membraneous 5. Complication of diphtheria (TIS, myocarditis, neuritis ets. )
CLINICS 1. Incubation period is 2 to 10 days Carrier state of С. d. (usually asymptomatic) formes after: - the disease (convalescent carrier) - in healthy persons (1 - 10 % in population ). No increasing level of antidiphtherical antibodies in blood. Carrier stage revealed only by bacteriologic detection in smears. Carriage С. d. may be: - Short-term - till 2 weeks - Moderate duration - 2 - 4 weeks - Lingering - more than 4 weeks - Chronic - more than 6 months
SUBCLINICAL FORM of DIPHTHERIA Patients have no any complaints. LOCAL STATUS: - Hyperemia of tonsils and pharynx -Slight edema -No any membranes - diagnosis should be confirmed by bacteriologic and serologic tests - Sometimes is revealed late complications – myocarditis or polyneuritis
DIPHTHERIA of TONSILS and PHARYNX The mild form of disease: - mild weakness with normal BP, normal or subfebrile temperature LOCAL STATUS: - hyperemia and edema of tonsils and mucous membranes; - tonsils are covered with spots of grey or with exudates (insula-form). These spots often form pseudomembranes (membranouse-form) - increased and slight painfull submandibular and cervical lymph nodes - often confuses with tonsillitis, pharyngitis , ARVD
Moderate severity of diphtheria: - acute beginning, fever up to 38 - 38, 5 гр. C, weakness; - pain in muscles and joints, headache, thirst, dicreased appetite, pale skin, sometimes acrocyanosis; - moderate pain in pharyx at swallowing (not leading sign); - relative tachycardia, tendency to hypotension, dull heart sounds, systolic murmurs; - myocarditis and peripheral neuratis may occur in two thirds of patients
LOCAL STATUS: - edema of tonsils and mucous membranes, cyanotic hyperemia; - pseudomembranes are generally firmly adherent, thick, fibrinous, gray-brown, often extends beyond the margins of the tonsils onto the pillars, palate or uvula, removing of them is difficult follows by bleeding; Membrane - doesnʹt grind between slides and - doesnʹt flow on the surface of water; - increased and painful submandibular lymph nodes; - moderate edema of subcutaneous tissue, regional lymphadenopathy; - paralysis of the soft palate and posterior pharyngeal wall;
Edema of anterior neck
Edema of the neck
Severe form of diphtheria: - acute beginning and high (febrile) fever, headache, myalgia, arthralgia, weaknees, vomiting, bed appetite; - cyanosis, signs of dyspnea and early myocarditis (arrhythmia, tachycardia then - bradycardia (bed prognostic sign), dull heart sounds; - peripheral paralysis of the soft palate, cranial neuropathies, myopathy; - sometimes hemorrhagic syndrom, kidney disturbance; LOCAL STATUS: - enlarged and edematous tonsils, cyanotic hyperemia; - tonsils and contiguous regions are covered with thick grey membranes; - regional lymphadenopathy; - edema of the subcutaneous tissue (till clavicles)
HYPERTOXIC FORM DIPHTHERIA: - develops due to penetration of high concentration of corynebacteria and it’s the highest toxin productivity; - starts as severe form diphtheria, but intoxication always prevails above local inflammatory manifestation until appearing of membranes; - rapid course and early complications (CVS failure, TIS, DIC); - the patients can die in the first 1 -3 days; - diagnosis is confirmed by bacteriologic test (postmortem); - Fibrinous films have no time to be generated on the surface of mucousa!!!
LARINGEAL DIPHTHERIA: (DIPHTHERIC CROUP, TRUE CROUP) 1. General intoxication is mild (larynx is covered with single -layer epithelium); 2. HYPOXIA – is dominant sign in the pathogenesis (upper respiratory obstraction due to membrane); 3. Involvement of the larynx is ussually secondary – the result of extension of the diphtheric membranes from the pharynx; 4. Primary laryngeal diphtheria is rare; 5. There are 3 stages of diphtheric (true) croup: a) dysphonic (catarral), b) stenotic, c) asphyxia
a) Catarral stage: - cotinues 1 - 2 days; - begins with subfebrie TºC, weekness, malaise; - cough which becomes burking cough and hoarseness with sputum; - laryngoscopy reveals hyperemia and edema of the mucousa of larynx, the vocal cords and trachea (the films on the mucousa are absent !!!)
b) laringostenosis: (MORE OFTEN ON the 2 – 3 -d DAY of ILLNESS) - duration of the stage - several hours to 2 - 3 days) - appearance of embarrassed breathing and noisy respiration (early symptoms); - retraction of acceassory muscles and intercostal spaces; - aphonia and soundless cough; - the patient is anxious and has forced position in the bed leaning on hands; - cyanosis of skin and mucous; - tachycardia, tachypnea, reduced BP, dull heart sounds; - laryngoscopy reveals edema, hyperemia with cyanosis and pseudomembranes; - if the petient does not received treatment in this stage, he can die.
forced position in bed
c) asphyxia (duration about 8 minutes !!!) - fast development of respiratory unsufficiency; - frequent, shallow, noisy, respiratory arrhythmia; - total cyanosis, chills, forced position; - anxiety which is followed by drowsiness; - weak and arrhythmic pulse, hypotonia; - loss of consciousness, convulsions and death of suffocation (without immediate tracheostomy!!) DIPHTHERIA of NOSE: - can be localized or wide-spread; - mild intoxication; LOCAL STATUS: - rhinoscopy reveals edema, hyperemia of mucous or membranes on the nasal septum; - serosasanguineous discharge, irritation of nostrils and lips; - nasal breathing is impeded; - diagnosis is confirmed by bacteriologic test
DIPHTHERIA of OTHER LOCALIZATION (eyes, skin, genital organs) - is always secondary and include the purulent and ulcerative conjunctivitis, otitis externa, cutaneous diphtheria and purulent and ulcerative vulvovaginitis; - diagnose confirms visually (injure of skin or mucous with presence of a fibrinous film on it) and by bacteriologic test. COMPLICATIONS in 2 types: 1) Those are result of spreading of the membrane in the RT (obstraction); 2) Those due to the effects of the toxin (TIS, DIC, myocarditis (early and late), neuritis (early and late), toxic nephroso-nephritis, hepatitis (only at the serious forms), pneumonia (activation of secondary bacterial flora), asphyxia)
LABORATORY DIAGNOSTICS: SPESIFIC: - Microscopy of the smears and its bacteriologic investigation (swabs should be taken from nose and tonsils beneath the membrane thrice and before AB-therapy); -Bacteriologic culture is essential to confirm the DS; - Serologic test – double serums (quantity of antibody titer to diphtherical exotoxin); - Toxigenisity test (PCR, ELISA);
NONSPESIFIC - CBC – moderate leucocytosis, increased ESR; - UA – leukocytes, erythrocytes, proteinuria (10 g/l) and casts; - biochemical tests - АSТ, LDG, acid-base equilibrium, electrolytes, serum protein, coagulogram, renal and hepatic enzymes; - ECG, medical consultations of neurologist, cardiologist and ENT. DIFFERENTIAL DIAGNOSTICS: 1. Diphtheria of a stomatopharynx: - Streptococcal and staphylococcal angina - Vincent tonsillitis - Infectious mononucleosis - Scarlet fever - Paratonsillitis or аbscess - Candidiasis of oral cavity
Streptococcal and staphylococcal angina
The infectious agent of Vincent tonsillitis
- Ludvig’s angina - Аngio-bubonic form of a tularemia - Secondary angina at a typhoid, lues, tuberculosis, neoplasm, leukosis, agranulocytosis, combustions of a mucous stomatopharynx (acid and alkaline) 2. Diphtheria of the nose: - Meningococcal nasopharyngitis - Streptococcal pharyngitis - Adenoviral pharyngitis 3. Diphtheria of larynx: - False croup (ARVD. parainfluenza, measles etc. ) - Asphyxia of foreign body - Streptococcal pharyngitis (severe)
TREATMENT Obligatory hospitalization and bed regime, treatment should be initiated even before confirmatory tests are completed because of the high potential mortality and morbidity!!! 2. Diet 3. Specific antitoxin – is the main therapy! Don’t be slow! Immediate introduction of an antitoxin: (in thousand IU) IV 40 80 120 160 mild moderate severe hypertoxic IM 60 110 160 220 Antitoxin is administered once at the emperic dose based on the degree of toxicity, site and size of the membranes and duration of illness. Antitoxin should be given i/v by infusion.
ANTIBACTERIAL therapy: - Benzylpenicillin 100. 000 -200. 000 IU/кg/day - Ampicillin 50 - 100 мg/кg/day - Amoxicillin 20 - 25 мg/кg/day - Rifampicin 9 мg/кg day / (мах. 600 мg) - Clindamycin 10 - 25 мg/кg/day - Eritromycin 20 - 30 мg/кg/day IM IM PO PO
PATHOGENIC THERAPY - detoxication and sufficient hydration - inhibitors of proteases antioxidants diuretics glucocorticoids nonsteroid antiinflammatory drugs antihistamine drugs treatment of myocardites, neuritises etc. PROPHYLAXIS - Common: - inspection of the contact persons, final disinfection in the focus, - quarantine for 7 days - Special (create active immunity): vaccination by diphtherial anatoxin: - primary immunization on the 3, 4, 5 -th months of life, - revaccination in 18 months, and then in 6, 11, 14, 18 years, - the adult population should be revaccinated every 10 years.
Be healthy and happy!