1. DIPHTHERIAThe Past, Present & the Future Dr Cummings HenryConsultant PaediatricianDELSUTH

2. PRE TEST • Diphtheria has been eradicated • The is a resurgence of diphtheria • The mainstay of treatment is antibiotics • Vaccination remain the most effective control measure.

3. Outline • The Past • The Present • The future

4. Diphtheria, The Past: • Introduction • Epidemiology • Aetio-pathogenesis • Immunology • Clinical Presentation • Complications • Differentials • Investigations • Treatment • Prognosis • Prevention

5. Introduction • An ancient disease described by Hippocrates in the 5th century BC • Plagued Europe & the American colonies in the 18th century • Diphtheria is an acute toxic infectious disease • A localized infection of mucous membrane &/or skin • May have systemic complications/manifestations

6. Epidemiology • Reservoir - Exclusively in humans - Skin infection and skin carriage constitute silent reservoir • Mode of spread * primarily by airborne respiratory droplets * direct contact with; -respiratory secretions of infected individuals -exudates from infected skin lesions

7. Epidemiology contd. • In the U.S - Pre-vaccination era(1920s) > 115,000 cases and 10,000 deaths reported annually - Recently, < 5 cases are reported annually • In Nigeria - 5,039 cases reported in 1989 - 3,995 cases in 2000 - 2,468 cases in 2001 - 312 cases in 2006 (7.8% of global report)

9. Epidemiology contd. • Carriers are important in transmission - constitute 3-5% of healthy individuals in endemic region • Estimated mortality rates→5-10% (up to 20% in <5yrs, & > 40yrs)

10. Epidemiology contd. • Sex No significant difference in the incidence in males & females of similar immunization status • Age - Commoner in 6month-12yrs (esp. in the pre-vaccination era)

11. Risk factors • Incomplete or absent immunization • Low herd immunity • Travel to endemic areas or regions with current epidemic • Immunocompromised states e.g. HIV/AIDS • Low socio-economic status • Poor health care facilities • Overcrowding

12. Aetio-pathogenesis • Caused by toxigenic Corynebacterium diphtheriae • Types - Corynebacterium diphtheriae * mitis * intermedius * belfanti * gravis - Corynebacterium ulcerans- causes cutaneous disease

13. Characteristics • Gram positive • Club-shaped bacillus • Aerobic • Non-motile • Non-encapsulated • About 2-4μm in length • Assume L &/or V configuration to each other • Form a Chinese lettering pattern

14. Corynebacterium diphtheria

15. Gram stain Methylene blue stain Corynebacterium diphtheria

16. Virulence • Depends on the ability to produce the diphtheria toxin-an exotoxin • Toxigenicity depends on the presence of a lysogenic bacteriophage • Non-toxigenic strain can become toxigenic by coming in contact with toxigenic strains

17. B-phage that carries the tox gene that encodes the diphtheria toxin

18. The Exotoxin • A 62,000 dalton polypeptide • Composed of 2 joined major segments (A and B)

19. Actions of the Toxin • Segment B bind receptors on susceptible cells and facilitate entrance of segment A • Segment A mediates toxic actions: - inactivates RNA translocase - inhibits protein synthesis - causing tissue necrosis

20. Actions of The Toxin contd. • Formation ofpseudomembrane * a dense necrotic coagulum of organism, epithelial cells, fibrin, leucocytes & RBCs * grayish-white or brown in colour

21. Histological Gross The Pseudomembrane

22. Other effects of the toxin • Paralysis of palate & hypopharynx • Systemic absorption: - renal tubules necrosis - thrombocytopenia - cardiomyopathy - demyelination of nerves - paralysis of the diaphragm • The toxin is converted to toxoid (for vaccination) when treated with formalin

23. Immunology • Organisms invasion usually remain localized • The main immune response is to the exotoxin • Immune response is antibody-mediated • The antibody is of the IgG type – Antitoxin • Immunity does not prevent colonization rather it protects against the effects of the toxin

24. Immunology Contd. • Active antibodies production may be induced by: - active disease - carrier state - vaccination with the toxoid • Passive immunity –transplacentally transferred • Immunity was previously thought to be life long

25. Assessment of immunity • The Schick test: - Intradermal injection of 0.1ml 1:50 dilution of toxin - positive result: inflammation appearing after 24-36hrs & persisting for ≥ 4days – no antitoxin – no immunity - negative result – has antitoxin - immune

26. Immunity assessment contd. • Assay of serum level of antitoxin - full protection: ≥0.1IU/mL - basic protection: ≥0.01- <0.1IU/mL - no protection : < 0.01IU/mL N.B: Epidemic outbreak is likely when > 90% of the population has < 0.01IU/mL of antitoxin

27. Clinical Presentation • Incubation: usually 2-4days with a range of 1-7days • Classified into: - Respiratory Tract Diphtheria - Non-Respiratory Tract disease - Complicated disease

28. Respiratory tract diphtheria • Nasal Diphtheria - commoner in infants - little or no constitutional symptoms - serosanguineous nasal discharge - epistaxis

29. Nasal Diphtheria contd. • - purulent foul smelling discharge - shallow ulcers +/- pseudomembrane - unilateral or bilateral - may persist for several weeks - major source of transmission

30. Tonsilo-Pharyngeal • Most common (90% of cases) • Malaise • Fever – mild to moderate • Sore throat – drooling, odynophagia +/- dysphagia • Bull-neck appearance • Pseudomembrane of variable extent

31. Bull-Neck appearance

32. Pseudomenbrane

33. Laryngeal Diphtheria • Usually an extension of pharyngeal disease • Hoarseness of voice • Cough • Inspiratory stridor

34. Laryngeal Diphtheria contd. • Suprasternal, substernal & subcostal recessions • Symptoms & signs of sudden airway obstruction • Sudden death • May require intubation/tracheotomy

35. Tracheo-bronchial diphtheria • Usually an extension from pharynx & larynx • Diphtheria pneumonia – hemorrhagic • Bronchiolar pseudomembrane • Airway obstruction/sudden death

36. Diphtheria Pneumonia

37. Non-Respiratory disease

38. Cutaneous diphtheria

39. Cutaneous diphtheria • superficial, non-healing ulcers • well defined margins • pseudomembrane on floor of ulcer • erythema & tenderness of surrounding skin • important in transmission in the community

40. Cutaneous diphtheria contd. • Predisposing factors: - pre-existing dermatoses - laceration - burns - bites - impetigo

41. Other non-respiratory disease • Ear- otitis externa • Eye – purulent and ulcerative conjunctivitis • Genital tract – purulent and ulcerative vulvo-vaginitis • Rarely septicaemia

42. Complications • Toxic Cardiomyopathy - commonly myocarditis, rarely endocarditis - usually occurs at the end of 2nd wk of illness - tachycardia out of proportion to fever - arrhythmias - symptoms & signs of CCF - occurs in 10-25% of patients - accounts for 50-60% of deaths

43. Toxic Cardiomyopathy contd. • ECG findings: - prolonged PR interval - ST segment elevation - 1st, 2nd, or 3rd degree heart block • Echocardiogram: - dilated cardiomyopathy - hypertrophic cardiomyopathy - vegetations

44. Toxic Neuropathy • Usually occurs at 3-4wks • Affects mainly motor functions • Paralysis of soft palate &pharyngeal wall - nasal voice - difficulty in swallowing (esp. fluids)

45. Toxic Neuropathy contd. • Occulomotor N. & cillary paralysis - strabismus &/or blurred vision • Peripheral neuritis – diminished DTR & paralysis - occasionally glove & stockings neuropathy ( like GBS) • Paralysis of the diaphragm

46. Airway obstruction • Commoner in laryngeal disease • May be sudden • Usually due to dislodgement of Pseudomembrane • May require intubation/tracheotomy & mechanical ventilation

47. Differentials • Tonsillo-Pharyngitis • Viral Croup • Epiglottitis • Peritonsilar abscess • Angioedema • Myocarditis (other causes) • Peripheral neuropathy 2o GBS

48. Laboratory Studies • Methylene blue &/or gram staining • Culture using tellurite-Loeffler media • Toxigenicity test: - Elek test - PCR

49. Laboratory studies contd. • FBC – moderate leucocytosis • Urinalysis – transient proteinuria • Serum assay of antibodies – immunity • Serum assay of troponin 1 – myocarditis

50. Radiological studies • Echocardiogram & ECG findings • Neck soft tissue X-ray – prevertebral soft tissue swelling: