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DIPHTHERIA The Past, Present & the Future Dr Cummings Henry Consultant Paediatrician DELSUTH.

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Presentation on theme: "DIPHTHERIA The Past, Present & the Future Dr Cummings Henry Consultant Paediatrician DELSUTH."— Presentation transcript:

1 DIPHTHERIA The Past, Present & the Future Dr Cummings Henry Consultant Paediatrician DELSUTH

2 PRE TEST 1. Diphtheria has been eradicated 2. The is a resurgence of diphtheria 3. The mainstay of treatment is antibiotics 4. Vaccination remain the most effective control measure.

3 Outline The Past The Past The Present The Present The future The future

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

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

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

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

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

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

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

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

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

14 Corynebacterium diphtheria

15 Gram stain Gram stain Methylene blue stain Methylene blue stain

16 Virulence Depends on the ability to produce the diphtheria toxin-an exotoxin Depends on the ability to produce the diphtheria toxin-an exotoxin Toxigenicity depends on the presence of a lysogenic bacteriophage Toxigenicity depends on the presence of a lysogenic bacteriophage Non-toxigenic strain can become toxigenic by coming in contact with toxigenic strains 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 A 62,000 dalton polypeptide Composed of 2 joined major segments Composed of 2 joined major segments (A and B) (A and B)

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

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

21 The Pseudomembrane Histological Histological Gross Gross

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

23 Immunology Organisms invasion usually remain localized Organisms invasion usually remain localized The main immune response is to the exotoxin The main immune response is to the exotoxin Immune response is antibody-mediated Immune response is antibody-mediated The antibody is of the IgG type – Antitoxin The antibody is of the IgG type – Antitoxin Immunity does not prevent colonization rather it protects against the effects of the toxin 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 antibodies production may be induced by: - active disease - active disease - carrier state - carrier state - vaccination with the toxoid - vaccination with the toxoid Passive immunity –transplacentally transferred Passive immunity –transplacentally transferred Immunity was previously thought to be life long Immunity was previously thought to be life long

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

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

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

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

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

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

31 Bull-Neck appearance

32 Pseudomenbrane

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

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

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

36 Diphtheria Pneumonia

37 Non-Respiratory disease

38 Cutaneous diphtheria

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

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

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

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

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

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

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

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

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

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

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

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

51 Treatment Diphtheria Antitoxin Diphtheria Antitoxin - mainstay of treatment - mainstay of treatment - give at clinical diagnosis - give at clinical diagnosis - can only neutralize free toxins - can only neutralize free toxins - efficacy diminishes with delay - efficacy diminishes with delay - only available from CDC/WHO - only available from CDC/WHO - preferably given IV - preferably given IV - dosage depends on site involved & duration of illness - dosage depends on site involved & duration of illness

52 Dosage of Antitoxin (units) Site and extent of lesion illness 72hrs Site and extent of lesion illness 72hrs Nasal 10,000-20,000 10,000-20,000 Nasal 10,000-20,000 10,000-20,000 One tonsil 20,000 20,000-40,000 One tonsil 20,000 20,000-40,000 Both tonsils+/- Both tonsils+/- Pharyngeal 20,000-40,000 40,000-60,000 Pharyngeal 20,000-40,000 40,000-60,000 Laryngeal or Laryngeal or Combined types 40,000-80,000 60,000-80,000 Combined types 40,000-80,000 60,000-80,000 Very extensive Very extensive Disease 60,000-80,000 80, ,000 Disease 60,000-80,000 80, ,000 N.B. Test for sensitivity before administration and desensitized if necessary

53 Testing for Sensitivity Skin test: Skin test: - Intradermal injection of 0.1mL of 1:10 dilution of antiserum in saline - Intradermal injection of 0.1mL of 1:10 dilution of antiserum in saline - read in 20mins - read in 20mins - a wheal ≥ 1cm – positive – sensitive - a wheal ≥ 1cm – positive – sensitive Conjunctiva test: Conjunctiva test: - conjunctivitis & lacrimation – positive - conjunctivitis & lacrimation – positive Caution! Ensure adrenalin is available Caution! Ensure adrenalin is available

54 Desensitizing 0.1ml of a 1:20 dilution subcut. - wait 20mins 0.1ml of a 1:20 dilution subcut. - wait 20mins 0.1ml of a 1:10 dilution subcut. - wait 20mins 0.1ml of a 1:10 dilution subcut. - wait 20mins 0.1 ml undiluted subcut. - wait 20mins 0.1 ml undiluted subcut. - wait 20mins 0.3ml undiluted IM - wait 20mins 0.3ml undiluted IM - wait 20mins 0.5ml undiluted IM - wait 20mins 0.5ml undiluted IM - wait 20mins If no reaction has occurred the rest of the dose can be given IM If no reaction has occurred the rest of the dose can be given IM

55 Antimicrobial therapy Role: Role: - halt toxin production - halt toxin production - treat localized infection - treat localized infection - prevent transmission - prevent transmission Drugs/dosage Drugs/dosage - IV/IM penicillin - IV/IM penicillin * iv xtapen 100,000/kg/day in 6hrly dosing * iv xtapen 100,000/kg/day in 6hrly dosing * im procaine pen. 25,000iu/kg/day, 12hrly * im procaine pen. 25,000iu/kg/day, 12hrly - Oral erythromycin, 40mg/kg/day 6hrly - Oral erythromycin, 40mg/kg/day 6hrly

56 Antimicrobial contd. Other drugs that can be used: Other drugs that can be used: - Clindamycin - Clindamycin - Tetracycline - Tetracycline Give for 10 – 14 days Give for 10 – 14 days Elimination of organism should be confirmed by at least 2 successive negative culture obtained 24hrs apart. Elimination of organism should be confirmed by at least 2 successive negative culture obtained 24hrs apart.

57 Treatment contd. Isolation Isolation - respiratory isolation for respiratory disease - respiratory isolation for respiratory disease - contact isolation for cutaneous disease - contact isolation for cutaneous disease Bed rest Bed rest Secure airway if necessary Secure airway if necessary NG tube feeding – palatal/pharyngeal paralysis NG tube feeding – palatal/pharyngeal paralysis

58 Treatment contd. IV fluid administration if needed IV fluid administration if needed Vaccinate – 1 0 series &/or boosters Vaccinate – 1 0 series &/or boosters Disease notification Disease notification Contact tracing Contact tracing

59 Contact tracing & Care The risk of developing the disease after household exposure to a case is ≈ 2% The risk of developing the disease after household exposure to a case is ≈ 2% The risk of disease after exposure to a carrier The risk of disease after exposure to a carrier is ≈ 0.3% is ≈ 0.3% Types of contacts: Types of contacts: - asymptomatic case contact - asymptomatic case contact - carrier - carrier

60 Asymptomatic case contact monitor for illness monitor for illness culture culture Antimicrobial prophylaxis Antimicrobial prophylaxis Vaccinate Vaccinate primary schedule. primary schedule. booster dose booster dose

61 Carrier The reported rate of carriage in household contacts of case patients is 0-25% The reported rate of carriage in household contacts of case patients is 0-25% Antimicrobial prophylaxis x 7days Antimicrobial prophylaxis x 7days Isolation Isolation Monitor Monitor Vaccination Vaccination

62 Prognosis Depends on: Virulence of the organism. Gravis has the highest fatality followed by intermedius and the least is mitis. Virulence of the organism. Gravis has the highest fatality followed by intermedius and the least is mitis. Age; higher mortality rates in individuals 40yrs. Age; higher mortality rates in individuals 40yrs. Immunization status: worse in the unimmunized Immunization status: worse in the unimmunized

63 Prognosis (contd.) Site of infection/involvement; mortality occur in: Site of infection/involvement; mortality occur in: < 1% of cutaneous disease < 1% of cutaneous disease ≈ 10% of uncomplicated respiratory disease ≈ 10% of uncomplicated respiratory disease 30 – 40% of bacteremic disease 30 – 40% of bacteremic disease % of those with cardiac involvement % of those with cardiac involvement. Speed of administration of antitoxin; worse with delay Speed of administration of antitoxin; worse with delay

64 Prevention Immunization is the mainstay of prevention Immunization is the mainstay of prevention Given as DPT Given as DPT Immunization schedule (NPI) Immunization schedule (NPI) - DPT1 – 6wks - DPT1 – 6wks - DPT2 – 10wks - DPT2 – 10wks - DPT3 – 14wks - DPT3 – 14wks

65 The Present

66 Emerging Issues Changing epidemiology Changing epidemiology - recent re-emergence in some developed and developing countries - recent re-emergence in some developed and developing countries - Shifting of the disease into the older population - Shifting of the disease into the older population

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68 Immunity wanes over time Immunity wanes over time

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70 Other Epidemiological issues Questionable Notification from Nigeria Questionable Notification from Nigeria Erratic values: Erratic values: - In 1996 reported 2016 cases - In 1996 reported 2016 cases - In 1997,, 31cases - In 1997,, 31cases *DPT3 coverage in 1996 – 30% *DPT3 coverage in 1996 – 30%

71 Inconsistent figures In 2003 & 2004 – no case reported In 2003 & 2004 – no case reported * In 2003 Nigeria had the worst immunization coverage in the world * In 2003 Nigeria had the worst immunization coverage in the world DPT1 coverage – 43.2% DPT1 coverage – 43.2% DPT3 coverage – 24.8% DPT3 coverage – 24.8% Only 12.8% were fully immunized Only 12.8% were fully immunized

72 Latest Immunization Coverage Global: 79% estimated DPT3 coverage Global: 79% estimated DPT3 coverage Current coverage in Nigeria: Current coverage in Nigeria: - DPT1 is ≈ 65% - DPT1 is ≈ 65% - DPT3 is ≈ 77% - DPT3 is ≈ 77% WHO proposed coverage is ≥ 90% WHO proposed coverage is ≥ 90%

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75 Changes In Immunization strategies Effect of passive immunity on 1 0 series Effect of passive immunity on 1 0 series Commencing 1 O series later e.g. Commencing 1 O series later e.g. - In the US - In the US DPT1 – 2mth DPT1 – 2mth DPT2 – 4mth DPT2 – 4mth DPT2 – 6mth DPT2 – 6mth

76 New Immunization Strategies contd. Boosters: Boosters: - Given at - Given at *18mths *18mths *5yrs *5yrs *adolescence *adolescence *every 10yrs thereafter *every 10yrs thereafter

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78 New Formulations of the Toxoid Td Td - tetanus toxoid with lower dose of diphtheria toxoid - tetanus toxoid with lower dose of diphtheria toxoid - adult type - adult type *for adolescence & beyond *for adolescence & beyond - less side effects - less side effects Tdap Tdap - tetanus toxoid + smaller dose diphtheria + acellular pertusis vaccine - tetanus toxoid + smaller dose diphtheria + acellular pertusis vaccine - may be used for pregnant women - may be used for pregnant women

79 Other Emerging Issues Antitoxin for Carriers: Antitoxin for Carriers: * To give or not to give ? * To give or not to give ? The need for vaccination of pregnant women The need for vaccination of pregnant women

80 The Future

81 Recommendations Improve coverage of 1 0 schedule to 90% at least Improve coverage of 1 0 schedule to 90% at least 4 th & 5 th DPT doses at 18mths & 5yrs respectively 4 th & 5 th DPT doses at 18mths & 5yrs respectively Improve disease Surveillance and notification Improve disease Surveillance and notification

82 Recommendations contd. Research to evaluate the need to Research to evaluate the need to - delay commencement of the primary series - delay commencement of the primary series - give booster doses at adolescence & thereafter every 10yrs, using Td - give booster doses at adolescence & thereafter every 10yrs, using Td - give Td or Tdap to pregnant women - give Td or Tdap to pregnant women

83 Conclusion The global goal is to eradicate diphtheria. This may only be achieved by not only making the right policies but also ensuring that these policies are completely and effectively implemented. The global goal is to eradicate diphtheria. This may only be achieved by not only making the right policies but also ensuring that these policies are completely and effectively implemented.

84 THANK YOU


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