DIPHTHERIA The Past Present the Future Dr Cummings

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

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.

The Past Outline n The Present n The future n

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

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

n n 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

Epidemiology contd. In the U. S - Pre-vaccination era(1920 s) > 115, 000 cases and 10, 000 deaths reported annually - Recently, < 5 cases are reported annually n 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) n

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

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

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

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

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

Corynebacterium diphtheria

Corynebacterium diphtheria n Gram stain n Methylene blue stain

Virulence n n n 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

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

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

Actions of the Toxin n 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 n

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

The Pseudomembrane n Histological n Gross

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

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

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

Assessment of immunity n The Schick test: - Intradermal injection of 0. 1 ml 1: 50 dilution of toxin - positive result: inflammation appearing after 24 -36 hrs & persisting for ≥ 4 days – no antitoxin – no immunity - negative result – has antitoxin - immune

Immunity assessment contd. n Assay of serum level of antitoxin - full protection: ≥ 0. 1 IU/m. L - basic protection: ≥ 0. 01 - <0. 1 IU/m. L - no protection : < 0. 01 IU/m. L N. B: Epidemic outbreak is likely when > 90% of the population has < 0. 01 IU/m. L of antitoxin

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

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

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

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

Bull-Neck appearance

Pseudomenbrane

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

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

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

Diphtheria Pneumonia

Non-Respiratory disease

Cutaneous diphtheria

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

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

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

Complications n Toxic Cardiomyopathy - commonly myocarditis, rarely endocarditis - usually occurs at the end of 2 nd 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

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

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

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

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

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

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

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

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

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

Dosage of Antitoxin (units) n n n n n • Site and extent of lesion Nasal One tonsil Both tonsils+/Pharyngeal Laryngeal or Combined types Very extensive Disease illness<72 hrs 10, 000 -20, 000 illness >72 hrs 10, 000 -20, 000 -40, 000 -60, 000 40, 000 -80, 000 60, 000 -80, 000 -100, 000 N. B. Test for sensitivity before administration and desensitized if necessary

Testing for Sensitivity Skin test: - Intradermal injection of 0. 1 m. L of 1: 10 dilution of antiserum in saline - read in 20 mins - a wheal ≥ 1 cm – positive – sensitive n Conjunctiva test: - conjunctivitis & lacrimation – positive n Caution! Ensure adrenalin is available n

Desensitizing n n n 0. 1 ml of a 1: 20 dilution subcut. 0. 1 ml of a 1: 10 dilution subcut. 0. 1 ml undiluted subcut. 0. 3 ml undiluted IM 0. 5 ml undiluted IM - wait 20 mins wait 20 mins If no reaction has occurred the rest of the dose can be given IM

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

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

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

Treatment contd. n IV fluid administration if needed n Vaccinate – 10 series &/or boosters n Disease notification n Contact tracing

Contact tracing & Care n n n The risk of developing the disease after household exposure to a case is ≈ 2% The risk of disease after exposure to a carrier is ≈ 0. 3% Types of contacts: - asymptomatic case contact - carrier

Asymptomatic case contact monitor for illness n culture n Antimicrobial prophylaxis n Vaccinate nprimary schedule. nbooster dose n

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

Prognosis Depends on: n Virulence of the organism. Gravis has the highest fatality followed by intermedius and the least is mitis. n Age; higher mortality rates in individuals < 5 yrs and those > 40 yrs. n Immunization status: worse in the unimmunized

n n Prognosis (contd. ) Site of infection/involvement; mortality occur in: n < 1% of cutaneous disease n ≈ 10% of uncomplicated respiratory disease n 30 – 40% of bacteremic disease n 60 - 90% of those with cardiac involvement. Speed of administration of antitoxin; worse with delay

Prevention n Immunization is the mainstay of prevention n Given as DPT n Immunization schedule (NPI) - DPT 1 – 6 wks - DPT 2 – 10 wks - DPT 3 – 14 wks

The Present

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

n Immunity wanes over time

Other Epidemiological issues n Questionable Notification from Nigeria Erratic values: - In 1996 reported 2016 cases - In 1997 , , 31 cases *DPT 3 coverage in 1996 – 30%

Inconsistent figures n In 2003 & 2004 – no case reported * In 2003 Nigeria had the worst immunization coverage in the world DPT 1 coverage – 43. 2% DPT 3 coverage – 24. 8% Only 12. 8% were fully immunized

Latest Immunization Coverage n n n Global: 79% estimated DPT 3 coverage Current coverage in Nigeria: - DPT 1 is ≈ 65% - DPT 3 is ≈ 77% WHO proposed coverage is ≥ 90%

Changes In Immunization strategies n n Effect of passive immunity on 10 series Commencing 1 O series later e. g. - In the US DPT 1 – 2 mth DPT 2 – 4 mth DPT 2 – 6 mth

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

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

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

The Future

Recommendations n n n Improve coverage of 10 schedule to 90% at least 4 th & 5 th DPT doses at 18 mths & 5 yrs respectively Improve disease Surveillance and notification

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

Conclusion n 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.

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