Diphtheria (??)

1
Diphtheria (??)

• Peng Xiaomou (???)
• The Third Affiliated Hospital

2
Definition

• Diphtheria is an acute, toxin-mediated disease
  caused by toxigenic Corynebacterium diphtheriae
  (??????).
• Its a very contagious and potentially
  life-threatening bacterial disease.

3
Definition

• Its a localized infectious disease, which
  usually attacks the throat and nose mucous
  membrane

4
Definition

• Common symptoms malaise, sore throat, anorexia,
  and low-grade fever.
• Typical sign specific membrane formation
  (pseudomembrane,??, in Greek diphthera, meaning
  leather, as tough as leather)
• In serious cases, it can attack the heart and
  nerves.

5
Definition

• Because of widespread immunization, diphtheria is
  very rare in China (no case was reported in
  recent years).
• It is re-emerging in some areas of the world
  where immunization practices are lax.

6
Etiology

• Diphtheria is caused by Corynebacterium
  diphtheriae, a bacterium, a bacillus.

7
Etiology

• C. diphtheriae is an aerobic gram-positive
  bacillus.
• Pleomorphic, club-end
• Non-spore-forming
• Non-acid-fast
• Non-motile

8
Etiology

• Culture of the organism requires selective media,
  tellurite agar or Loeffler serum slants under
  aerobic conditions.

9
Etiology

• If isolated, the organism must be distinguished
  in the laboratory from other Corynebacterium
  species that normally inhabit the nasopharynx and
  skin (e.g., diphtheroids).

10
Etiology

• The major virulence determinant is an exotoxin,
  diphtheria toxin. After binding to the host
  cells, the active subunit will interrupt the
  protein synthesis of the target host cell and
  results in cell death.
• Toxoid made from diphtheria toxin can be used as
  vaccine.

11
Etiology

• There are three biotypes gravis, intermedius,
  and mitis. The most severe clinical type of this
  disease is associated with the gravis biotype,
  but any strain may produce toxin.

12
Etiology

• Toxin production occurs only when the bacillus is
  itself infected by a specific virus
  (bacteriophage, a lysogenic ?-phage) carrying the
  genetic information for the toxin (toxin gene).

13
Etiology

• Only toxigenic strains can cause severe disease.
  So, all isolates of C. diphtheriae should be
  tested by the laboratory for toxigenicity (ELISA
  or the Elek tests).

14
Etiology

• The bacteria can be killed by mild heating(58?
  for 10 minutes) and sensitive to UV or sunlight.
• Resistance to damage from drying, be cultured
  from the floor dust for 5 weeks or longer, once
  the floor dust was contaminated.

15
Epidemiology

• Sources of infection
• Patients and asymptomatic carriers
• Patients Transmission time is variable, usually
  persist 12 days or less, and seldom more than 4
  weeks, without antibiotics.

16
Epidemiology

• Sources of infection
• Asymptomatic carriers (even important) 1 in
  population, but may be up to 10-20 during
  outbreaks in the past. Most of them were
  transient carriers (less than 2 weeks), but
  chronic carriers may shed organisms for 6 months
  or more.

17
Epidemiology

• Transmission
• Transmission is most often person-to-person
  spread from the respiratory tract (by small
  droplet when coughing or sneezing).
• Rarely, transmission may occur from skin lesions
  or articles soiled with discharges from lesions
  of infected persons.

18
Epidemiology

• Susceptibility
• The susceptibility are influenced by widespread
  immunization in childhood and immunity obtained
  after infection.
• Children of 2-10 years old before widespread
  immunization.
• The unimmunized or inadequately immunized adults
  after widespread immunization.

19
Epidemiology

• Susceptibility
• The susceptibility can be demonstrated by
  Schicks test (dermal test, positive result
  implies sensitiveness or no resistance to the
  disease) or ELISA (serologic assay).

20
Epidemiology

• Epidemical features
• Diphtheria occurs worldwide, but clinical cases
  are more prevalent in temperate zones, and in
  socioeconomic conditions of poor personal
  hygiene, crowding and limited access to medical
  care.

21
Epidemiology

• Epidemical features
• Diphtheria most frequently occurs during the
  autumn and winter or early in the spring.
• Children were subjected to this disease in the
  past, but the unimmunized or inadequately
  immunized adults now.

22
Epidemiology
23
Epidemiology
24
Pathogenesis and pathology

• Susceptible persons may acquire toxigenic
  diphtheria bacilli in the nasopharynx, skin,
  middle ear or anterior nares.

25
Pathogenesis and pathology

• The organism produces a toxin that inhibits
  cellular protein synthesis and is responsible for
  local tissue destruction and pseudomembrane
  formation.

26
Pathogenesis and pathology

• The pseudomembrane consists of coagulated fibrin,
  inflammatory cells, destructed mucous tissues and
  bacteria.
• The pseudomembrane in larynx, trachea or bronchia
  may have the potential for airway obstruction.

27
Pathogenesis and pathology

• The toxin produced at the site of the
  pseudomembrane is absorbed into the bloodstream
  and then distributed to the tissues of the body.

28
Pathogenesis and pathology

• The toxin is responsible for the major
  complications of myocarditis and neuritis, and
  can also cause low platelet counts
  (thrombocytopenia) and protein in the urine
  (proteinuria).

29
Pathogenesis and pathology

• The rapidity of onset, the severity of disease,
  and the ultimate outcome are determined by the
  site of infection, the virulence of the strain
  and the status of host immunization, in actual,
  by the site and magnitude of the local lesions
  (pseudomembrane).

30
Clinical manifestations

• The incubation period of diphtheria is 2-4 days
  (range, 1-7 days).
• This disease can involve almost any mucous
  membrane.

31
Clinical manifestations

• The major sign is pseudomembrane. The typical
  pseudomembrane is adherent to the tissue, and
  forcible attempts to remove it cause bleeding.
• Pseudomembrane.

32
Clinical manifestations

• For clinical purposes, it is convenient to
  classify diphtheria into four categories
  depending on the site of disease (or
  pseudomembrane).

33
Pharyngeal diphtheria

• Its the most common type, gt80.
• The sites of infection are the tonsils and the
  pharynx.
• Infection at these sites is usually associated
  with substantial systemic absorption of toxin.

34
Pharyngeal diphtheria

• Mild type
• Symptoms malaise, sore throat, anorexia, and
  low-grade fever.
• Within 2-3 days, small patches of white
  pseudomembrane on the tonsils are found.
• Often occurs in outbreaks and is easily
  misdiagnosed.

35
Pharyngeal diphtheria

• Ordinary type
• Symptoms malaise, sore throat, anorexia,
  vomiting and middle-grade fever.
• Typical adherent, bluish- or greyish-white
  pseudomembrane forms on the congested tonsils.
• With lymph nodes enlargement in the submandibular
  areas (???) of neck.

36
Pharyngeal diphtheria

• Grave type
• Serious early symptoms, high-grade fever.
• Skin becomes pale, tachycardia, blood pressure
  may be normal or slightly depressed (Shock).

37
Pharyngeal diphtheria

• Grave type
• Large, thick pseudomembrane, and greyish-green or
  black in color if there has been bleeding,
  covering the tonsils, uvula, and some soft
  palate, odoriferous in mouth.
• With enlarged lymph nodes in the submandibular
  areas of neck.

38
Pharyngeal diphtheria

• Extra-grave type
• Tachycardia, tachypnea, depressed blood pressure.
  Highly congested tonsils and pharynx.
• The pseudomembrane is larger than that of grave
  type, black in color.
• Extensive pseudomembrane formation may result in
  respiratory obstruction.

39
Pharyngeal diphtheria

• Extra-grave type
• Patients develop marked edema of the
  submandibular areas and the anterior neck along
  with lymphadenopathy, giving a characteristic
  bullneck appearance.

40
Pharyngeal diphtheria

• Extra-grave type
• Complications, include myocarditis and
  thrombocytopenia may occur.
• May even die within 6 to 10 days.

41
Laryngeal diphtheria

• Laryngeal diphtheria can be either an extension
  of the pharyngeal form (often) or the only site
  involved (rarely).
• Symptoms include mild fever (with little
  absorption of toxin), dyspnea, hoarseness, and a
  barking cough.
• The pseudomembrane can lead to airway
  obstruction, coma, and death.

42
Anterior nasal diphtheria

• The onset is indistinguishable from that of the
  common cold and is usually characterized by a
  mucopurulent nasal discharge (containing both
  mucus and pus) which may become blood-tinged.
• A white pseudomembrane usually forms on the nasal
  septum.

43
Anterior nasal diphtheria

• The clinical symptoms of this disease is usually
  fairly mild because of apparent poor systemic
  absorption of toxin in this location, and can be
  terminated rapidly by antitoxin and antibiotic
  therapy.

44
Cutaneous and Other site diphtheria

• Skin infections are quite common in the tropics
  and are probably responsible for the high levels
  of natural immunity found in these populations.

45
Cutaneous and Other site diphtheria

• Skin infections may be manifested by a scaling
  rash or by ulcers with clearly demarcated edges
  and pseudomembrane.
• In general, the severity of the skin disease
  appears to be less than in other forms of
  infection.

46
Cutaneous and Other site diphtheria

• Other sites of involvement include the mucous
  membranes of the conjunctiva and vaginal area, as
  well as the external auditory canal.

47
Laboratory findings

• Routine examination
• Leukocytosis, 1020 G/L, neutrophil is dominant.
• Low platelet count (thrombocytopenia), rise
  profiles of the serum enzyme tests and
  proteinuria were found in serious cases.

48
Laboratory findings

• Bacteriological examinations
• Smear and gram stain can found C. diphtheriae,
  but can not identify from the diphtheroids.

49
Laboratory findings

• Bacteriological examinations
• Fluorescent antibody-stain can found toxigenic C.
  diphtheriae, favourable for early diagnosis, but
  definitive diagnosis (false positive).

50
Laboratory findings

• Bacteriological examinations
• C. diphtheriae can be cultured from the swabs
  from nose, pharynx or other sites.

51
Laboratory findings

• Immunological examinations
• Schick test (not to be used any more), positive
  result supports diagnosis
• Specific antibody detection. Positive results
  deny the diagnosis since it is a protective
  antibody.

52
Complications

• Most complications of diphtheria, including
  death, are attributable to effects of the toxin.
• The severity of the disease and complications are
  generally related to the extent of local disease.
  
• The most frequent complications of diphtheria are
  myocarditis and neuritis.

53
Complications

• Myocarditis
• Present as abnormal cardiac rhythms and can occur
  early in the course of the illness or weeks
  later, and can lead to heart failure and abrupt
  deterioration (sudden death).
• If myocarditis occurs early, it is often fatal.

54
Complications

• Neuritis
• Most neuritis often affect motor nerves and
  usually recovers completely.
• Paralysis of the soft palate is most frequent
  during the third week of illness.

55
Complications

• Neuritis
• Eye muscles, limbs, and diaphragm paralysis can
  occur after the fifth week.
• Secondary pneumonia and respiratory failure may
  result from diaphragmatic paralysis.

56
Complications

• Other complications
• Include otitis media and respiratory
  insufficiency due to airway obstruction,
  especially in infants.

57
Diagnosis

• Clinical diagnosis is usually made based on the
  epidemiological data and clinical presentation
  since it is imperative to begin presumptive
  therapy quickly.

58
Diagnosis

• Gram stain of material from the pseudomembrane
  can be helpful when trying to confirm the
  clinical diagnosis.

59
Diagnosis

• Culture of the lesion is even important to
  confirm the clinical diagnosis. It is critical to
  take a swab of the pharyngeal area, especially
  any discolored areas, ulcerations, and tonsillar
  crypts.

60
Diagnosis

• If diphtheria bacilli are isolated, they must be
  tested for toxin production by ELISA or Elek
  test.
• If toxin test is positive, the definitive
  diagnosis can be made.
• The presence of staphylococci and streptococci do
  not rule out diphtheria.

61
Diagnosis

• In patients with negative culture and prior
  antibiotic therapy, the presumptive diagnosis
  (????) may be confirmed with evidences
• (1) isolation of the C. diphtheriae from
  culturing of close contacts, and/or (2) a low or
  non-protective diphtheria antibody titer in sera
  (lt0.1 I.U.) or Schick test (-).

62
Differential diagnosis

• Dyspnea
• Acute laryngitis foreign body in trachea
  laryngeal edema
• Pseudomembrane
• Streptococcal pharyngitis (??????)
• Oral candidiasis (??????)
• Infectious mononucleosis (??????????)
• Vincents angina (?????)

63
Differential diagnosis

• Streptococcal pharyngitis
• The pus covering on the tonsils sometimes is
  misunderstood as the pseudomembrane of
  diphtheria. Its usually yellow in color, and
  easy to remove.

64
Differential diagnosis

• Oral candidiasis
• The oral candidiasis often occurs in infants. The
  general conditions of such patients are very
  well. The membrane is very white, and easy to
  remove

65
Differential diagnosis

• Infectious mononucleosis and Vincents angina
• Sometimes also have things like membranes on the
  surface of tonsils or pharynx. However, they can
  be remove without bleeding of the tissues.

66
Prognosis

• The overall case-fatality rate for diphtheria is
  about 5, with higher death rates (up to 20) in
  persons lt5 and gt40 years of age.

67
Treatments

• Strict isolation
• Use antitoxin and antibiotics for neutralization
  of free toxin, elimination of further toxin
  production and to control local infection.
• Use supportive interventions during
  disintoxication.

68
Treatments

• General measures
• Relax on bed for more than 3 weeks, 4-6 weeks for
  patients with myocarditis.
• Provide adequate energy and nutriments

69
Treatments

• Diphtheria antitoxin
• Diphtheria antitoxin, produced in horses.
• It will not neutralize toxin that is already
  fixed to tissues, but will neutralize circulating
  toxin.
• Early use will prevent progression of disease.
• The earlier, the better.

70
Treatments

• Diphtheria antitoxin
• Dose 3-5104 U for early (lt3-4d) and mild or
  ordinary patients 6-10 104 U for later (gt3-4d)
  or grave patients reduce in larynx diphtheria
• 1-2104 U is given intravenously and the rest is
  given intramuscularly.

71
Treatments

• Diphtheria antitoxin
• The patient must be tested for sensitivity before
  antitoxin is given.
• Respiratory support and airway maintenance should
  also be administered as needed. (Pseudomembrane
  shedding often happens during disintoxication)

72
Treatments

• Antibiotics
• Prevention of further toxin production.
• Control local infection.
• Reduction of transmission.

73
Treatments

• Antibiotics
• Procaine penicillin G daily, intramuscularly
  (300,000 U/day for those weighing 10 kg or less
  and 600,000 U/day for those weighing more than 10
  kg) for 7-10 days.
• Erythromycin orally or by injection (40-50
  mg/kg/day maximum, 2 gm/day) for 14 days.

74
Treatments

• Antibiotics
• The disease is usually not contagious 48 hours
  after antibiotics are used.

75
Preventions

• Management of infection sources
• Isolation of patients (gt7d), or elimination of
  the organism should be documented by two
  consecutive negative cultures after therapy is
  completed.

76
Preventions

• Management of infection sources
• Persons with suspected diphtheria should be given
  antibiotics and antitoxin in adequate dosage and
  placed in isolation (7d) after the provisional
  clinical diagnosis (??????) is made and
  appropriate cultures are obtained.

77
Preventions

• Management of infection sources
• For close contacts, especially household
  contacts, a diphtheria booster, appropriate for
  age, should be given. Antitoxin 1000-2000 U,
  intramuscularly

78
Preventions

• Management of infection sources
• Contacts should also receive antibioticsbenzathin
  e penicillin G or a 7- to 10-day course of oral
  erythromycin.

79
Preventions

• Interruption of the transmission routes by
  disinfections of discharges and articles of
  patients

80
Preventions

• Protect the susceptibles by vaccination
• The effective measure
• Primary series (DTP, multivalent vaccine) given
  at age of 3, 5, 6 months.
• Boosters (DTP) given at 15 months and 4-6 years
  old, and booster (DT) every 10 years after then.

81
Summary of the definition

• Acute, communicable, toxin-mediated, sometime
  life-threatening bacterial disease
• Preventable with widespread immunization

82
Summary of the definition

• Pseudomembrane usually in the throat or nose
• The typical pseudomembrane is adherent to the
  tissue, and forcible attempts to remove it cause
  bleeding.

83
Gram staining
84
Neisser staining
85
Pharyngeal diphtheria
86
Pharyngeal diphtheria
87
Pharyngeal diphtheria
88
Pharyngeal diphtheria
89
Pharyngeal diphtheria
90
Laryngeal diphtheria
91
Cutaneous (skin) diphtheria