Clinical Management of Diphtheria

1
Clinical Management of Diphtheria
????????????????????
??.(?????)??????????? ?????????????? ????????????
?????? 11, ????????????????????????????????? ?????
?????? ???????????????? ?????? 30 ?????? 2555
?.????????????
2
???????? - ????????????????????? ???????????????
??????????????????? ??????????? ?
3
???????????????????????? (Diphtheria)

• ????????????? diphthera (leather hide)
• ????????????? Hippocrates ????????? 5
  ?????????????
• ?????????????????????????????? 6
• ????? C. diphtheriae ????? Klebs ?? ?.?.1883
• DAT ?????????????????? ?.?.1891
• Diphtheria toxoid ?????? ?.?.1920

4
Diphtheria Situation in Thailand 1975 - 1995
2001-2010
DPT vaccinination in EPI Program-1980
Case Rate
Fatality Rate
Rate
01-05 06-10
Year
5
???????????????? ???? ?.?. 2553

• ?? 12 ??? ????????? 5 ???
• ????????? 10 ?? ???? 2 ??
• ????????????????? 9 ??? (??? 4) ???????
  ?.?.-?.?.2553
• ????????????????????? ????????? ???????? ?.?. ??
  1 ???
• ???????????????????????? ????????????????
• ???????????????????????????????

( ??????????????? 29 ?.?. 4 ?.?. 2553 )
6
?????????????????(Diphtheria) ???????????
?????? - 24 ??????? 2555 (1)

• ??????? 72 ??? ??? 6 ???????
• ??? 3 ???
• ?.??? ?? 7.9 / ??????????
• ?.????????? ?? 1.4 / ??????????
• ?.??????? ?? 0.77 / ??????????
• ?.???? ?? 0.42 / ??????????
• ?.??????????? ?? 0.2 / ??????????

7
?????????????????(Diphtheria) ???????????
?????? - 24 ??????? 2555 (2)

• ?????????????????? 10-14 ?? 29.17
• 7-9 ?? 16.67
• 35-44 ?? 12.5
• ?????????? 98.6 , ??? 1.4
• ???????? 60 , ??????? 26.4

8
??????????????????? ??? ?.??? / ???????????

• ???????????????/???? ??????? C diphtheriae,
  Toxin positive ???/???? Biochem positive
• ?.??? - ??????????????? 53 ??? (3 ??????????? 4
  ?.?.2555)
• - ?. ???????? (37 ???) ?.???????? (13 ???)
  ?.???? ??? 3 ???
• - ?????? 33 ??? (?? ?.???????? 32 ???)
• ?.??????????? - ??????????????? 4 ???
  (?.?????????? 4 ???)
• - ?????? 1 ??? (?.?????????? 1 ???)

( ????????? ??.????? ????????????,
??????????????? ?????? 5 ??. 2555 )
9
Pathogenesis
10
????? Corynebacterium diphtheriae

• Gram positive bacillus, toxin producing
• ????????????????????????????????
• ???? (Carrier) (??????????) ??????????
• 4 biotypes - C. diphtheriae biotype gravis
• - C. diphtheriae biotype mitis
• - C. diphtheriae biotype intermedius
• - C. diphtheriae biotype belfanti

11
?????????? ???????????? Diphtheria (1)

• ????? C. diphtheriae ?????????????????????????????
  ?? ???????
• ??????????????????????? exotoxin (???? 62-kd
  polypeptide)
• Exotoxin ------gt ????????????? epithelial
  cell,
• fibrin, WBC, RBC etc.
• Pseudomembrane ????? ??????
• ????????? ????????????????

( Nelson Textbook of Pediatric, 17th edition,
P886-889. )
12
?????????? ???????????? Diphtheria (2)

• Exotoxin ---gt Cardiomyopathy ---gt myocarditis
  (1-2 wk)
• ---gt Demyelination of nerve ---gt
  neuritis (2-8 wks)
• ---gt Necrosis of renal tubule ---gt
  nephritis (2-10 wks)
• ---gt Blood components ---gt
  thrombocytopenia
• (2-10 wks)
• ?????????????? ??. 2-4 ?????????????????????

( Nelson Textbook of Pediatric, 17th edition,
P886-889. )
13
??????????????
14
????????????????? ????????

• 1. ?????????????
• 2. ?????????????
• 3. ?????????????????

15
?????????????????????????

• Incubation period ?????? 2-4 ???
• Low grade fever
• ?????? (?????????????????? ?????????) ?? throat
  patch(????????)
• ?????????????????? diphtheriatic patch
• 1. Nasal ????????????? (????????????????)
• 2. Tonsillar, pharyngeal ?????? ???????????????
  ??????? ????????? ( Bullneck diphtheria)
• 3. laryngeal ????? airway obstruction
• 4. Others eg. cutaneous, vaginal etc.

16
Diphtheria and Clinical Forms

• 1. Pharyngotonsillar diphtheria very severe,
  high
• fatality rate Bull neck(most severe form)
• 2. Laryngeal diphtheria severe with airway
  obstruction
• 3. Nasal diphtheria less severe, nasal
  obstruction
• 4. Others - cutaneous, ear, eye, genital.

17
Frequency of presenting symptoms among all
hospitalized diphtheria patients and 19
diphtheria deaths, Kyrgyz Republic, 1995
Myocarditis 22, Neuritis 5
(Kadirova R.JID2000181(Suppl1)S110-5.)
18
?????????????????????Throat Patch

• 1. Diphtheria
• 2. Streptococcal Pharyngotonsillitis and other
  
• streptococcal pharyngitis
• 3. Infectious mononucleosis
• 4. Moniliasis
• 5. Post Tonsillectomy
• 5. Adenoviral infection
• 6. Agranulocytosis
• 7. Histiocytosis X (Letterer-Siwe Syndrome)

19
?????????????????????Croup Syndrome

• Croup Upper airway obstruction from any causes
• Viral croup eg. PIV, influenza, RSV, etc.
• Bacterial croup eg. Diphtheria, Staphylococcal
  tracheitis etc.
• Foreign body in upper or lower respiratory tract
• Epiglottitis eg. viral or bacteria (Hib)
• Spasmodic croup

20
????????????????? ????????

• 1. ?????????????
• 2. ?????????????
• 3. ?????????????????

21
Laboratory Findings
22
???????????????????????? C. diphtheriae

• Swab ??? patch ????????????????? Chinese letter
  (??????????????? ? )
• Swab ??? patch, ??? patch ???? patch
  ??????????????? sheep blood and Tellurite media
  -Amie ?
• Blood agar plate
• ?
• Corynebacterium (?????? 3)
• gram stain Biochem. Gel diffussion
• (ve bacilli) ?? toxin
  (?????? 5-6)

23
?????????????????????? diphtheria
24
????????????????????(Diphtheria)
??????????????/?????

• 1. ??? DAT ????????????????????????????????????
• 2. ???????????????????????????????- culture with
  toxin test
• 3. ???????????????????????- Penicillin,
  Erythromycin
• 4. ?????????????????????? ?????????????????????
  
• ????????? myocarditis, neuritis etc.

25
?????? DAT ????????? ????? -

• ?????????? diphtheria toxicogenic strain
• ????????? diphtheria toxicogenic strain ?????
• 2.1 ????????????????????????????
• 2.2 ????????????????????????(????????????)
• 2.3 ???????????????????????????????????????
• 2.4 ?????????????????????????????????????????????
  ????????????
• 2.5 ?????????????????????????????????
• ???????????????? diphtheria ??????? ?? ???????
  ?????????????????????? DAT (cutaneous diphtheria
  ?????????????????????????????? DAT)

26
??????? DAT ?????????????????????/?????????????

• ??? DAT ?? Normal saline, ??? IV drip ????
  ??????????????????
• - Anterior nasal 10,000 -
  20,000 units
• - Pharyngeal or laryngeal (????? 2???)
  20,000 - 40,000 units
• - Nasopharyngeal or combine type
  40,000 - 60,000 units
• - Bull neck ???????????????? 3 ???
  80,000 -120,000 units
• ?????????????????????? DAT ???????????????????????
  ???????

27
?????????????????????????????? DAT

• ?????????????????????????? (horse serum) ??????
  5-20
• ????? skin test ??????
• - ?????????????????? 1 1000 ???? 0.02 ??.??.
  ID
• - ???????? - ????? positive control ????
  Histamine
• - ????? negative control ???? saline
• - ????? 15-20 ????
• - ???????????? (wheal) ??????????? 3 ?.?.
  ??????????
• negative control ?????? positive
• - ??? DAT ?????? desensitization - ??? skin
  test positive

(Feigin, Cherry. Textbook of Ped. Infect. Dis.
edition 6th, 2009p1399-1400)
28
Desensitization of Horse Serum, IV

• IV ???????? ?????????????????????????????
• ??? IV ??? 15 ???? ??????????????
• 0.1 ml of 11000 dilution. IV
• 0.3 ml of 11000 dilution. IV
• 0.6 ml of 11000 dilution. IV
• 0.1 ml of 1100 dilution. IV
• 0.3 ml of 1100 dilution. IV
• 0.6 ml of 1100 dilution. IV
• 0.1 ml of 110 dilution. IV
• 0.3 ml of 110 dilution. IV
• 0.6 ml of 110 dilution. IV
• 0.1 ml of undilute dilution. IV
• 0.3 ml of undilute dilution. IV
• 0.6 ml of undilute dilution. IV
• 1 ml of undilute dilution. IV
  ??????????? IV ???? ?????

(Feigin, Cherry. Textbook of Ped. Infect. Dis.
edition 6th, 2009p1399-1400)
29
????????????????????(Diphtheria)
??????????????/?????

• 1. ??? DAT ????????????????????????????????????
• 2. ???????????????????????????????- culture with
  toxin test
• 3. ???????????????????????- Penicillin,
  Erythromycin
• 4. ?????????????????????? ?????????????????????
  
• ????????? myocarditis, neuritis etc.

30
??????? Antibiotics ?????????????????????/????????
?????

• ???? - PGS 100,000 200,000
  ?????/??/??? ??????? 6 ?.?.x 14 ???
• - Erythromycin 50 ??/??/??? ??????? 6
  ?.?.x 14 ???
• ??????? - PGS 3-4 ?????????, IV drip ??? 6
  ??????? x 14 ???
• - Erythromycin 2 ????/???
  ??????? 6 ?.?.x 14 ???

???????????.???????? ???????? ????????????
31
Penicillin VS Erythromycin in the Treatment of
Diphtheria

• Penicillin group - PGS 50,000 u/kg/d x5 d, then
  oral Pen V x 5d
• Erythromycin group - 50 mg/kg/d x 10d
• Result -

Penicillin Erythromycin P
N 44 42 -
Fever clearance 27 hr (95 CI 19-30) 46 hr (95 CI 34-54) 0.0004
Myocarditis 3 1 NS
C. diphtherial resistant 0 27 -
Penicillin is recommended as drug of first choice Penicillin is recommended as drug of first choice Penicillin is recommended as drug of first choice Penicillin is recommended as drug of first choice
( Kneen R, et al. Clin Infect Dis 1998 27
845-50. )
32
????????????????????(Diphtheria)
??????????????/?????

• 1. ??? DAT ????????????????????????????????????
• 2. ???????????????????????????????- culture with
  toxin test
• 3. ???????????????????????- Penicillin,
  Erythromycin
• 4. ?????????????????????? ?????????????????????
  
• ????????? myocarditis, neuritis etc.

33
?????????????????????????????????????????

• 1. Admit ?????????????? absolute bed rest 2-4
  ???????
• 2. ??????????????????????
• 2.1 record vital sign ??? 6 ??.
• 2.2 record intake / output ??????
• 2.3 ????????????????? ??????????????????????
• 2.4 ???????????? ??????????????????????????????
  
• 3. Lab. Investigation
• 3.1 ???? EKG ??????
• 3.2 ???? urine exam ??? 1-2 ???/?????
• 3.3 culture ??????????????????????????????????
  14 ???

34
Diphtherial Myocarditis

• ???????? 1-6 ??????????????? (????????????????
  2-3)
• ????????????? 10-25 ?????????? ??? 50-60
• ?????????????? ??? ??? DAT ??????????
  ?????????????????
• ????????????????? heart failure dopamine,
  dobutamine, milrinone
• Steroid, IVIG ?????????????
• ????? - sinus tachycardia
• - prolonged PR interval, ST-T wave change
• - 1st , 2nd , 3rd degree heart block

35
Diphtherial Neuritis

• ???????? 2-3 ???????????????, facial N.
  paralysis ?????????????? 5
• ????? - ??
• - paralysis of soft palate
• - paralysis of post pharyngeal, laryngeal,
  facial N
• - ???????????????? ????????????????????
• - symmetric polyneuropathy eg. motor weakness,
  reflex ? , strabismus, blurred
  vision
• - GBS- like syndrome

36
?????????????????????????????????

• ???????????????? endotracheal tube,
  ??????????????????? airway obstruction
  ??????????? tube ??????????????????, toxin
  ????????????????? ????????????????????????
• ??? oxygen mask ???????????
• Steroid ????????
• ???????? diphtheria ??? DAT ??? antibiotic ?????
• ??????????????????????????????????????? 2
  ?????

37
????????????????????? diphtheria
38
?????????????????????????????????????????(1)

• ??????????????????????????? C. diphtheriae,
  toxigenic strain
• 1. ?????????????????????????
• 1.1 Benzathine Penicillin 6000,000-1,2000,000
  unit ??????????(?????????)
• 1.2 Erythromycin 50 ??/??/??? ??? 7-10 ???
• 2. ??????????????????????
• 3. ??? DPT ???? Td ???? Tdap ??????? 1
  ???????????????????????????????
• ?????????????? ?????????????????????
  ???? ???????????????????? DPT
• (????????????????? 6 ??) ???? Td
  ????? 3 ???? ??? 0, 1-2, 6-12 ?????
• 4. ????????????? DAT ???? 10,000 unit
  ?????????????????????????????????

39
?????????????????????????????????????????(2)
?????????????????? - Erythromycin 7-10 ??? -
TSC for toxigenic C. diphtheriae
?? ve ?? ve (????, carrier)
TSC ??? 24 ??. ????????????
???????? - ????-
?? ve ?? ve
(?? 20) ??? Erythromycin???x10???
??? TSC ve ??????????? ????? TSC ve ?????? 2
?????
??? 2 ??????? ?? TSC ????????
TSC ???
?? ve ??? 2 ??????? ?? TSC ????????
?? ve ?????????????????? ????????
40
?????? DAT ??????????? ????? -

• DAT ????????????????????????????
  ??????????????????? (US-CDC)
• 1. ????????????????????????????????????
  toxigenic C. diphtheriae
• 2. ?????????????????????????????????
  ????????????????? toxigenic
• C. diphtheriae ?????????????????? /
  ???????
• 3. ???????????????????????????????????????
  ?????????????????????? toxigenic
• C. diphtheriae ?????????????????????
  
• ??? DAT 10,000 unit, IM ???????????????????
  ?

41
Number of hospitalized diphtheria patients in the
Kyrgyz Republic in 1995,according to the
WHO/UNICEF classification system.
(Kadirova R.JID2000181(Suppl1)S110-5.)
42
Prognosis
43
??????????????????? Diphtheria ??? Carrier (????)

• ??????????????????? carrier ??????????????????????
  ??????? 0 - 25
• ??????????????????? diphtheria ???????????????????
  ?????????? 2
• ??????????????????? diphtheria ??????????????
  carrier 0.3

44
???????????????????????????

• ??????????????????????? diphtheria
• ????? immunity (DAT) ??? host
• ????????? diphtheria toxoid ?????? ??? booster
• ?????????????? host

45
???????????????????

• ??????????????????????????? ???????? 5-10
• ???????????????????????
• - Myocarditis 10-25
• - Neuritis 5
• ??????????? myocarditis 50-60
• ??????????? bull neck diphtheria 50
• ???????????????????? DAT ??????????????????????
• ????????????????????????????????????? diagnosis
  ???????

46
??????????
47
???????????????? Diphtheria Toxoid

• ??????? C. diphtheriae toxin ??????????
  ?????????????????????????? (Diphtheria antitoxin
  DAT) ???
• ??????????? (DAT) ?????????????????? C.
  diphtheriae ??????
• ??????????? (DAT) ??????????????? (???????????)
  ???

48
DAT Level for Protection

• DAT lt0.01 IU/ml no protection
• DAT 0.01-0.1 IU/ml partial protection
• DAT gt0.1 IU/ml full protection
• DAT gt1.0 IU/ml long term protection
• (several years)

( N Emgl J Med 1954 251 459-66. )
49
How many dose of Td for good protection?
?????????????????????? diphtheria ????????????
diphtheria toxoid (Td.) ??????? 1 ???? 2 ???? 3
???
50
Immunogenicity of Tetanus-Diphtheria Toxoids (Td)
among Ukrainian Adults Implications for
Diphtheria Control
(Sutter RW.JID2000181(Suppl1)S197-202.)
51
Immunogenicity of Tetanus-Diphtheria Toxoids (Td)
among Ukrainian Adults Implications for
Diphtheria Control
Td 1 ???? 2 ???? booster ??????????????????
(Sutter RW.JID2000181(Suppl1)S197-202.)
52
Immune Response to Diphtheria Booster Vaccine in
the Baltic States
A single dose of Td vaccine contain D 3,6,12 Lf
No different in response
(Ronne T..JID2000181(Suppl1)S213-9.)
53
Immune Response to Diphtheria Booster Vaccine in
the Baltic States
A single dose of Td vaccine in children very good
response
(Ronne T..JID2000181(Suppl1)S213-9.)
54
How Many Doses of Diphtheria Toxoid Are Required
for Protection in Adults? Results of a
Case-Control Study among 40- to 49-Year-Old
Adults in Russian
Td 3 ?????????????????????????????????????
(Brennan M.JID2000181(Suppl1)S193-6.)
55
?????? DPT, Td ??????????????????????

• DPT ?? EPI program ????? ?.?.2520 (2 ????)
  (??? 3 ??????
  ?.?.2528)
• Td ???????????????? booster ???????????? ?.?.2525
• Td ????????????????????????????????? ?.?.2548

56
???????????? Td ??????????????????????????
?????? Diphtheria

• ??????????? ?????????????????????????????????????
  1
• ??????????????????? ??? booster Td ??? 10 ??
  ??????????????????????????????????????????????????
  ???????????? ????????????????????????????????2
• ??????????????????? ?????? Td vaccine ????? 1
  ?????????????, ?????? 2 ??????????????

1 Eur J Epidimiol 1995 11 107-17. 2 Eur J
Epidimiol 1995 11 95-105.
57
?????????????? Td. vaccine

• ???????? ??? ???????????? ?????? ????????????
  ?????????????????????????
• ?????????????????? (Arthus-like reaction)
  ???????????? ??????????????????????????????????
  2-8 ??.??????? ???????????????????????????????????
  ??? Tetanus ??? Diphtheria ?????? ??????????????
  ?????? booster ???????? 10 ??

58
???????????????????????????? C. diphtheriae
???????????

• 1. Respiratory diphtheria
• - ?????????? droplet precaution
• - ????????????? mask, glove, gown, (goggle)
• 2. Cutaneous diphtheria
• - ?????????? contact precaution
• - ????????????? glove, gown
• 3. Admit ???????????????, cohort ward

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