rickettsioses qsnich

7/31/2019 RICKETTSIOSES QSNICH

1/67

SUPAWAN CHANPRADABDivision of Infectious Diseases

Department of PediatricsQueen Sirikit National Institute of Child Health


2/67

Bacteriology Definition of Rickettsiaceae family

Small gram-negative bacteria, associated

(or not) with arthropods and necessitating

(or not) eukaryotic cells from growth

16 S r RNAsequence-based phylogeny


3/67


4/67

Rickettsiae are traditionally dividedinto 3 groups Spotted fever group

Typhus group

Epidemic typhus : R. prowazekii

Murine typhus : R. typhi

Scrub typhus groupOrientia tsutsugamushi


5/67

Rickettsiales Intracellular alpha proteobacteria

associated with eukaryotic hosts

(arthropods or helminths)

Obligate intracellular pleomorphic coccobacilli

Multiply by binary fission

Zoonotic disease : human are incidental hostexcept for R. prowazekii( Epidermic typhus )

Incidence vary by geographic areas, arthropod vectorsand seasonal


6/67


7/67

Pathophysiology Rickettsia species escape rapidly from the

phagosome to multiply within the cytoplasm

Spotted fever rickettsiae : motile in the

cytoplasm through actin polymerization

invade neighboring cells

R.probazekii : destruction of the host cell

Target cell


8/67Pathophysiology


9/67


10/67

Rickettsiosis Spotted fever group

Typhus group

Epidemic typhus : R. prowazekii

Murine typhus : R. typhi

Scrub typhus groupOrientia tsutsugamushi


11/67


12/67

Spotted fever group Most tick - borne rickettsiosis

R. akari(Ricketsialpox) : mite

R. felis: flea

Disease named by geographic distribution

Rocky Mountain spotted fever

Queensland tick typhus

North asian tick typhus.

Human are incidental host

Natural host are small mammal

wild rodents, mouse, dog


13/67

Prototype : Rocky mountain spotted fever

(RMSF)

severe clinical manifestation

Case fatality rate of 23%

R.rickettsii Fever, myalgia, headache and rash

Meningitis, meningoencephalitis

Renal failure

pulmonary involvement

Few reports in Thailand


14/67

Epidemiology Annual incidence for RMSF

by state in the United States for 2002


15/67

First cases of spotted fever grouprickettsiosis in Thailand

Presented with fever, headache,

lymphadenopathy and petechial maculopapular

rash.

Diagnosis by indirect fluorescent antibody test,

indirect immunoperoxidase test and ELISA for

spotted fever group.

All response well to single dose of doxycycline.

Am J Trop Med Hyg 1994 Jun;50(6)682-6


16/67


17/67

Typhus group Epidemic typhus

R. prowazekii

Human - natural and incidental host

Louse - vector and natural reservior

Brill - Zinsser disease (recurrence years

after 1st attack)

IC 8-16 days


18/67

Typhus group Murine typhus

R. typhi

Natural host Rodents, opossums

Flea - vector and natural reservior

No eschar, less severe than epidemic

typhus


19/67


20/67

Scrub typhus First report in Thailand in

1952.

Most common rickettsial

infection in Thailand.

One of the most common

cause of FUO in Thailand

Zoonotic


21/67

Etiologies of Acute UndifferentiatedFebrile Illness in Thailand

J Med Assoc Thai Vol. 87 No.5 2004

Etiologies could be found in 471 cases (1,240 cases)


22/67

Annual Epidemiological Surveillance Report 2004

http://epid.moph.go.th/


23/67

Annual Epidemiological Surveillance Report 2004

http://epid.moph.go.th/


24/67

Annual Epidemiological Surveillance Report 2004http://epid.moph.go.th/


25/67

Etiology Orientia tsusugamushi

(formerly rickettsia)

Obligate intracellular bacteria grow in the

cytoplasm of infected cells Transmission

Human : incidental host

Chigger : vector and reservoir

Wild rodents : natural host


26/67

Chigger Larval stage of trombiculid

mite

Fed only once on human or

rodents

Stay within several meters of

where they hatch

90 - 100 % of their offspring

from infected mite are capable

for transmitting the organism


27/67


28/67

Pathogenesisinoculation of pathogen when infected chigger feeds

local multiplication at bite site

Eschar and regional lymphadenopathy

Rickettsemiainfect target cell ( vascular endothelium )


29/67

Infect vascular endothelium cause direct cell injury at foci:

vasculitis thrombosis rupture and necrosis of the vessels


30/67

Clinical manifestation Incubation period : 6-18 days

Abrupt fever, severe headache, myalgia

Tender regional lymphadenopathy,splenomegaly

Eschar (60% in primary infection)

small painless papule in day 9-18

blackened scab seen at axillary, inguinal,

genital area and bitten site


31/67

Maculopapular rash on trunk and spread

to extremities on day 5

Slow pulse despite of high fever

ocular pain, conjunctivitis, non productive

cough, tinnitus

Self limited in 2 weeks (without antibiotic)


32/67

Complication Aseptic meningitis, meningoencephalitis Myocarditis -> heart failure Pneumonia -> ARDS DIC

Laboratory finding Routine studies are no diagnostic value Leukopenia may occur early then

lymphocytosis in the later Albuminuria is common


33/67

Laboratory diagnosis Direct detection

Isolation

Serologic tests

Molecular techniques


34/67

Direct detectionCluster of fluorescence

with O.tsutsugamushi

showed in the

cytoplasm of leukocyte

I l ti


35/67

Isolation Embryonated chicken egg

yolk sacs

Laboratory animals:

guinea pigs, mouse

Cell cultures: monocyte,

L929 mouse fibroblast cell

Shell vial assay: Vero,

L929 cells


36/67

Serologic test

Detection of Antibody

Weil-Felix (OX-K, OX-2, OX-19) Indirect immunofluorescent assay (IFA) Indirect immunoperoxidase assay (IIP) Enzyme-linked immunosorbent assay (ELISA) Dot-bloted ELISA

Latex agglutination


37/67

Weil-Felix (WF) reactionDetection of Abto Proteus Ag which contains Ag with

cross-reacting epitopes to Rickettsial Ag

(except for R.akari)

Proteus mirabilis OX-K

Proteus vulgaris PX-19 (OX-19)

Proteus vulgaris OX-2

UTI, relapsing fever, leptospirosis, severe liver diseases

Single serum: positive : titer 1:320

Paired serum: four fold rising

I di t i fl t tib d t t (IFA)


38/67

Indirect immunofluorescent antibody test(IFA)

Positive antibody

Negative antibody

Sensitivity 54 % , Specificity 96%

Am J Trop Med Hyg 1983;32:1101-7


39/67

Diagnosis of scrub typhus is based on

Fever plus anyone of the following :A. Eschar (round or oval-shaped painless ulcer at

the probable site of the chigger bite).B. A four-fold or greater rise in the IFA titer to at

least a 1:200 for paired acute and convalescentsamples.C. A single serum IgM IFA titer > 1:400 or an IgG

IIP titer > 1:1600


40/67

Evaluation of immune status for scrub typhus1. Neither IgG nor IgM titers

- absence of exposure to the agent

( except at a very early stage , 3 days after the onset ) 2. Positive with low IgM and negative IgG titers

- a very early stage of active infection- should be followed up

3. High IgG and high IgM titers

- active recent infection


41/67

Evaluation of immune status for scrub typhus4. Low IgM and very high IgG titers

- decreasing phase of IgM after an initial infection

- the re-infection in a very early stage5. Moderate IgG and negative IgM titers

- prior infection of more than 1 or 1.5 years6. Low IgG and negative IgM titers

- prior infection many years ago ( 5-15 years )

M l l h i


42/67

Molecular techniqueClinical samples:

Skin biopsy specimen

Paraffin-embeddedtissues

CSF

Peripheral bloodmononuclear cells

(PBMC)


43/67

Gene amplification by the polymerase chain

reaction(PCR) technique :- it is useful when it is difficult to perform

immunological diagnosis or to isolate thecausative agent

- early rickettsemic stage, before the Ab titer hasincreased

- in immunodeficiency patients, when has low orno Ab productiuon

high cost and the complexity of the technique

Laboratory Diagnosis Tests


44/67

Technique Advantages Drawbacks

Shell vial assay - Early diagnosis

before seroconversion

- positive result within

3 days after sampling

- Limited facilities

- Negative if prior

ATB

-Inoculation in same

day

PCR-based - Positive result within

24 hrs

- May be positive

even prior ATB

- Limited facilities

Laboratory Diagnosis Tests


45/67

Laboratory Diagnosis TestsTechnique Advantages Drawbacks Note

Weil-Felix Inexpensive Lack sen &

spec

Limited use

IFA Commercially

available

Sen & Spec

Requires

fluorescence

microscope

Good for both

DX and

sero-epid

IIP Sen & Spec Does not

require

fluorescence

microscope

Alternative for

IFA


46/67

Laboratory Diagnosis TestsTechnique Advantages Drawbacks Note

ELISA Sen & Spec - Good for Dx

and sero-epid

Latex

agglutination

Simple Expensive Should be used

in non-

equipped

laboratory

Western

immunoblot

Sen & Spec Time-

consuming

Probably best

tool for sero-

epid

T


47/67

Treatment

Doxycycline, tetracycline andchloramphenicol are effective Px

Fever dissipates in less than 24 hr. in most

patients Relapse may occur, esp. when Rx. begun

before d4-d5 of illness


48/67

Treatment

In children recommended

: doxycycline : 2.2 mg/kg/dose x 2 dose

then2.2 mg/kg/day divided bid

In severe cases/can not eat:chloramphenicol 50-100 mg/kg/dayIV

-----> oral form doxycycline

Rx.duration until fever subside 2-4 d or atleast 5 d. for prevent relapse


49/67

ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, Nov. 1995, p. 24062410


50/67

Antibiotics for treating scrub typhus (Review)The Cochrane Collaboration and published in The Cochrane Library 2007, Issue 3


51/67

Antibiotics for treating scrub typhus (Review)The Cochrane Collaboration and published in The Cochrane Library 2007, Issue 3

D li d if i i f ild b t h i f ti


52/67

Doxycycline and rifampicin for mild scrub-typhus infections

innorthern Thailand: a randomised trial

Lancet2000; 356: 105761


53/67

Rifampicin is more effective than doxycycline against

scrub-typhus infections acquired in northern Thailand,where strains with reduced susceptibility to antibiotics

can occur.Lancet2000; 356: 105761

S b t h i f ti l i t tibi ti i


54/67

Scrub typhus infections poorly responsive to antibiotics innorthern Thailand

Prototype and naturally occurring strains of R tsutsugamushi were

tested for susceptibility to chloramphenicol and doxycycline in mice andin cell culture. Findings By the third day of treatment, fever had cleared

in all seven patients from Mae Sod, but in only five of the 12 (40%) from

Chiangrai (p


55/67

Why are the diseases poorlyrecognized by physicians ?

Non-specific clinical manifestations. Wide range of disease severity Lack of a convenient sensitive and specific

diagnostic test.

Paediatric scrub typhus in Thailand :


56/67

Paediatric scrub typhus in Thailand:a study of 73confirmed cases

Transactions of the Royal Society of Tropical Medicine and Hygiene (2004) 98, 354-359



57/67



a study of 73 confirmed cases



58/67

ypa study of 73 confirmed cases




59/67

ypa study of 73 confirmed cases

Treatment and response to therapy

68 (93%) started antibiotics on median day 11 of illness15 (20%)received chloramphenicol41 ( 56%) received doxycycline

( 38 prescribed as a single oral dose)

The median interval to defervescenceafter doxycycline 1 d (range 13 d)

chloramphenicol 3 d (range 15 d) (P= 0.006) Children who received either of these two drugs were

afebrile within the median interval of 2 d (range 15 d)

compared with 5 d (range 214 d)for those who received

none or other antibiotics (P


60/67

Paediatric scrub typhus in Thailand :a study of 73 confirmed cases

Initial diagnoses :Only 40 (55%) of 73 patients

16 (22%) : diagnosed as acute PUO

Other common misdiagnoses: enteric fever 11% ,

DHF 10%


Epidemiologic, clinical and laboratory features


61/67

Epidemiologic, clinical and laboratory featuresof scrub typhus in thirty Thai children

Pediatr Infect Dis J 2003 22:3415

E id i l i li i l d l b f


62/67


20 had one eschar each, 1 patient had 2eschars.

sites: genitalia and perineum (10)

neck (6)

inguinal area (3)

umbilicus (2)axilla (1)

nonpainful ulcers, surrounded by red areolaeandusually covered by dark scabs.

diameters rangedfrom 0.7 to 1.25 cm.

Pediatr Infect Dis J, 2003;22:3415

E id i l i li i l d l b f


63/67


From January 1, 2000 to December 31, 2001at ChiangMai University Hospital

who had obscure fever for >5 days were tested forindirect immunofluorescent antibody (IFA) againstOrientia tsutsugamushi

11 patients had interstitial pneumonitis and 1 patient hadmeningitis.

All patients responded well to doxycycline orchloramphenicol.

The average interval to defervescence after treatmentwas 29 h (range, 6 to 72).

Pediatr Infect Dis J, 2003;22:3415


64/67


65/67

J Med Assoc Thai Vol. 88 No. 12 2005


66/67

Thank you


67/67

rickettsioses qsnich

Documents