Scrub typhus is caused by Orientia tsutsugamushi and transmitted by trombiculid mites. It presents as an acute febrile illness with non-specific symptoms like headache and rash. Confirmation requires serology or PCR. Doxycycline is the treatment of choice and reduces mortality from 60% in the pre-antibiotic era. Scrub typhus is underdiagnosed in India and accounts for up to 50% of undifferentiated fevers.

2. Scheme of Presentation
Introduction
Historical Perspective
Epidemiology & Indian Scenario
Pathogenesis
Clinical features & Complications
Approach to the Disease
Management
Prevention & Control

3. SCRUB TYPHUS - Introduction
• Aka., Japanese river fever
• known in Japanese folklore to be associated with the jungle mite
or chigger, termed ‘tsutsugamushi’ in Japanese
• (tsutsuga = disease,harm, noxious and mushi = bug).
• is a zoonosis, with humans being accidental, dead
end hosts

4. Historical Perspective
• Rickettsial infection has been one of the great scourges of mankind,
occurring in devastating epidemics during times of war and famine.
• Hippocrates in 460 bc used the term typhus,
meaning ‘smoke’, to describe the ‘confused
state of the intellect – a tendency to stupor’
associated with high fevers.

5. Why is it linked to War ?
• Napoleon’s retreat from Moscow
was forced by rickettsial disease
breaking out among his troops.
• Lenin is said to have remarked, in
reference to rickettsial disease during
Russian revolution,“either socialism will
defeat the louse or the louse will defeat
the socialism”

6. Major Impact on research during WW2..
• Its impact on immunologically naive Allied
troops between 1942 and 1945 resulted in
18 000 cases and 639 deaths (4.0%), as
well as an estimated 20 000 cases in
Japanese troops.
• First batch of scrub typhus vaccine used
to inoculate human subjects was
dispatched to India for use by the Allied
Land Forces, South-East Asia Command,
in June 1945.
• Leading cause of pyrexia of unknown
origin (PUOs) in forces of USA during the
VietNam conflict.

7. Indian Scenario
• In India, the disease had occurred among troops
during the Second World War in Assam and West
Bengal, and in the 1965 Indo-Pak war.
• There was a resurgence of the disease in 1990 in a
unit of an army deployed at the Pakistan border of
India.
• Occurrence reported from several states in India
including Jammu and Kashmir, Himachal Pradesh,
Uttarakhand, Bihar, West Bengal, Meghalaya,
Rajasthan, Maharashtra, Karnataka, Tamil Nadu
and Kerala.
• Scrub typhus accounts for upto 50% of
undifferentiated fever presenting to hospitals.
• It remains a major underdiagnosed(suspected)
cause of undifferentiated fever.

8. TsuTsugamushi Triangle
South and Southeast
Asia,
the Asian Pacific rim,
Northern Australia
Geographic Distribution

9. The Rickettsial diseases
Modern classification based on whole-genome analysis…
Typhus
Group
•Epidemic Typhus - R.prowazekki
•Murine Typhus - R.typhi
•Scrub Typhus - O.tsutsugamushi
Spotted
Fever
Group
•Indian tick typhus - R.conorii
•Rocky Mountain spotted fever
•Rickettsial pox - R.akari
others
•Q Fever - C.brunetti
•Trench Fever - Rochalimaea Quintana

10. Agent
• gram-negative, rod-shaped (cocco-bacillus) bacterium
Orientia (Rickettsia) tsutsugamushi.
Budding of O. tsutsugamushi on the cellular surface
• wide phenotypic and genotypic diversity
• reported serotypes are
• does not have a vacuolar membrane and
hence it grows freely in the cytoplasm of
infected cells.
• Cell wall lacks lipopolysaccharide and
peptidoglycan and does not have an outer
slime layer
Karp, Kato, Gilliam, Boryong, Kawazaki

11. Vector - Primary Reservoir
• Transmitted by bite of infected larvae of the trombiculid mite
Leptotrombidium deliense (“chiggers”)
• feeds on lymph and tissue fluid rather than blood.
• bite of the mite leaves a characteristic black eschar

12. Earlier it was thought that
rodents were the natural
reservoir of infection, but it
is now believed that mites
are both the vector and the
reservoir.
Natural Reservoir

14. Grasslands
Areas Around Houses
Rice Fields
The term scrub of scrub
typhus came from the
type of vegetations
(terrain between woods
& clearings) that harbor
the vectors.
Moist Areas: Swamp & Bog
Chigger’s Habitats

15. Pathogenesis – “Vasculitis like”
Organism divides and
breeds within the
phagocytes
escape from the cell,
back into the
circulation
proliferate on the
endothelium of small
blood vessels
cytokines which
damage endothelial
integrity
fluid leakage,
platelet aggregation,
polymorphs and
monocyte
proliferation
focal occlusive end-
angitis microinfarcts

16. Incubation Period
• 7–21 days (mean, 10–12 days)

17. Clinical Presentation – Eschar
… a pathognomonic sign
• A painless papule occurs at the bite site, later ulcerates, & transforms into
a black crust or ‘eschar’ in a variable proportion of patients, the border of
the eschar is surrounded by reddish erythema.
• Difficult to spot in darker individuals; moist intertriginous surfaces may be
missed if not looked into carefully

18. Clinical Presentation -Eschars

19. Onset: Appears at the end of the 1st week, lasts
3~7days.
Location: Chest, abdomen, whole trunk, or upper
and lower limbs. rarely involves the face, palms
and soles.
 Initially rash is in the form of pink, blanching,
discrete maculae which subsequently becomes
maculopapular, petechial or hemorrhagic.
Maculopapular Rash

20. Lymphadenopathy
 Regional lymphadenopathy:
occurs at the end of the 1st week.
localize: the draining lymph node around the primary eschar
characterized by tenderness and enlargement
 Generalized lymphadenopathy: appears 2-3 days later.

21. Clinical Features

22. Clinical Presentation - Complications
• More virulent strains of O. tsutsugamushi can cause
Respiratory
• interstitial
pneumonitis
• overwhelming
pneumonia with ARDS
Cardiac
•Toxic myocarditis
Hematological
• Thrombocytopenia
• Pancytopenia
• disseminated
intravascular
coagulation (DIC)
Neuropsychiatric
• Meningitis, Encephalitis
• Cochlear component of 8th nerve
involvement
• Transverse Myelitis
Abdominal
• acute hepatic failure
• acute renal failure
• GI bleeding
• para-aortic, portahepatic and the
splenic hilar lymphadenopathy

23. Clinical Profile - Comparison
• SYMPTOMS
• FEVER
• 220 (99.5%)
• HEADACHE
• 61(27.6%)
• COUGH
• 39(17.6%)
• VOMITING
• 39(17.6%)
• ALTERED SENSORIUM
• 34(15.4%)
• PAIN ABDOMEN
• 30(13.6%)
• BODYACHES
• 30(13.6%)
• DYSPNEA
• 21(9.5%)
• DECREASED URINE OUTPUT
• 16(7.2%)
• DIARRHOEA
• 12(5.4%)
• CHEST PAIN
• 5(2.3%)
• HEMOPTYSIS
VijayKumar
Et.al
Varghese et.al Subbalaxmi et.al Kedareshwar
et.al
Place/Year 2015/Kolar 2013/Vellore 2013/Andhra 2010/Goa
Patients no. 41 154 176 15
Fever 100% 100% 100% 100%
Myalgia 85% 38% 80%
Headache 78% 66% 52.3%
Vomiting 54.4% 100%
Abdomen Pain 11% 46.7%
Cough 37.3% 53.4% 46.7%
Diarrhea 6.2% 12% 15.9% 26.7%
Altered
Sensorium
2.43% 18% 13.1% 6.7%
Eschar 2.43% 55.9%% 13.1% 13.3%

24. Clinical Presentation - Complications
Varghese GM, Janardhanan J, Trowbridge P, Peter JV, Prakash JA, Sathyendra S, Thomas K, David TS, Kavitha
ML, Abraham OC, Mathai D. Scrub typhus in South India: clinical and laboratory manifestations, genetic
variability, and outcome. International Journal of Infectious Diseases. 2013 Nov 30;17(11):e981-7.

25. DDx – “typhus-like illness”
Typhus
(SFG, TG and/or STG)
distinguished only by specific serological tests with
acute and convalescent samples (IFA, IIP, ELISA, RFD) or
PCR assays tests, same treatment for all
Malaria by stained blood films, antigen detection assays
Arbovirus infections
(e.g. dengue, chikungunya)
serological methods (NS1, IgM, IgG assays). Dengue rash
is finer and more erythematous than scrub typhus and
with marked thrombocytopenia
Leptospirosis PCR (full blood) or culture (blood, CSF)
Relapsing fever
(lice or ticks)
demonstration of Borrelia in blood smears, serology or
PCR
Meningococcal disease blood and CSF cultures
Typhoid blood and bone marrow cultures
Viral fevers with macular rash, for example Epstein–Barr virus,
infectious mononucleosis, and primary HIV infection,
distinguished serologically

26. APPROACH GUIDELINES

27. The Problems faced by us..
• Diagnosis is greatly hampered by the lack of accurate and accessible
laboratory diagnosis.
• Given the large populations of India and China, the numbers
potentially exposed are enormous.
• With the growth of ecotourism in Asia, more travellers are returning
to non-endemic areas with this disease.

28. LABORATORY DIAGNOSIS
Weil-Felix test
ELISA based tests, particularly immunoglobulin M (IgM) capture
assays
Molecular diagnosis by PCR
Indirect Immunoperoxidase Assay (IPA)
Immunofluorescence Assay (IFA)
GOLD STANDARD

29. WEIL FELIX
• Sharing of the antigens between rickettsia and proteus is the basis of
this heterophile antibody test.
• Demonstrates agglutinins to Proteus vulgaris strain OX19, OX2 and
Proteus mirabilis OXK.
• Though this test lacks high sensitivity and specificity but still serves as
a useful and inexpensive diagnostic tool for laboratory diagnosis of
rickettsial disease.
• Should be carried out only after 5-7 days of onset of fever.

30. Weil Felix Test Interpretation
• Titre of 1:80 is to be considered possible infection.

31. IgM and IgG ELISA
• ELISA techniques, particularly immunoglobulin M (IgM) capture assays
for serum, are probably the most of sensitive tests available for
rickettsial diagnosis.
• In cases of infection with O. tsutsugamushi,
• a significant IgM antibody titre is observed at the end of 1st week,
• IgG antibodies appear at the end of 2nd week.

32. WEIL FELIX ELISA
PRINCIPLE HETEROPHILE AGGLUTINATION WITH
PROTEUS ANTIGEN
(OX19, OX2 & OXK)
RECOMBINANT ANTIGEN OF
ORIENTIA
TIME OVERNIGHT 2 HRS
EASE OF
PERFORMING
SIMPLE BUT TIME CONSUMING EASY BUT TECHNICALLY
DEMANDING
COST CHEAP COST EFFECTIVE
NO OF SAMPLES
REQUIRED
PAIRED SERA ;FOUR FOLD RISE SINGLE SERA ;> CUT OFF
RESULT
INTERPRETATION
SUBJECTIVE; NO CONSENSUS ON
SINGLE SIGNIFICANT TITRE
OBJECTIVE; CUT OFF BASED
ON CALCULATION ON
NORMAL SERA
ANTIBODY TESTED MAINLY IgM SEPARATE ASSAYS FOR IgM
AND IgG
SENSITIVITY 30- 60 93-97
SPECIFICITY 60- 90 91-95

33. Polymerase Chain Reaction
• a rapid and specific test for diagnosis, available only at few centres in
India.
• can be used to detect rickettsial DNA in whole blood and eschar
samples.
• PCR is targeted at the gene encoding the major 56 Kda and/or 47
KdHTRa surface antigen gene.
• The results are best within first week for blood samples because of
presence of rickettsemia in first 7-10 days.

34. Immunufluoroscence Assay (IFA)
• IFA slide presents antigens from only 3 serotypes namely
Karp, Kato and Gilliam
• Therefore, it is recommended only for research and in
areas where sero-prevalence of rickettsial diseases has
been established
• This is a reference serological method for
diagnosis of Rickettsial Diseases
• considered serological ‘gold standard’; however,
cost and requirement of technical expertise limit
its wide use.

35. Immunoperoxidase Assay (IPA)
• is a modification of IFA technique that
replaces the fluorochrome with
peroxidase.
• Slide is observed using a bright-field
microscope.
• Staining reaction is positive when O.
tsutsugamushi particles stain light
brown. Control Infected

36. SERO
LOG
Y
Acute
sensitiv
ity
Sp
ec
ifi
cit
y
Cost/
samp
le
Time Ea
se
Setting Comments
IFA +
+
+
+
+
+
+
+
+
2hours ++ Reference
lab/hospit
al
Serology gold standard, Requires
propagation & purification of BSL3 agents
as antigen for assay, Requires
fluorescence microscope, Standardization
problems & Requires paired samples
(retrospective diagnosis)
IPA +
+
+
+
+
+
+
+
2hours ++
++
Reference
lab/hospit
al
-do- except requires light
microscope only
Weil-
Felix
OXK2
+ ++ + 6-18
hours
++
++
Primary
hospital
•Poor sensitivity for acute
disease
• Requires paired samples
(retrospective diagnosis)

37. Supportive laboratory Investigations
• WBC count may become elevated to more
than 11,000 / cu. mm.
• Thrombocytopenia (i.e. < 1,00,000/ cu.mm) is
seen in majority of patients.
• Raised Transaminase levels are commonly
observed
• Chest X-Ray showing infiltrates, mostly
bilateral
Before admission
After treatment

38. Suspected/Clinical case
• Acute undifferentiated febrile illness of 5 days or more with or
without eschar - suspect Rickettsial infection.
• If eschar is present, fever of less than 5 days duration should be
considered as scrub typhus.
• Other presenting features: headache and rash, lymphadenopathy,
multi-organ involvement like liver, lung and kidney involvement.

39. Probable case
 Points to consider as positive for typhus and spotted fever groups of
Rickettsiae.
A suspected clinical case
titres of 1:80 or above in OX2, OX19 and OXK antigens by Weil
Felix test
optical density (OD) > 0.5 for IgM by ELISA

40. Confirmed case
Rickettsial DNA detection in eschar samples or whole blood by PCR
Or
Rising antibody titers on acute and convalescent sera detected by
Indirect Immune Fluorescence Assay (IFA) or Indirect
Immunoperoxidase Assay (IPA)

41. TREATMENT
• Without waiting for laboratory confirmation of the Rickettsial
infection, antibiotic therapy should be instituted when rickettsial
disease is suspected.
• Preantibiotic era -- Mortality was variable , approached ~60%,
• Antibiotic therapy brings about prompt disappearance of the fever
and dramatic clinical improvement.
• Rapid defervescence after antibiotic treatment is so characteristic that
it is used as a diagnostic test for O. tsutsugamushi infection

42. Primary Health Centre Level
• Less severe cases.....
ADULT CHILDREN PREGNANCY
Doxycycline 200 mg/day in
two divided doses for 7
days
Or
Azithromycin 500 mg in a
single oral dose for 5
days.
Doxycycline 4.5 mg/kg
body weight/day in two
divided doses for 7 days
Or
Azithromycin 10mg/kg body
weight in a single oral dose
for 5 days.
Azithromycin 500 mg in a
single oral dose for 5
days.

43. Primary Health Centre Level
If presents with Complications
• Refer to secondary or tertiary centre - ARDS, acute renal failure,
meningo encephalitis, multi-organ dysfunction.
• Doxycycline should be initiated before referring the patient.
• In addition to recommended management of community acquired
pneumonia, Doxycycline is to be initiated when scrub typhus is
considered likely.

44. Secondary and Tertiary Care
• (wherever available) 100mg twice daily in 100 ml normal saline to be
administered as infusion over half an hour initially followed by oral
therapy to complete 7-15 days of therapy.
I.V Doxycycline
• in the dose of 500mg IV in 250 ml normal saline over 1 hour once daily
for 1-2 days followed by oral therapy to complete 5 days of therapy.
I.V Azithromycin
• 50-100 mg/kg/d 6 hourly doses to be administered as infusion over 1
hour initially followed by oral therapy to complete 7-15 days of
therapy.
I.V Chloramphenicol

45. Prophylaxis
• Recommended under special circumstances where disease is endemic.
• Oral chloramphenicol or tetracycline given once every 5 days for
thirty-five days or weekly doses of doxycycline during and for 6 weeks
after exposure have both been shown to be effective regimens.
• Resistance to antibiotics has been noted in several areas, therefore
prophylaxis with antibiotics cannot be guaranteed.

46. Vaccine against scrub typhus?
• There is enormous antigenic variation in Orientia tsutsugamushi
strains, and immunity to one strain does not confer immunity to
another
• A vaccine developed for one locality may not be protective in another
locality, because of antigenic variation.
• This complexity continues to hamper efforts to produce a viable
vaccine

47. PREVENTION
• Protective clothing.
• Insect repellents containing dibutyl phthalate, benzyl benzoate,
diethyl toluamide etc applied to the skin and clothing to prevent
chigger bites.
• Do not sit or lie on bare ground or grass
• Clearing of vegetation and chemical treatment of the soil may help to
break up the cycle of transmission from chiggers to humans to other
chiggers.

48. CONTROL STRATEGY
Public
Education
Rodent
Control
Habitat
Modification
Case
Identification
&
Treatment

49. Take home message
Scrub typhus is a re-emerging disease in India.
an important cause of community acquired undifferentiated febrile illness in India.
It has to be considered in the differential diagnosis of sepsis and multiorgan dysfunction
syndrome.
Failure of early diagnosis is associated with significant mortality and morbidity and also leads
to expensive PUO workup.
Search for an eschar in hidden areas of body.
Screening by Weil-Felix & Diagnosis is done by IgM scrub typhus ELISA.
Drug of choice - - - - Doxycycline.