CD Alert Scrub typhus

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CD Alert
National Centre for Disease Control,
Directorate General of Health Services, Government of India
May 2018
SCRUB TYPHUS
SCRUB TYPHUS
Scrub typhus, a rickettsial disease, is an acute,
febrile, infectious illness that is caused by
Orientiatsutsugamushi(formerly Rickettsia sp.).
It is also known as tsutsugamushi disease.
Scrub typhus was first described from Japan in
1899. Humans are accidental hosts in this
zoonotic disease.
Rickettsial diseases are considered some of the
most covert emerging and re-emerging
diseases and are being increasingly recognized
in India. Rickettsial diseases are classically
divided into the typhus group and spotted fever
group (SFG), although the genus has been
subdivided further based on phylogenetic
analysis. Orientiaspp. makes up the scrub
typhus group.
Scrub typhus is the commonest occurring
rickettsial infection in India.
Scrub typhus (Chigger borne typhus,
Tsutsugamushi fever) is caused by
Orientiatsutsugamushi. Orientia is a small (0.3
to 0.5by 0.8 to 1.5 m), gram negative
bacterium of the family Rickettsiaceae. It differs
from the other members in its genetic make up
and in the composition of its cell wall structure
sinceit lacks lipopolysaccharide and
peptidoglycan and does not have an outer slime
layer. It is endowed with a major surface protein
(56kDa) and some minor surface protein (110,
80, 46, 43, 39, 35, 25 and 25kDa). There are
considerable differences in virulence and
antigen composition among individual strains of
O.tsutsugamushiwhich has many serotypes
(Karp, Gillian, Kato,Kawazaki and Boryong).
GLOBAL SCENARIO
Scrub typhus is endemic to a part of the world
known as the “tsutsugamushi triangle”, which
extends from northern Japan and far-eastern
Russia in the north, to northern Australia in the
south, and to Pakistan in the west.
There is an estimated one million new scrub
typhus infections each year, and over one billion
people around the world are at risk. Scrub
typhus is a serious public health problem in the
Asia-Pacific area. The vector of scrub typhus is
present in most countries of the South-East Asia
Region and it is endemic in certain geographical
regions of India, Indonesia, Maldives, Myanmar,
Nepal, Sri Lanka and Thailand.
Without appropriate treatment, the case fatality
rate of scrub typhus can reach 30% or even
higher.
The seasonal occurrence of scrub typhus varies
with the climate in different countries. However,
outbreaks have been reported during the cooler
season in southern India.
INDIAN SCENARIO
Rickettsial diseases have been documented in
India since the 1930s with reports of scrub
typhus from Kumaon region, in soldiers during
the Second World War in Assam, scrub and
murine typhus from Jabalpur area in Madhya
Pradesh and of murine typhus from Kashmir.
Surveillance in animals and humans in different
parts of India has documented significant levels
of exposure to infections. With the increasing
awareness, availability of diagnostics and
improved surveillance, scrub typhus is being
widely detected from various parts of the
country including north eastern states (Assam,
Arunachal Pradesh, Manipur, Mizoram,
Meghalaya, Nagaland, Sikkim, Tripura), Jammu
CAUSATIVE AGENT

and Kashmir, Uttar Pradesh, Himachal Pradesh,
Uttarakhand, Bihar, West Bengal, Rajasthan,
Gujarat, Maharashtra, Karnataka, Tamil Nadu,
Puducherry and Kerala. In some regions, scrub
typhus accounts for upto 50 per cent of
undifferentiated fever presenting to hospital.
Scrub Typhus outbreaks reported (2008-2012)
Scrub Typhus outbreaks reported (2013-2018)
State wise no. of outbreaks of Scrub Typhus
reported under IDSP during 2008-2018 (till March)
Year wise no of outbreaks of Scrub Typhus
reported under IDSP during 2008-2018 ((till
March)
The characteristic features of an outbreak of
scrub typhus in Indian context are:
(i) It is no longer associated with certain
types of terrain;
(ii) It is no longer localized to certain small
foci;
(iii) a large percentage of susceptible
people may be infected simultaneously
following exposure over relatively short
periods;
(iv) Thehistory of bites or attack by
arthropods may not be easily elicited
from the patient;
(v) Rapid response to treatment to
tetracyclines/ macrolide group of drugs.
FEATURES OF OUTBREAKS

Scrub typhus is transmitted by the mite
Leptotrombidiumdeliense. The vector mitesinhabit
sharply demarcated areas in the soil where the
microecosystem is favourable (mite islands).
Human beings are infected when they trespass
into these mite islands and are bitten by the mite
larvae (chiggers). Only the larval stages take
blood meal. The mite feeds on the serum of warm
blooded animals only once during its cycle of
development, and adult mites do not feed on man.
The microbes are transmitted transovarially in
mites. Scrub typhus normally occurs in a range of
mammals, particularly field mice and rodents.
The L.deliensegroup of vector mites are widely
distributed all over the country coexisting primarily
with rodents and other small mammals. On the
body of small mammalian hosts, the chiggers
attach in clusters on the tragus of the ear, the belly
and on the thighs. The Leptotrombidium mites, on
the rat host, may appear orange or pink. The
typical vector L.delienseis generally found
associated witheither established forest vegetation
or secondary vegetation after clearance of forest
areas. This species is generally abundant on
grasses and herbs where bushes are scarce.
Incidence of scrub typhus is higher among rural
populationthough also being increasingly reported
from urban areas. Cases are more likely to have
exposure to rodents at home or at work. Cases are
exposed to the risk of encountering chiggers sitting
in grass blades, bushes and shrubs during
occupational (farming) or outdoor activities such as
open defecation and recreation. The disease is
seasonal in many parts of India, which correlates
with the appearance and activity of mites.
Sentinel animals can also be used for collection of
trombiculid mites from the field. These animals are
generally white laboratory mice or rats kept in
small cages containing food and water and placed
in the field overnight to attract chiggers. Chiggers
can also be collected from field directly on human
beings, by walking in the field after wearing
stockings. The following morning, chiggers can be
collected from the body of the sentinel animals.
The mites can be preserved in 70% alcohol till
they reach laboratory for identification. Chigger
index (average number of chiggers infesting a
single host) of > 0.69 (critical value) is an indicator
for implementation of vector control measures.
Incubation Period
Incubation Period: 5-20 days (average 10-12
days) after the initial bite.
The chigger bite is painless and may become
noticed as a transient localized itch.
Bites are often found on the groin, axillae,
genitalia, perianal area or neck.
An eschar is often seen in humans at the site
of the chigger bite.
The illness begins rather suddenly with
shaking chills, fever, severe headache,
infection of the mucous membrane lining the
eyes (the conjunctiva), and swelling of the
lymph nodes.
A spotted rash on the trunk may be present.
Eschars are rare in patients in countries of
South-East Asia and indigenous persons of
typhus-endemic areas commonly have less
severe illness, often without rash or eschar.
Symptoms may include muscle and
gastrointestinal pains.
More virulent strains of O. tsutsugamushi can
cause haemorrhage and intravascular
coagulation.
Complications may include atypical
pneumonia, overwhelming pneumonia with
adult respiratory distress syndrome (ARDS)–
like presentation, encephalopathy,
myocarditis, disseminated intravascular
coagulation (DIC) and multiple organ
dysfunction syndrome (MODS).
Patients with scrub typhus often exhibit
leucopenia.
The case fatality rate of scrub typhus can be
as high as 30-70% if no appropriate
treatment is received.
Total leucocytes count (TLC) during early
course of the disease may be normal but
later in the course of the disease,
leucocytosisis seen i.e. WBC count >
11,000/μl.
Mild thrombocytopenia.
Deranged liver function tests.
Albuminuria
Chest X-ray shows infiltrates, mostly bilateral
DISEASE TRANSMISSION
CLINICAL PICTURE
SUPPORTIVE INVESTIGATIONS

Scrub Typhus axillary eschar
Characteristic Eschar
Maculopapular rash on the base of a case of scrub typhus
Chigger mite
Suspected/clinical case: Acute undifferentiated
febrile illness of five days or more withor without
eschar should be suspected as a case of
rickettsial infection (if eschar is present, fever of
less than five days duration should be
considered as scrub typhus). Other presenting
features may be headache and rash (rash more
often seen in fair persons),
lymphadenopathy,encephalopathy, multi-organ
involvement like liver, lung and kidney and acute
respiratory distress. Patients presenting with
features of AES could be scrub typhus.
CASE DEFINITION
Common clinical manifestations of the Rickettsial Infections
Encephalopathy

The differential diagnosis of dengue, malaria,
pneumonia, leptospirosis and typhoid should
be kept in mind.
Probable case: A suspected clinical case
showing titres of 1:80 or above in OX2,
OX19and OXK antigens by Weil-Felix test and
an optical density (OD) > 0.5 for IgM by ELISA
is considered positive for members of typhus
and spotted fever groups of Rickettsiae.
Confirmed case: A confirmed case is the one
in which (a) Rickettsial DNA is detectedin
eschar samples or whole blood by PCR, or (b)
Rising antibody titres on acute and
convalescent serum samples detected by
indirect immune fluorescence assay (IFA).
Laboratory diagnosis
Rickettsial diseases may be diagnosed in the
laboratory by:
(i) serology
(ii) molecular diagnosis (PCR).
(iii) isolation of the organism
Collection, storage & transportation of
specimen
The collection, transportation and storage of
specimens are extremely vital steps in
laboratory diagnosis and hence, must be
undertaken with utmost care.
Specimen
Serum
Blood collected in tubes containing EDTA or
Sodium citrate
Blood clot
Eschar, whole blood, buffy coat fraction and
tissue specimen
Blood collection in tubes and vials
Aseptically collect 4-5 ml of venous blood.
Allow blood to clot at room temperature,
centrifuge at 2000 rpm to separate serum.
Collect the serum in sterile dry serum
/EDTA/citrate vial
Fix the cap with adhesive tape, wax or other
sealing material to prevent leakage during
transport.
Use adhesive tape marked with pencil,
indelible ink, or a typewritten self adhesive
label to identify the container. The name of
the patient, identification number and date of
collection must be indicated on the label.
Do’s/Don’ts while collecting specimen:
Collect sufficient quantity of specimen
Avoid contamination by using sterile
equipment and aseptic precautions.
Dispatch the specimen immediately to
laboratory at 2-8ºC (ice box) as soon as
possible.
Don’t freeze whole blood as haemolysis may
interfere with serology test results.
In case the delay is inevitable, keep the
specimen at + 4ºC in a refrigerator.
Label all specimens accurately and send all
pertinent information to laboratory which will
help in better interpretation of the laboratory
findings.
I. Serological diagnosis
Serological assays are the simplest &
mainstay diagnostic tests for rickettsial
diseases and some of the available tests can
easily be done in modest laboratory facilities
available at PHC/District hospitals.
Diagnosis of the etiology of rickettsial
diseases can be accomplished most easily
and rapidly by demonstrating a significant
increase in antibodies in the serum of the
patient during the course of infection and
convalescence. Paired serology/ IgM and IgG
ELISA certainly help in diagnosis of Rickettsial
diseases in resource constrained settings.
Several serological tests are currently
available for the diagnosis of rickettsial
diseases like Weil Felix test, Enzyme linked
Immunosorbent assay (ELISA), Indirect
Immunofluorescence (IIF), etc. Although many
techniques have been used successfully for
rickettsial serodiagnosis, relatively few are
used regularly by most laboratories. Further,
baseline titres need to be standardized for
each region.
(A) Weil-Felix Test (commonly used test)
The Weil Felix test uses antigens from three
proteus strains: P.vulgaris Ox 2, P. vulgaris Ox
19 and P. mirabilis Ox k. Weil-Felix test has
reasonable sensitivity and specificity as per
NCDC experience of last 10 years and can be
performed even in resource poor settings.
High titre in single specimen has higher
positive predictive value. However, four fold
rise in titre is confirmatory in paired serology.
Whenever possible IgM/IgG based serologic
test may be done for scrub typhus.
LABORATORY DIAGNOSIS

The interpretation of Weil-Felix testis given in
table 1.
Table 1 : Weil-Felix Test
OX 19 OX 2 OXK
Epidemic typhus ++++ + 0
Brill Zinsser disease ++++ + 0
Murine typhus ++++ + 0
Scrub typhus 0 0 +++
RMSF ++++ + 0
Other tick borne
infection
+ ++++ 0
Indian tick typhus + ++++ 0
(B) Enzyme linked Immunosorbent Assay
(ELISA)
ELISA techniques, particularly IgM and Ig G
capture assays to specific antigen, are probably
the most sensitive tests available for rickettsial
diagnosis. The presence of IgM antibodies,
indicate recent infection with rickettsial
diseases. In cases of infection with
O.tsutsugamushi, a significant IgM antibody titer
is observed at the end of the first week, whereas
IgG antibodies appear at the end of the second
week.
(C) Indirect Immunofluorescent antibody
(IFA) test
Traditionally, Micro immunofluorescence is used
as a reference technique to test several
antigens simultaneously to help identify the
causative organism (Rickettsia and Orientia).
The availability and cost of reagents/
equipments are major constraints and is not
available in most of the laboratories. Further
technique takes long time, requires a pool of
antisera and lacks reproducibility. Therefore, it is
recommended only for research and in areas
where seroprevalence of rickettsial diseases
has been established and a reference facility is
already available which has the necessary
expertise required to conduct these tests.
II. Molecular diagnosis – PCR
Molecular techniques may be used for detection
of O.tsutsugamushi, R.prowazeki, R.conorii,
R.typhi. DNA extracted from clinical specimens
(eschar, whole blood, buffy coat fraction and
tissue specimen) can be used to diagnose
rickettsial infections by PCR/Real time PCR.
The specific target sequence for 56 kDa / 47kDa
surface antigens have been attempted for
identification of O.tsutsugamushi. The other
targets for identification of rickettsial diseases
attempted are 16 s r RNA, outer membrane
protein, lipoprotein gene etc. The results are
best within the first week for blood samples
because of presence of rickettsemia
(O.tsutsugamushi, R.rickettsii, R. typhi and R.
prowazekii) in first 7-10 days.
III. Isolation of the organism (Not for Routine
Diagnosis)
As rickettsiae are highly infectious and have
caused several serious and fatal infections
among laboratory workers, it comes under Risk
Group 3 organisms. Isolation should be done in
laboratories equipped with appropriate safety
provisions preferably Biosafety level-3
laboratory following strict biosafety precautions.
Rickettsiae have been isolated by several
different methods such as animal inocaulation,
embryonated eggs and various cell lines.
Rickettsia may be isolated in male guinea pigs
or mice; yolk sac of chick embryos; vero cell line
or MRC 5 cell lines from patients in early phase
of the disease. Egg and animal inoculation
methods have been replaced by faster and
more sensitive cell cultures. Rickettsiae grow
well in 3-5 days on Vero cell and MRC 5 cell
coverslip cultures and can be identified by
immunofluorescence using group and strain
specific monoclonal antibodies or gene based
identification.
Rapid Diagnostic Tests do not give consistent
results and may not be used as a single test for
diagnostic purposes.
Prompt institution of effective antibiotic therapy
against rickettsiae is the single most effective
measure for preventing morbidity and mortality
due to rickettsial diseases. Anti rickettsial
therapy improves the outcome of all
rickettsioses, with the occasional exception of
fulminate or complicated cases of RMSF,
epidemic typhus and scrub typhus where the
illness is no longer susceptible to intervention. If
the illness is severe, the cardiac, pulmonary,
renal, and central nervous systems should be
assessed and additional measures instituted to
prevent complications.
TREATMENT

Tetracyclines and chloramphenicol remain the
only proven therapy for the rickettsial diseases.
Without waiting for laboratory confirmation of the
rickettsial infection, antibiotic therapy should be
instituted when rickettsial disease is suspected.
At primary level: The health care provider
needs to do the following:
I. Recognition of disease severity. If the
patient comes with complications to primary
health facility and treating physician
considers it as rickettsial infection, treatment
with doxycycline should be initiated before
referring the patient.
II. Referral to secondary or tertiary centre in
case of complications like ARDS, acute
renal failure, meningoencephaliltis, multi-
organ dysfunction. In addition to
recommended management of pneumonia,
treatment of scrub typhus (doxycycline) is to
be provided to the patient.
III. In fever cases of duration of five days or
more where malaria, dengue and typhoid
have been ruled out; the following drugs
should be administered –
In adults:
A. Doxycycline 200 mg/day in two divided doses
for individuals above 45 kg for a duration of
seven days. OR
B. Azithromycin 500 mg in a single dose for five
days.
If the clinical sign and symptoms persist,
alternative diagnosis should be considered.
In children:
A. Doxycycline in the dose of 4.5 mg/kg
body weight/day in two divided doses for
children below 45 kg. OR
B. Azithromycin in the dose of 10 mg/kg
body weight for five days.
In pregnant women:Azithromycin 500 mg in
a single dose for five days. Azithromycin is the
drug of choice in pregnant women, as
doxycycline is contraindicated.
At secondary and tertiary care level
I. The treatment as specified above in
uncomplicated cases.
II. In complicated cases the following
treatment is to be initiated:
Intravenous doxycycline (wherever
available) 100 mg 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. OR
Intravenous azithromycin in the dose of
500 mg intravenous (iv) in 250 ml
normal saline over one hour once daily
for 1-2 days followed by oral therapy to
complete five days of therapy. OR
Intravenous chloramphenicol 50-100
mg/kg/day 6-hourly doses to be
administered as infusion over one hour
initially followed by oral therapy to
complete 7-15 days of therapy.
III. Management of the individual
complications should be done as per the
existing practices.
Doxycycline and/or chloramphenicol resistant
strains have been seen in South-East Asia.
These strains are sensitive to azithromycin.
Tetracyclines may cause discoloration of teeth,
hypoplasia of the enamel, and depression of
skeletal growth in children; the extent of
discolouration is directly related to the number
of courses of tetracycline therapy received.
Therefore, tetracycline should not be used for
children under 8 years of age and for pregnant
women.
An effective vaccine for humans has not been
developed till now, mainly due to serotypic
heterogeneity of the organism.
Preventive and control measures
Persons who cannot avoid infested terrain
should wear protective clothing, impregnate
their clothing and bedding with a miticide.
People should wash themselves and their
clothes after every potential exposure.
Insect repellents containing dimethyl phthalate
(DMP), benzyl benzoate and diethyl toluamide
(DEET) can be applied to the skin and clothing
to prevent chigger bites.
Do not sit or lie on bare ground or grass; use a
suitable ground sheet or other ground cover.
PREVENTION AND CONTROL

Clearing of vegetation and chemical treatment
of the vegetation/ soil may help to break up the
cycle of transmission from chiggers to humans.
A single oral dose of chloramphenicol or
tetracycline given every 5 days for a total of 35
days, with 5-day non-treatment intervals. This is
recommended under special circumstances
incertain areas where the disease is endemic.
I. Rapid case identification by health-care
workers can help provide prompt treatment:
The early diagnosis of acute scrub typhus can
greatly reduce the chance of life-threatening
complications and guide optimal therapy. It will
be necessary to increase awareness of
empirical therapy options for scrub typhus and
to develop diagnostic assays that are
affordable, require limited expertise and
equipment, and are sensitive and specific such
that can be used in endemic, resource poor
countries.
States should consider planning for
prepositioning diagnostic kits for scrub typhus,
ahead of peak seasons, to be able to better
control the situation.
II. Public education on case recognition and
personal protection will help in the
identification and prompt treatment of cases:
Advocacy, awareness and education activities
should be targeted at schoolchildren, teachers
and women groups in endemic areas.
Involvement of community-based organizations in
prevention & control of scrub typhus is important.
III. Rodent control and habitat modification:
Rodent control is a multidimensional activity
that requires multisectoral cooperation.
Different control strategies such as trapping,
poisoning and use of natural predators are in
practice. Rodent control is primarily the
responsibility of the agriculture sector -
poisoning is a common practice.
Vector control: Chiggers can be controlled by
insecticide treatment of the vegetation/ forest
pathways.
Several wildlife rehabilitation organizations
encourage the natural form of rodent control
through exclusion and predator support and
preventing secondary poisoning altogether.
Habitat modification will make areas less
attractive to commensal rodents and thereby
prevent new populations from recolonizing the
habitat. Allowing weeds to grow around buildings
also encourages rats and mice. Good sanitation
in and around buildings creates an environment
that is less suited for rodent populations.
Repeated increase in rodent population even
after the use of poisons is a good indication that
habitat modification is needed.
(DISCLAIMER: The CD Alert on Scrub Typhus
has been updated keeping in line with:
DHR-ICMR Guidelines for Diagnosis &
Management of Rickettsial Diseases in India
(Indian J Med Res. 2015 Apr; 141(4): 417–422)
(http://icmr.nic.in/ijmr/2015/april/0406.pdf)
A Brief Guide to Emerging infectious diseases
and Zoonoses
(http://www.searo.who.int/entity
/emerging_diseases/ebola/a_brief_guide_emer
ging_infectious_diseases.pdf);
FAQs on Scrub Typhus
(http://www.searo.who
.int/entity/emerging_diseases/CDS_faq_Scrub_
Typhus.pdf)
CHEMOPROPHYLAXIS
….about CD Alert
CDAlertis a technical newsletter of the National Centre for Disease Control (NCDC), DirectorateGeneral of Health
Services, to disseminate information on various aspects of communicable diseases to medical fraternity and health
administrators. The newsletter may be reproduced, in part or whole, for educational purposes.
Publisher: Director, National Centre for Disease Control, 22 Shamnath Marg, Delhi 110 054
Tel: 011-23971272, 23971060 Fax : 011-23922677
E-mail: dirnicd@nic. in Website: www.nicd.nic.in
Acknowledgement: ‘Supported by WHO Country Office forIndia’.
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