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Chapter
6
Scrub Typhus
V Ramasubramanian, P Senthur Nambi
INTRODUCTION AND HISTORY
Scrub typhus, caused by Orientia (formerly Rickettsia) tsutsugamushi,
is an acute infectious disease of variable severity that is transmitted
to humans by an arthropod vector of the Trombiculidae family.
“Tsutsuga” means small and dangerous and “mushi” means insect
or mite. It affects people of all ages including children. Humans
are accidental hosts in this zoonotic disease. While scrub typhus is
confined geographically to the Asia Pacific region, a billion people
are at risk and nearly a million cases are reported every year.1
Scrub typhus was first described from Japan in 1899. It was a
dreaded disease in pre-antibiotic era and a militarily important
disease that affected thousands of soldiers in the far east during
the second World War.2 The overall mortality varied from 7% to 9%,
second only to malaria among infectious diseases. Furthermore,
severe epidemics of the disease occurred among troops in Myanmar
and Sri Lanka during the Second World War.3 In India, scrub typhus
broke out in an epidemic form in Assam and West Bengal during
the Second World War. Later, the presence of this disease was found
throughout India in humans, trombiculid mites and rodents.4 It was
the third most common infection reported in United States (US)
troops stationed in Vietnam.5
The term “scrub” is used because of the type of vegetation (terrain
between woods and clearings) that harbors the vector; however,
the name is not entirely correct because certain endemic areas can
also be sandy, semiarid and mountain deserts. The word “typhus”
is derived from the Greek word “typhus”, which means “fever with
stupor” or smoke.1
chigger (Figure 1).7 The bite of the mite leaves a characteristic black
eschar. The adult mites have a four-staged lifecycle: (1) egg, (2) larva,
(3) nymph and (4) adult. The larva is the only stage (chigger) that can
transmit the disease to humans and other vertebrates, since the other
life stages (nymph and adult) do not feed on vertebrate animals. Both
the nymph and the adult are free-living in the soil.
Chigger mites act as the primary reservoirs for O. tsutsugamushi.
Once they are infected in nature by feeding on the body fluid of
small mammals, including the rodents, they maintain the infection
throughout their life stages and as adults, pass the infection on to
their eggs in a process called transovarial transmission. Similarly, the
infection passes from the egg to the larva or adult in a process called
transstadial transmission. In this way, chigger mite populations
autonomously maintain their infectivity over long periods of time.
Early workers thought that rodents were the natural reservoir of
infection, but it is now believed that mites are both the vector and the
reservoir.7 Clinical scrub typhus is not known to occur naturally in
animals. This mite is fastidious in matters of temperature, humidity
and food, and finds everything suitable in restricted areas. Scrub
typhus is generally seen in people whose occupational or recreational
activities bring them into contact with ecotypes favorable with vector
chiggers.8
PATHOGEN
Orientia tsutsugamushi is an obligate intracellular Gram-negative
bacterium that has a large number of serotypes. This pathogen does not
have a vacuolar membrane and hence it grows freely in the cytoplasm
of infected cells. Even though, it is recognized as one of the tropical
rickettsioses diseases, it has a different cell wall structure and genetic
composition than that of the rickettsiae. It includes heterogeneous
strains classified in five major serotypes: (1) Boryon, (2) Gilliam, (3)
Karp, (4) Kato and (5) Kawazaki.6 In each geographic area, there are
several genetic variations and these differ from the genetic variants in
other regions. Differentiation of serotypes is important for laboratory
diagnosis.
EPIDEMIOLOGY
Scrub typhus is transmitted to humans and rodents by some species
of trombiculid mites (“chiggers”, Leptotrombidium deliense and
others). Humans acquire the disease from the bite of an infected
Figure 1: Chigger (larva of trombiculid mite)
Infectious Diseases
Section 1
available in all places. Therefore, the precise incidence of the disease
is unknown. Mortality rates in untreated patients range from 0–30%.
CLINICAL FEATURES
Figure 2: Endemic areas of scrub typhus in Asia
Source: World Health Organization
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.9 Increase in the prevalence of scrub typhus
has been reported from some Asian countries (Figure 2), which
coincides with the widespread use of b-lactam antimicrobial drugs
and urbanization in rural areas.10
Scrub typhus is prevalent in many parts of India but specific data
are not available. It is a re-emerging infectious disease in India.11
There have been outbreaks in areas located in the sub-Himalayan
belt, from Jammu to Nagaland. There were reports of scrub typhus
outbreaks in Himachal Pradesh, Pondicherry, Tamil Nadu, Sikkim
and Darjeeling.12-14 The seasonal occurrence of scrub typhus varies
with the climate in different countries. The period of epidemic is
influenced by the activities of the infected mite. It occurs more
frequently during the rainy season. However, outbreaks have been
reported during the cooler season in southern India.15 Certain
areas such as forest clearings, riverbanks and grassy regions provide
optimal conditions for the infected mites to thrive.
Scrub typhus is difficult to recognize because the symptoms and
signs are often nonspecific. The nonspecific presentation and lack of
the characteristic eschar in 40–60% of patients lead to misdiagnosis
and under-reporting. On the other hand, diagnostic facilities are not
A
B
The clinical spectrum of scrub typhus is broad, with most infections
being of mild-to-moderate severity. After an incubation period of
7–21 days (mean, 10–12 days), the first sign of disease in patients is
a vesicular lesion at the site of mite feeding, which later on becomes
an eschar or an ulcer with regional lymphadenopathy. An eschar is
seen at the site of the chigger bite and are often found in the groin,
axilla, genitalia and neck (Figures 3A to C).7 It forms in one-half of the
primary infections, whereas in secondary infections it occurs only in a
minority of the cases.16 It is the single most important clue for diagnosis
and is pathognomonic when seen by an experienced physician. Rarely
multiple eschars may be found, for example, under a trouser belt.
Fever commences a few days later accompanied by headache,
myalgia and cough. It is the most common complaint starting
abruptly, and has the usual typhus accompaniments of suffused
conjunctiva, severe headache, drowsiness, apathy, pain in the shins
and other muscles, and more characteristically lymphadenopathy
and hepatosplenomegaly.17 Severe headache occurs almost
invariably and is a key criterion for identifying suspected cases. A
spotted rash on the trunk may appear.
The disease may get complicated by interstitial pneumonitis,
adult respiratory distress syndrome (ARDS) (Figure 4), acute hepatic
failure, acute renal failure, disseminated intravascular coagulation
(DIC), meningitis and myocarditis.18 The chances of developing
ARDS is more in patients of scrub typhus who have higher white
blood cell (WBC) counts, lower hematocrit, higher bilirubin levels
and delayed treatment with antibiotics.19 Abdominopelvic lymph
nodes may be enlarged especially in the para-aortic, portahepatic
and in the splenic hilum. It may involve other abdominopelvic
organs including the gastrointestinal (GI) tract and kidneys. There
may be bleeding in case of GI tract involvement.
DIAGNOSIS
• Blood counts: Normal WBC or leukocytosis may be seen.
Thrombocytopenia may occur.
• Liver function tests: Elevated transaminases may be seen in 75–
95% of patients. Hypoalbuminemia occurs in about half the cases
while hyperbilirubinemia is not uncommon.
• Renal function tests: Creatinine may be elevated in severe cases.
• Chest X-ray: It may reveal pneumonitis, pleural effusion or
bilateral infiltrates.
• Ultrasound abdomen: It may reveal liver or spleen enlargement.
C
Figures 3A to C: Eschar in (A) shoulder, (B) scrotum and (C) neck
20
Chapter 6 Scrub Typhus
Section 1
TABLE 1 │ Scrub typhus—treatment options
Figure 4: Adult respiratory distress syndrome (ARDS) in a patient
with scrub typhus
SPECIFIC TESTS
Serology
• The cheapest and most easily available serological test is the WeilFelix test. It is easy to perform and results are available overnight.
Fifty percent of patients have a positive test result during the
second week. However, this test lacks specificity and sensitivity.20
• The gold standard is indirect immunofluorescence antibody
(IFA). Indirect immunoperoxidase (IIP) is a modification of the
standard IFA method that can be used with a light microscope,
and the results of these tests are comparable to those from IFA.20
Serological methods are most reliable when a fourfold rise in
antibody titer is looked for.
• Qualitative enzyme-linked immunosorbent assay (ELISA)
for detection of immunoglobulin M (IgM) antibodies to
O. tsutsugamushi in serum is now commercially available. This
makes use of an O. tsutsugamushi derived recombinant antigen
mixture. This test aids in the diagnosis of human exposure to O.
tsutsugamushi species.
Culture
The organism can be grown in tissue culture or mice from the blood
of patients with scrub typhus. Isolation of O. tsutsugamushi requires
biosafety level-3 facilities and the median time to positivity is 27 days.
Polymerase Chain Reaction
Polymerase chain reaction (PCR) is possible from skin rash biopsies,
lymph node biopsies or ethylenediaminetetraacetic acid (EDTA)
blood. O. tsutsugamushi can be demonstrated by standard and by
nested PCR.21 Real-time PCR assays are as sensitive as standard PCR
but are more rapid and can give quantitative results.22
TREATMENT
• Treatment of scrub typhus must be initiated early in the course
of the disease, based on a presumptive diagnosis, to reduce
mortality and morbidity (Table 1).
Drug of choice
Doxycycline 100 mg BD
Alternatives
Azithromycin 500 mg OD
Chloramphenicol 500 mg QID
Children and pregnant women
Azithromycin 500 mg OD
Drug-resistant serotypes
Azithromycin + rifampicin
Doxycycline + rifampicin
• The recommended treatment duration is 7–14 days. Treatment
for less than a week is initially curative but may be followed by
relapse.
• Doxycycline is the drug of choice.
• In case of small children and pregnant women, azithromycin is
the drug of choice. It has been shown to have comparable efficacy
when compared to doxycycline in a small trial.23
• Rifampicin has also been used as an alternative drug. Importantly,
it should not be used alone because of the risk of resistance. It
has been used in combination with azithromycin. A combination
therapy with doxycycline and rifampicin should be used in areas
where there is poor response to doxycycline alone.24
• 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.25
• Meticulous supportive management is necessary to abort
progression to DIC and septic shock. Further studies are needed
to improve antibiotic treatment of severe and resistant scrub
typhus as well as to improve treatment in children and pregnant
women.
MORTALITY IN SCRUB TYPHUS
Mortality rates in untreated patients range from 0% to 30% and tend
to vary with patients age and region of infection. In the pre-antibiotic
era, mortality rates in Japan averaged 30%. In Taiwan, the overall
mortality was estimated at 11%, but only 5% in children and as high
as 45% in the elderly. With appropriate treatment, mortality is quite
rare. However, mortality is still approximately 15% in many areas
due to missed or delayed diagnosis.16 Mortality is higher if severe
complications like ARDS develop.
PREVENTION
Avoidance of Mite—Human Contact
• Avoid mite infested areas
• Wear protective clothing
• Personal prophylaxis against the mite vector by impre-gnating
clothes with miticidal chemicals (permethrin and benzyl
benzoate) and the application of mite repellants (diethyl
toluamide) to exposed skin surfaces
• Eliminate mites from sites by application of chlorinated hydro­
carbons (lindane, dieldrin and chlordane) to the ground and
vegetation in camps and other populated zones in endemic areas.
Chemoprophylaxis
Weekly once dose of 200 mg doxycycline is effective. It should be
considered for nonimmune people sent to work in endemic areas
and in high-risk travelers.
Vaccine
There are no effective vaccines for scrub typhus. There is enormous
antigenic variation in O. tsutsugamushi strains and immunity to one
21
Infectious Diseases
strain does not confer immunity to another. Any scrub typhus vaccine
should give protection to all the strains present locally, in order to
give an acceptable level of protection. This complexity continues to
hamper efforts to produce a viable vaccine.
POINTS TO REMEMBER
• Scrub typhus is a re-emerging disease in India.
• It is 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.
• Search for an eschar in hidden areas of body
• Doxycycline is the drug of choice.
• Diagnosis is done by IgM scrub typhus ELISA.
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22
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