Scrub Typhus

Background: Scrub typhus is an acute, febrile, infectious illness caused by Rickettsia tsutsugamushi, which also is known as Rickettsia orientalis. Humans are accidental hosts in this zoonotic disease. 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 and semiarid. Cases diagnosed in the United States have been imported from regions of Southeast Asia and the southwestern Pacific where the disease is endemic.

Pathophysiology: Humans acquire the disease when an infected chigger, the larval stage of trombiculid mites (Leptotrombidium deliense and others), bites them while feeding and inoculates R tsutsugamushi pathogens. The bacteria multiply at the inoculation site with the formation of a papule that ulcerates and becomes necrotic, evolving into an eschar, with regional lymphadenopathy that progresses to generalized lymphadenopathy within a few days. Before symptoms develop, patients are rickettsemic. As in other rickettsial diseases, perivasculitis of the small blood vessels occurs.

Frequency:

• In the US: Reported cases are imported by travelers, military personnel, and persons who have emigrated from abroad.

• Internationally: Scrub typhus is endemic in regions of eastern Asia and the southwestern Pacific (Korea to Australia) and from Japan to India and Pakistan.

Mortality/Morbidity:

• Mortality rates in untreated patients range from 0-30%.

• Complications may include atypical pneumonia, overwhelming pneumonia with adult respiratory distress syndrome (ARDS)–like presentation, myocarditis, and disseminated intravascular coagulation (DIC).

• No significant morbidity or mortality occurs in patients who receive appropriate treatment.

History:

• Elicit any history of travel to endemic areas.

• Patients most commonly present with high fever, severe headache, and generalized myalgia.

• The incubation period from the mite bite is 6-18 days following inoculation.

Physical:

• Patients experience abrupt onset of high fever (104-105°F), severe headache, myalgia, and eschar with tender regional lymphadenopathy. Less frequently, ocular pain, wet cough, malaise, and injected conjunctiva are present.

• Toward the end of the first week, approximately 35% of patients develop a centrifugal macular rash on the trunk, which may become papular. By this time, hepatosplenomegaly and generalized lymphadenopathy are present.

• A small number of patients have CNS involvement, with tremors, nervousness, slurred speech, nuchal rigidity, or deafness during, the second week of the disease; however, results from the cerebrospinal fluid examination either are normal or indicate a low number of monocytes.

Causes:

• R tsutsugamushi

• This is an obligate intracellular bacterium that, unlike most other rickettsiae, has a large number of serotypes. Three serotypes, Karp, Gilliam, and Kato, are helpful in serologic diagnosis.

• This pathogen does not have a vacuolar membrane; thus, it grows freely in the cytoplasm of infected cells.

Other Problems to be Considered:

Lab Studies:

• Routine laboratory studies reveal early lymphopenia with late lymphocytosis.

• Albuminuria is a common laboratory finding.

• Weil-Felix OXK strain agglutination test

• Approximately 50% of patients have a positive test result during the second week of the disease. A positive test result is defined as a single titer of at least 1/320 or a 4-fold elevation from a titer of 1/50.

• This test is not very sensitive, but it is rather specific, despite having cross-reactivity in patients with leptospirosis.

• Other tests include the indirect microimmunofluorescent test (in which a titer more than 1/400 is considered positive), the immunoperoxidase test, and polymerase chain reaction (PCR).

Medical Care:

• Tetracycline and chloramphenicol both are highly effective in the treatment of scrub typhus. It is generally recommended that tetracycline should not be used in children younger than 8 years because of dental discoloration. However, because of the potential toxicities associated with chloramphenicol, its use may be warranted in children younger than 8 years. Monitor chloramphenicol levels during therapy.

• Other antibiotics studied for the treatment of scrub typhus include doxycycline and ciprofloxacin. Further studies are needed on the use of ciprofloxacin in children.

• To reduce the risk of relapse, treatment should be administered for at least 14 days.

• Meticulous supportive management is necessary to abort progression to DIC or circulatory collapse in severe cases.

Drug Category: Antibiotics -- Tetracycline derivatives are the mainstays of treatment.

Drug Name	Tetracycline (Sumycin) -- Inhibits bacterial protein synthesis by binding with 30S and possibly 50S ribosomal subunit(s).
Adult Dose	250-500 mg PO q6h
Pediatric Dose	Higher end of 25-50 mg/kg/d PO divided q6h; not to exceed 2 g/d
Contraindications	Documented hypersensitivity; severe hepatic dysfunction
Interactions	Bioavailability decreases with antacids containing aluminum, calcium, magnesium, iron, or bismuth subsalicylate; can decrease effects of oral contraceptives, causing breakthrough bleeding and increased risk of pregnancy; tetracyclines can increase hypoprothrombinemic effects of anticoagulants
Pregnancy	D - Unsafe in pregnancy
Precautions	Photosensitivity may occur with prolonged exposure to sunlight or tanning equipment; reduce dose in renal impairment; consider drug serum level determinations in prolonged therapy; tetracycline use during tooth development (last one-half of pregnancy through age 8 y) can cause permanent discoloration of teeth; Fanconilike syndrome may occur with outdated tetracyclines

Drug Name	Doxycycline (Bio-Tab, Doxy, Vibra-Tabs) -- Inhibits protein synthesis and, thus, bacterial growth by binding to 30S and possibly 50S ribosomal subunits of susceptible bacteria.
Adult Dose	100-200 mg PO bid
Pediatric Dose	5 mg/kg/d PO/IV divided bid; not to exceed 200 mg/d
Contraindications	Documented hypersensitivity; severe hepatic dysfunction
Interactions	Bioavailability decreases with antacids containing aluminum, calcium, magnesium, iron, or bismuth subsalicylate; tetracyclines can increase hypoprothrombinemic effects of anticoagulants; tetracyclines can decrease effects of oral contraceptives, causing breakthrough bleeding and increased risk of pregnancy
Pregnancy	D - Unsafe in pregnancy
Precautions	Photosensitivity may occur with prolonged exposure to sunlight or tanning equipment; reduce dose in renal impairment; consider drug serum level determinations in prolonged therapy; tetracycline use during tooth development (last one half of pregnancy through age 8 y) can cause permanent discoloration of teeth; Fanconilike syndrome may occur with outdated tetracyclines

Drug Name	Chloramphenicol (Chloromycetin) -- Binds to 50 S bacterial-ribosomal subunits and inhibits bacterial growth by inhibiting protein synthesis. Oral chloramphenicol is no longer available in the United States. Monitor serum levels closely and adjust dose to achieve therapeutic concentrations (ie, peak 10-20 mcg/mL, trough 5-10 mcg/mL).
Adult Dose	50-100 mg/kg/d PO/IV divided q6h
Pediatric Dose	50-100 mg/kg/d PO/IV divided q6h; not to exceed 4 g/d; monitor serum levels closely
Contraindications	Documented hypersensitivity
Interactions	Concurrently with barbiturates, chloramphenicol serum levels may decrease while barbiturate levels may increase causing toxicity; manifestations of hypoglycemia may occur with sulfonylureas; rifampin may reduce serum chloramphenicol levels, presumably through hepatic enzyme induction; may increase effects of anticoagulants; may increase serum hydantoin levels, possibly resulting in toxicity; chloramphenicol levels may be increased or decreased
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Do not use in pregnancy near term because of potential development of gray baby syndrome (ie, circulatory collapse, cyanosis, acidosis, coma, and possibly death) Use only for indicated infections, or as prophylaxis for bacterial infections; serious and fatal blood dyscrasias (aplastic anemia, hypoplastic anemia, thrombocytopenia, granulocytopenia) can occur; evaluate baseline and perform periodic blood studies approximately every 2 d while in therapy; discontinue upon appearance of reticulocytopenia, leukopenia, thrombocytopenia, anemia, or findings attributable to chloramphenicol; adjust dose in liver or kidney dysfunction

Further Inpatient Care:

• Inpatient care may be necessary for patients with severe illness.

Deterrence/Prevention:

• Preventive measures in endemic areas include protective clothing and insect repellents.

• Short-term vector reduction using environmental insecticides and vegetation control can be instituted.

• Chemoprophylaxis using doxycycline in high-risk groups (eg, military personnel) has been successful. Doses are weekly and must be started before exposure and continued for 6 weeks after exposure.

• No vaccine for scrub typhus is available.

Prognosis:

• Prognosis is variable and depends on the severity of illness, which relates to the different strains of R tsutsugamushi.

• Severe disease is uncommon with antimicrobial treatment.