AUTHOR AND EDITOR INFORMATION

Section 1 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• References

INTRODUCTION

Section 2 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• References

Background

Scrub typhus is an acute, febrile, infectious illness that was first described by the Chinese about 2000 years ago. This illness is caused by Orientia (formerly Rickettsia) tsutsugamushi, an obligate intracellular gram-negative bacterium, which was first isolated in 1930. Even though it is recognized as one of the tropical rickettsioses diseases, O tsutsugamushi has a different cell wall structure and genetic composition than that of the rickettsiae. 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 the "tsutsugamushi triangle," which extends from northern Japan and far-eastern Russia in the north, to northern Australia in the south, and to Pakistan and Afghanistan in the west, where the disease isendemic.

It is estimated that about one million cases of this disease occur annually. Because of reports of O tsutsugamushi strains with reduced susceptibility to antibiotics, as well as reports of interesting interactions between this bacterium and HIV, a renewed interest in this illness has emerged.

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 O 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. The endothelium is involved, however, the basic histopathologic lesions suggest that macrophages might be more affected.

Frequency

United States

Reported cases are imported by travelers, military personnel, and persons who have emigrated from abroad.

International

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.

CLINICAL

Section 3 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• References

History

• Elicit any history of travel to endemic areas.
• Patients most commonly present with high fever, severe headache, generalized myalgia, and malaise.
• The incubation period from the mite bite is 5-20 days following inoculation.

Physical

• Patients experience abrupt onset of high fever (104-105°F), severe headache, myalgia, and eschar (resembling a cigarette burn) 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

• O tsutsugamushi
• • This is an obligate intracellular gram-negative bacterium that has a large number of serotypes. Five serotypes, Karp, Gilliam, Kawazaki, Boryon, 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.

DIFFERENTIALS

Section 4 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• References

Other Problems to be Considered

Other Flavivirus infections

WORKUP

Section 5 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• References

Lab Studies

• Routine laboratory studies reveal early lymphopenia with late lymphocytosis.
• Albuminuria is a common laboratory finding.
• The confirmatory tests are the indirect immunoperoxidase test and the immunofluorescent assay. An infection is confirmed by a 4-fold increase in antibody titers between acute and convalescent serum specimens. A single high titer with classic clinical features is considered a probable case.
• A dot immunoassay has also been used in the serodiagnosis of scrub typhus.
• The organism has been identified by the polymerase chain reaction (PCR) technique in clinical specimens.
• The Weil-Felix OX-K strain agglutination reaction may be the only serologic test available in less developed countries, but it is not a very sensitive assay.

TREATMENT

Section 6 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• References

Medical Care

• Treatment must be initiated early in the course of the disease, based on presumptive diagnosis, to reduce morbidity and mortality. Doxycycline and chloramphenicol are both effective in the treatment of scrub typhus. Tetracycline products are generally not recommended for use 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.
• Seven days of antibiotic treatment is usually effective.
• Meticulous supportive management is necessary to abort progression to disseminated intravascular coagulation (DIC) or circulatory collapse in severe cases.
• Rifampin and azithromycin have been used successfully in areas where scrub typhus is resistant to the conventional therapy.
• In a small Korean trial in children, roxithromycin, a macrolide antibiotic, was as effective as doxycycline and chloramphenicol in the treatment of scrub typhus.
• 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.

MEDICATION

Section 7 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• References

Drug Category: Antibiotics

Tetracycline derivatives are the mainstays of treatment.

Drug Name	Doxycycline (Bio-Tab, Doxy, Vibra-Tabs)
Description	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)
Description	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

FOLLOW-UP

Section 8 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• References

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 O tsutsugamushi.
• Severe disease is uncommon with antimicrobial treatment.

REFERENCES

Section 9 of 9

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• References

• Baxter JD. The typhus group. Clin Dermatol. May-Jun 1996;14(3):271-8. [Medline].
• Edwards MS, Feigen RD. Rickettsial diseases. In: Textbook of Pediatric Infectious Diseases. 2004;2:2508-2509.
• Jensenius M, Fournier PE, Raoult D. Rickettsioses and the international traveler. Clin Infect Dis. Nov 15 2004;39(10):1493-9. [Medline].
• Raoult D. Scrub typhus. Mandell, Douglas and Bennett's Principles and Practice of Infectious Diseases. 2005;2:2309-2310.
• Seong SY, Choi MS, Kim IS. Orientia tsutsugamushi infection: overview and immune responses. Microbes Infect. Jan 2001;3(1):11-21. [Medline].
• Watt G, Parola P. Scrub typhus and tropical rickettsioses. Curr Opin Infect Dis. Oct 2003;16(5):429-36. [Medline].

Article Last Updated: Jul 14, 2006