Scrub Typus

Introduction

Scrub typhus, also known as tsutsugamushi disease, is an acute, febrile, infectious illness caused by the obligate intracellular bacterium Orientia tsutsugamushi. Historically, it was a major cause of fever among soldiers during World War II and the Vietnam conflict. Today, it remains an important cause of acute febrile illness in the Asia-Pacific region, including India, where it is increasingly recognized as a significant public health burden. It is a zoonosis where humans are accidental hosts.

Etiology and Microbiology

• Causative Agent: The etiologic agent is Orientia tsutsugamushi.
• Classification: Formerly classified in the genus Rickettsia, it was reclassified into the genus Orientia based on distinctive phenotypic and genetic features. Unlike other rickettsiae, O. tsutsugamushi lacks lipopolysaccharide (LPS) and peptidoglycan in its cell wall.
• Antigenic Heterogeneity: The organism exhibits remarkable antigenic heterogeneity, with multiple serotypes recognized (e.g., Karp, Gilliam, Kato, Boryon, Kawazaki). This diversity hampers vaccine development and means that infection with one strain does not necessarily confer long-term immunity against others.
• ** Emerging Species:** A new Candidatus species, "Orientia chuto", has been isolated in the Middle East, and "Orientia chiloensis" has been identified in Chile, suggesting the geographic range of the disease may be wider than traditionally thought.

Epidemiology

• Geographic Distribution: Scrub typhus is endemic to a region 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 and Afghanistan in the west.
• Burden: Approximately 1 billion people are at risk, with at least 1 million infections occurring annually.
• Indian Scenario: In India, scrub typhus has been reported from various states including Himachal Pradesh, Jammu and Kashmir, the Northeast, West Bengal, Maharashtra, Karnataka, Kerala, and Tamil Nadu. It is an important cause of acute undifferentiated febrile illness.
• Habitat: The disease is distributed according to the habitat of its vectors. It occurs in diverse environments ranging from sea level to alpine meadows, in arid and humid regions, and in agricultural and scrubland areas (terrain between woods and clearings).
• Seasonality: Infections are most common during the rainy months (June to November) when mite activity is high.

Transmission and Life Cycle

• Vector: The disease is transmitted by the bite of the larval stage (chigger) of trombiculid mites, primarily of the genus Leptotrombidium (e.g., L. deliense).
• Reservoir: The mite serves as both the vector and the natural reservoir. The organism persists in the mite through transstadial (across life stages) and transovarial (from adult to egg) transmission.
• Mode of Infection: Only the larval stage (chigger) feeds on mammals. Nymphs and adults feed on plant matter. Humans are accidental dead-end hosts. Infection occurs when a chigger bites a human to take a blood meal, typically in areas of thin skin or where clothing restricts access (groin, axilla, neck).
• Rodents: Wild rodents, particularly rats, are preferred hosts for chiggers and play a role in the ecology of the disease but are not the primary reservoir for the bacterium itself.

Pathogenesis

• Entry and Dissemination: Following the bite, the organisms multiply locally and then disseminate via the lymphatic system and bloodstream.
• Target Cells: O. tsutsugamushi is a vasculotropic bacterium that primarily infects endothelial cells, causing widespread vasculitis. It also infects macrophages and cardiac myocytes.
• Mechanism of Injury: The organism escapes the phagosome and replicates in the cytoplasm. It is released from infected cells by budding. The infection triggers a perivascular inflammatory response involving lymphocytes and macrophages. This vasculitis leads to vascular integrity compromise, fluid leakage, platelet aggregation, and microvascular occlusion.
• Systemic Effects: The diffuse vasculitis and perivascular inflammation result in end-organ injury, most often affecting the lungs (pneumonitis), brain (meningoencephalitis), heart (myocarditis), and kidneys.

Clinical Manifestations

The incubation period typically ranges from 6 to 21 days (usually 9–11 days). The severity can range from mild self-limiting illness to fatal multisystem failure.

Prodrome and Onset

• The onset is often sudden with shaking chills, high-grade fever, severe headache, and malaise.
• Fever: Nearly universal, often high (up to 104°F).
• Headache: Severe, often retro-orbital or frontal.

Cutaneous Manifestations

• Eschar (Tache Noire): A painless, necrotic, cigarette-burn-like lesion with an erythematous rim found at the site of the chigger bite. It is the pathognomonic sign but is variably present (7–68% of cases). It begins as a papule, ulcerates, and forms a black crust. Common sites include the axilla, groin, neck, and genitalia. It is often missed if not specifically looked for, especially in dark-skinned individuals.
• Rash: A macular or maculopapular rash may appear around the 5th day of fever, starting on the trunk and spreading to the extremities. It is evanescent and seen in less than half of patients.

Systemic Involvement

• Lymphadenopathy: Regional lymphadenopathy draining the eschar site is common, often progressing to generalized lymphadenopathy (23–93% of cases).
• Hepatosplenomegaly: Hepatomegaly is seen in about two-thirds of children, and splenomegaly in about one-third.
• Respiratory: Cough is very common. Interstitial pneumonia is a frequent complication.
• Gastrointestinal: Nausea, vomiting, diarrhea, and abdominal pain are common presenting symptoms.
• Neurological: Sensorineural hearing loss occurring concurrently with fever is a useful diagnostic clue. Meningoencephalitis can occur, presenting with altered sensorium, seizures, or meningeal signs.
• Ocular: Conjunctival suffusion/hyperemia is frequently observed.

Complications

Severe complications arise from widespread vasculitis and include:

• Respiratory: Acute Respiratory Distress Syndrome (ARDS), interstitial pneumonia.
• Cardiovascular: Myocarditis, shock.
• Neurological: Meningoencephalitis, aseptic meningitis.
• Renal: Acute Kidney Injury (AKI).
• Hematological: Disseminated Intravascular Coagulation (DIC), Hemophagocytic Lymphohistiocytosis (HLH).

Differential Diagnosis

Scrub typhus mimics many other tropical febrile illnesses. The differential diagnosis includes:

• Malaria: Fever, splenomegaly, anemia.
• Dengue: Fever, rash, thrombocytopenia, retro-orbital pain.
• Enteric Fever (Typhoid): Prolonged fever, hepatosplenomegaly, abdominal symptoms.
• Leptospirosis: Fever, myalgia, conjunctival suffusion, renal involvement.
• Other Rickettsioses: Murine typhus, Spotted fevers.
• Meningococcemia: Fever, rash, shock.
• Measles: Fever, rash, coryza.

Laboratory Diagnosis

Diagnosis is challenging in the early phase due to nonspecific presentation.

Nonspecific Laboratory Findings

• Hematology: Normal to low leukocyte counts initially, followed by leukocytosis. Thrombocytopenia is common (seen in up to 3/4 of patients). Anemia may be present.
• Biochemistry: Elevated hepatic transaminases (AST, ALT) are very common. Hypoalbuminemia and hyponatremia may be observed.
• CSF: In cases with CNS involvement, CSF shows mild mononuclear pleocytosis with normal glucose and normal to slightly elevated protein.

Specific Diagnostic Tests

• Serology:
  • Immunofluorescence Assay (IFA): Considered the gold standard. A fourfold rise in IgG titer between acute and convalescent sera is diagnostic. However, it is expensive and requires fluorescent microscopy.
  • ELISA: Detects IgM and IgG antibodies. IgM ELISA is increasingly used and is commercially available in India. It has high sensitivity and specificity. An optical density (OD) > 0.5 is often considered positive.
  • Weil-Felix Test: Based on cross-reaction of patient antibodies with Proteus mirabilis OXK strain. It is cheap and widely available but lacks both sensitivity (positive in only ~50% of cases) and specificity. It is no longer recommended as the sole diagnostic test.
• Molecular Methods:
  • PCR: Polymerase chain reaction targeting the 56-kDa antigen gene can detect rickettsial DNA in blood or eschar samples. Eschar PCR has high sensitivity and specificity.
• Culture: Isolation of O. tsutsugamushi requires cell culture or mouse inoculation, which is hazardous and restricted to reference laboratories.

Treatment

Prompt antibiotic therapy shortens the duration of fever and reduces mortality.

Specific Antimicrobial Therapy

• Drug of Choice: Doxycycline is the treatment of choice for children of all ages.
  • Dosage: 2.2 mg/kg/dose (max 100 mg/dose) twice daily orally or intravenously.
  • Duration: Minimum of 5–7 days and until the patient is afebrile for at least 3 days to prevent relapse.
  • Note: Short courses of doxycycline in children <8 years have a negligible risk of tooth staining and are recommended by the AAP and CDC for rickettsial diseases.
• Alternatives:
  • Azithromycin: 10 mg/kg/day orally once daily for 5 days. Useful in pregnant women and in areas with doxycycline resistance.
  • Chloramphenicol: 50–100 mg/kg/day divided every 6 hours (max 3 g/day). Requires monitoring for bone marrow suppression.
  • Rifampicin: Has been used in cases of doxycycline resistance or poor response, sometimes in combination.

Supportive Care

• Management of complications like shock, ARDS, and renal failure requires intensive care.
• Hemodynamic status must be monitored carefully to avoid iatrogenic pulmonary edema due to vascular leakage.

Prognosis

• Untreated: Mortality rates in the pre-antibiotic era ranged from 0% to 60% depending on the strain and host factors.
• Treated: With appropriate antibiotics, fever usually subsides within 24–48 hours, and fatalities are rare.
• Relapse: Relapses can occur if treatment is stopped too early. Reinfection is possible due to strain diversity.

Prevention

• Vector Control: Avoiding chigger-infested areas (scrub vegetation, forests). Clearing vegetation around habitations.
• Personal Protection:
  • Wearing protective clothing (long sleeves, pants tucked into socks).
  • Use of insect repellents like DEET (N,N-diethyl-meta-toluamide) on skin and clothing.
  • Treating clothing with permethrin.
• Chemoprophylaxis: Weekly doxycycline (200 mg) has been shown to be effective in some high-risk groups (e.g., soldiers) but is not routinely recommended for the general population.
• Vaccination: No effective vaccine is currently available due to the significant antigenic diversity of O. tsutsugamushi.

Summary Table: Scrub Typhus