Relapsing Fever

Relapsing fever is a vector-borne disease caused by multiple species of the spirochete Borrelia. There are 2 major forms of relapsing fever: tick-borne relapsing fever (caused by multiple species, such as B. hermsii, B. miyamotoi, and B. turicatae) and louse-borne relapsing fever (caused by B. recurrentis). Patients go through recurrent stages of fever, crisis phase, and afebrile periods. Severe manifestations can include myocarditis, ARDS, and meningitis. Diagnosis is based on the clinical history and visualization of spirochetes on a thick and thin blood smear obtained during a febrile episode. Management of relapsing fever is with antibiotics, such as doxycycline, penicillin, or ceftriaxone. Patients should be monitored closely for Jarisch-Herxheimer reaction.

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Overview

Causative organism

  • Borrelia spp.
    • Spirochetes (spiral morphology)
    • Gram negative (weak) 
    • Can be visualized using dark-field microscopy, Wright stain, or Giemsa stain
    • Possess axial filaments for motility
    • Microaerophilic
    • Difficult to culture
  • Associated diseases:
    • Tick-borne relapsing fever (TBRF) is caused by multiple species of Borrelia including:
      • B. hermsii, B. turicatae: most common in North America
      • B. miyamotoi
      • B. hispanica
      • B. duttoni
      • B. persica
    • Louse-borne relapsing fever (LBRF) is caused by B. recurrentis.
May-Gruenwald-Giemsa showing Borrellia recurrentis

May-Grünwald-Giemsa (MGG)–stained thin blood smear showing numerous spirochetes (arrows) identified as Borrelia recurrentis

Image: “MGG stain” by Department of Clinical and Biomedical Sciences Luigi Sacco, University of Milano, Milano, Italy. License: CC BY 4.0

Epidemiology

Tick-borne relapsing fever:

  • Locations: 
    • United States (west of the Mississippi River, mountainous locations)
    • North, Central, and South America
    • Asia
    • Africa
    • Mediterranean region
  • Frequently seen in summer months (peaks in August)
  • Mortality:
    • < 2% in treated patients
    • 4%–10% in untreated patients (highest in B. duttoni infections)

Louse-borne relapsing fever:

  • Endemic in developing countries of Africa, such as Ethiopia, Sudan, and Somalia
  • Often occurs in areas of war, famine, overcrowding (homeless), and mass migration (refugees)
  • Cases peak during the rainy season.
  • Mortality:
    • 4% in treated patients
    • 10%–70% in untreated patients

Pathogenesis

Relapsing fever vectors cycle

The vectors and reservoirs for Borrelia in relapsing fever

Image by Lecturio.

Transmission of TBRF

  • Reservoir hosts:
    • Rodents (B. turicatae, B. hispanica, B. miyamotoi)
    • Birds (B. hermsii)
    • Bats (B. persica)
  • Vector for transmission:
    • Ornithodoros ticks (B. duttoni, B. hermsii, B. turicatae, B. hispanica, B. persica) 
    • Ixodes ticks (B. miyamotoi)
  • Groups at risk:
    • Hikers
    • Campers
    • Spelunkers
    • Woodworkers
    • Individuals residing in certain homes (rustic/log cabins, thatched roof, mud walls and floors)

Transmission of LBRF

  • Reservoir hosts: humans
  • Vector for transmission: Pediculus humanus corporis (human body louse)
  • Groups at risk:
    • Refugees
    • Homeless

Pathophysiology

  • Borrelia enters the body through:
    • Tick bite via the tick’s saliva in TBRF
    • Skin or mucous membranes in LBRF 
      • Occurs when the louse is crushed by humans
      • B. recurrentis grows in the body cavity of the louse, but does not appear in the saliva or feces of the louse.
  • Spirochetes enter the vasculature.
    • Replication occurs every 6–12 hours.
    • Symptoms occur in conjunction with spirochetemia (spirochetes in the blood).
      • Generalized symptoms (e.g., fever, myalgia)
      • Nonfocal CNS symptoms
      • Adherence of spirochetes to blood cells → microaggregates → occlusion of small vessels and sequestration of blood cells to the spleen and liver → organ dysfunction
    • Allows dissemination to organs throughout the body → tissue invasion:
      • Hepatosplenomegaly
      • Impaired organ function
      • Focal CNS abnormalities
      • Can cross the maternal-fetal barrier → inflammation and impairment of placenta → intrauterine growth retardation and congenital infection
  • The immune system attempts to clear the disease. 
    • Creation of antibodies directed at the surface lipoproteins of spirochetes
    • Opsonization and complement fixation → lysis of spirochetes 
    • Products of lysis (lipoproteins and bacterial products) → cause worsening of symptoms with fever, hypotension, and shock/crisis phase
    • Crisis phase: symptoms similar to the Jarisch-Herxheimer reaction
  • Afebrile periods occur when the spirochetes are cleared from the blood.
  • Antigenic variation allows some spirochetes to evade the immune system and re-emerge later → creates cycles of the disease → relapses of fever and symptoms

Clinical Presentation

Relapsing fever timeline

  • Incubation period: 3–12 days
  • Relapsing course: febrile periods with afebrile periods of a few days
  • Febrile phase/period:
    • Febrile episode characterized by sudden onset of fever lasting:
      • 1–3 days in TBRF
      • 3–6 days in LBRF
    • 1st episode is usually the most severe.
    • Febrile episode ends in a crisis phase lasting 15–30 minutes.
  • Crisis phase: 
    • Mortality is most commonly associated with this phase.
    • Characterized by rigors and rising temperature, heart rate, and blood pressure
    • Followed by several hours of diaphoresis, ↓ temperature, and hypotension
  • Afebrile period: follows febrile period and can last 4–14 days
  • Relapse:
    • Fever tends to be milder with each relapse.
    • TBRF: Multiple relapses are experienced.
    • LBRF: generally a single, milder relapse

Associated symptoms and manifestations

  • General:
    • Headache
    • Myalgia
    • Arthralgia
    • Chills
    • Nausea
    • Abdominal pain
    • Diarrhea
  • Hepatic:
    • Jaundice
    • Hepatosplenomegaly
  • Cardiopulmonary:
    • Myocarditis (both TBRF and LBRF)
    • Non-productive cough (LBRF)
    • ARDS (occurs during TBRF crisis phase)
  • Neurologic:
    • Delirium
    • Stupor
    • Dizziness
    • Coma
    • Localized signs (due to spirochetemia) associated with TBRF:
      • Hemiplegia
      • Cranial neuritis (causing Bell’s palsy and/or deafness)
      • Myelitis
      • Meningitis or meningoencephalitis
      • Radiculopathy
  • Ophthalmological (more common in TBRF):
    • Iridocyclitis
    • Panophthalmitis
    • Bilateral involvement may result in vision loss.
  • Dermatological (more common in TBRF):
    • Macular or purpuric rash may occur.
    • Erythema multiforme
  • Hematological findings due to ↓ platelets, clotting factors (more common in LBRF):
    • Epistaxis
    • Hemoptysis
    • Petechiae and ecchymoses
    • Disseminated intravascular coagulation

Prognosis

Findings indicative of poor prognosis:

  • Stupor or coma
  • Pneumonia
  • Myocarditis
  • Diffuse bleeding
  • Severe liver disease
  • Malnutrition
  • Coinfection with typhus, malaria, typhoid

Diagnosis

  • Thick and thin blood smear is the 1st step:
    • Attempt to visualize the microorganisms using:
      • Giemsa or Wright staining
      • Dark-field microscopy
      • Immunofluorescence
    • Optimal between the onset and peak of fever
    • Lower yield, once the temperature is declining
  • For tissue specimens: silver stain or immunofluorescence
  • If blood smear is unremarkable, but there is high clinical suspicion:
    • PCR can be performed using blood, CSF, or tissue samples.
    • Culture:
      • Requires special culture media
      • Only a few laboratories have this capability.
Blood smear diagnosing Borrellia infection

Blood smear showing Borrelia:
Blood smear of a patient with tick-borne relapsing fever secondary to Borrelia hispanica. Irregular coils of spirochetes are seen.

Image: “Blood Smear” by Irmin Leen et al. License: CC BY 4.0

Other supporting tests and findings:

  • CBC:
    • Normocytic or hemolytic anemia
    • Leukopenia during a crisis
    • Thrombocytopenia
  • ↑ Erythrocyte sedimentation rate
  • ↑ Aminotransferases and unconjugated bilirubin
  • ↑ Prothrombin and partial thromboplastin
  • CSF analysis:
    • ↑ Monocytes
    • ↑ Protein
    • Normal glucose
  • ECG: in myocarditis, prolonged QTc interval
  • Chest X-ray: may show pulmonary edema

Management

Tick-borne relapsing fever

  • Most patients will require hospitalization due to severe symptoms.
  • Antibiotic therapy:
    • Initial intravenous (IV) therapy:
      • Penicillin G
      • Ceftriaxone (preferred for neurological involvement)
    • Transition to oral, once clinically stable:
      • Doxycycline
      • Azithromycin

Louse-borne relapsing fever

Most patients can be treated with a single dose of:

  • Penicillin G
  • Doxycycline or tetracycline
  • Erythromycin

Jarisch-Herxheimer reaction

  • Caused by an immune response to the antigens released by dying spirochetes
  • Symptoms:
    • Rigors
    • Myalgias
    • Rise in temperature
    • Increased respiratory rate
    • Hypotension
  • All patients should be monitored after therapy is initiated.
    • Often occurs within 4–6 hours
    • Can last up to 24 hours
    • Seen in:
      • Approximately 80% of patients with LBRF
      • Approximately 50% of patients with TBRF
  • Supportive care may be given:
    • Antipyretics (e.g., acetaminophen, aspirin, ibuprofen)
    • IV fluids

Prevention and Prophylaxis

Prevention of TBRF

  • Avoid rodent infestation.
  • Seal floors and walls in houses.
  • Use tick repellents.

Prevention of LBRF

  • Improve hygiene.
  • Wash clothing.
  • Avoid crowding.

Post-exposure prophylaxis

  • Given to individuals: 
    • At high risk of infection 
    • With suspected exposure
    • In endemic areas
    • After accidental inoculation (infected blood or culture in a laboratory setting)
  • Antibiotic choices:
    • Doxycycline
    • Tetracycline

Differential Diagnosis

  • Lyme disease: an infection caused by B. burgdorferi, which is transmitted by the Ixodes tick. Presentation depends on the stage of the disease and may include a characteristic erythema migrans rash. Neurological, cardiac, ocular, and joint manifestations are also common in later stages. Diagnosis relies on clinical findings and tick exposure and is supported by serological testing. Antibiotics are used for treatment. 
  • Leptospirosis: a disease caused by Leptospira interrogans. Leptospirosis causes a mild flu-like illness in a majority of cases and the manifestations are biphasic. In about 10% of infections, icterohemorrhagic leptospirosis develops, manifesting as hemorrhage, renal failure, and jaundice. Bacterial culture takes weeks, so other diagnostic tests such as serology and dark-field microscopy are used. Treatment is primarily with penicillin.
  • Babesiosis: a tick-borne infection caused by Babesia. Patients can be asymptomatic or develop fever, fatigue, malaise, and arthralgias. Asplenic, immunocompromised, and elderly patients are at risk for severe disease, which can result in hemolytic anemia, thrombocytopenia, hepatosplenomegaly, renal failure, and death. Diagnosis is based on a peripheral blood smear, serological testing, and PCR. Treatment is with antibiotics, such as atovaquone plus azithromycin.
  • Ehrlichiosis and anaplasmosis: tick-borne infections caused by Ehrlichia chaffeensis and Anaplasmosis phagocytophilum, respectively. Symptoms include fever, headache, and malaise. A rash is uncommon, but can appear petechial or maculopapular. The diagnosis is based on serology or PCR. Treatment of both diseases is with doxycycline.
  • Rocky Mountain spotted fever: a disease caused by Rickettsia rickettsii that presents with fever, fatigue, headache, and a rash following a tick bite (Dermacentor tick). Diagnosis is based on the clinical features, biopsy of the rash, and serological testing. Treatment is with antibiotics, including doxycycline.
  • Epidemic typhus: a louse-borne disease caused by Rickettsia prowazekii that presents with myalgia, arthralgia, rash, and encephalitis. A rash starts on the trunk and spreads outward to the extremities. Diagnosis is based on the clinical picture and serological testing. Treatment is with antibiotics, including doxycycline. 
  • Infectious mononucleosis: a disease caused by the Epstein-Barr virus that is characterized by fever, fatigue, lymphadenopathy, and pharyngitis. Diagnosis is based on clinical features and testing, using a heterophile antibody test or serology. Treatment is with supportive care. 
  • Malaria: an infection caused by Plasmodium. Patients may also present with periodic fever. Other symptoms include rigors, night sweats, diarrhea, abdominal pain, seizure, hemolytic anemia, and splenomegaly. Diagnosis is confirmed by visualizing Plasmodium on a peripheral smear and based on a rapid test for the detection of Plasmodium antigens. Treatment with antimalarials depends on the species. 
  • Typhoid fever: a systemic disease caused by Salmonella enterica serotype typhi. Patients may have high fever, abdominal pain, and rose spots (rashes) on the body. Unlike relapsing fever, typhoid predominantly manifests with GI symptoms. Diagnosis is based on clinical presentation and confirmed using culture studies. Treatment is with antibiotics, including ceftriaxone, fluoroquinolones, and azithromycin.
  • Brucellosis: an infection caused by Brucella, which spreads predominantly after the ingestion of unpasteurized dairy products or direct contact with infected animal products. Clinical manifestations include fever, arthralgias, malaise, lymphadenopathy, and hepatosplenomegaly. Diagnosis is based on clinical manifestations, exposure history, serology, and culture studies. Management of brucellosis involves a combination of antibiotics, including doxycycline, rifampin, and aminoglycosides.

References

  1. Barbour, A.G. (2020). Clinical features, diagnosis, and management of relapsing fever. In Mitty, J. (Ed.), UpToDate. Retrieved December 21, 2020, from https://www.uptodate.com/contents/clinical-features-diagnosis-and-management-of-relapsing-fever
  2. Barbour, A.G. (2020). Microbiology, pathogenesis, and epidemiology of relapsing fever. In Mitty, J. (Ed.), UpToDate. Retrieved December 27, 2020, from https://www.uptodate.com/contents/microbiology-pathogenesis-and-epidemiology-of-relapsing-fever
  3. Bush, L.M., and Vazquez-Pertejo, M.T. (2020). Relapsing fever. [online] MSD Manual Professional Version. Retrieved December 22, 2020, from https://www.merckmanuals.com/professional/infectious-diseases/spirochetes/relapsing-fever
  4. Bobkova, E., and Kauser, A. (2017). Relapsing fever. In Bronze, M.S. (Ed.), Medscape. Retrieved December 22, 2020, from https://emedicine.medscape.com/article/227272-overview
  5. Snowden, J., Yarrarapu, S.N.S, and Oliver, T.I. (2020). Relapsing fever. [online] StatPearls. Retrieved December 29, 2020, from https://www.ncbi.nlm.nih.gov/books/NBK441913/

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