Relapsing Fever: Modern Lessons from an Ancient Disease

Jan. 31, 2023

Magnified image of Ornithodoros adult soft-tick, a vector of relapsing fever.
Magnified image of Ornithodoros adult soft-tick, vector of relapsing fever.
Source: Wikimedia Commons.
"When sleeping in the house of the commandant, an insect, well known in the southern country by the name Tampan, bit my foot. It is a kind of tick … I shall detail the effects of the bite … it soon causes violent vomiting and purging. Where these effects do not follow, as we found afterward at Tete, fever sets in; and I was assured by intelligent Portuguese there that death has sometimes been the result of this fever."
-David Livingstone (1857)

Relapsing fever was once a feared disease that ravaged Africa, Asia and Europe, causing large epidemics and millions of deaths. Transmitted by arthropods, relapsing fever is a bacterial infection that produces high fevers and other flu-like symptoms that reoccur. The disease, though it still occurs throughout many inhabited continents, is largely forgotten by Western medicine. However, research on this illness has helped produce important breakthroughs in modern infectious disease studies, most notably contributing to the discovery of the Lyme disease agent (Borrelia burgdorferi). Lessons from this largely forgotten disease demonstrate how neglected diseases can continue to inform modern research.

Symptoms of Relapsing Fever

Relapsing fever produces a series of reoccurring fevers interspersed with periods of relatively good health, hence the origin of the name. Numerous bacterial species belonging to the genus Borrelia cause relapsing fever, and members of this genus are broadly divided into those that cause relapsing fever and those that are responsible for Lyme disease. Additional symptoms of relapsing fever are similar to the flu, including headaches, vomiting, chills and others, though jaundice can be a distinguishing factor. The disease can be fatal and cause still births if left untreated.

Diagnosis of Relapsing Fever

Photomicrograph showing the relapsing fever bacterium Borrelia hermsii among human blood cells.
Photomicrograph showing the relapsing fever bacterium Borrelia hermsii (arrows) among human blood cells.
Source: CDC Public Health Image Library.
During periods of fever, the Borrelia reach bacteremic levels, and the illness can be diagnosed by microscopic visualization of the pathogen among the red blood cells. However, if the bacteremic peak is missed or relapsing fever is not considered, then a misdiagnosis is likely.

Complications in accurate diagnosis occurs for different reasons in different parts of the world. In areas where malaria is also present and common, health care professionals generally assume that reoccurring fevers are due to malaria and prescribe drugs that are not effective against bacteria. Conversely, in countries where relapsing fever is now rare, physicians are generally unaware of the disease and seek alternative explanations for the symptoms. When accurately diagnosed, antibiotics such as doxycycline are effective in resolving the infection. Current research in relapsing fever largely focuses on understanding the ecology of the host-tick-microbe infectious cycle and unusual aspects of Borrelia biology.

A Deadly Bacteria Transmitted by Ticks and Lice

All Borrelia share several common features, including a wave-like shape and transmission by blood-feeding arthropods. However, relapsing fever Borrelia are transmitted by a broader range of arthropods than those that cause Lyme disease and can be subdivided into louse-borne relapsing fever (LBRF) versus the many species that are transmitted by ticks (tick-borne relapsing fever or TBRF). Tick-borne relapsing fever is endemic in regions where the ticks are indigenous, including Africa, the Americas, Asia and Europe. Most tick species that transmit relapsing fever Borrelia reside in the dens and nests of the animals that they feed upon. When these niches are disturbed the ticks seek whatever hosts are available, including humans.

Historical Impact of Relapsing Fever

Borrelia are bacteria from the phylum Spirochaetes and display a wave-like shape, as shown in this image.
Borrelia are bacteria from the phylum Spirochaetes and display a wave-like shape, as shown in this image.
Source: NIAID.
Historically, LBRF, caused by B. recurrentis, has been attributed to large, deadly epidemics in Europe (sixth and 19th century), the Middle East and Africa (20th century) that have killed millions of people. Conditions that allow the body louse to thrive, such as poverty, overcrowding, war, famine or lack of access to hygiene resources, have produced outbreaks of LBRF. As sanitation and hygiene improved, LBRF epidemics subsided and the disease itself has largely become forgotten. However, LBRF remains endemic in the horn of Africa, and asylum seekers from this region recently generated a small outbreak in Europe.

To learn more about the 2,000-year history of relapsing fever and those who studied it and its effects, see our interactive timeline.

Present Day Prevalence of Relapsing Fever

Today, about 40 cases of TBRF occur each year in the U.S., most caused by B. hermsii. Infections typically occur in Western states and are often associated with rustic cabins or cave-related activities. Because these ticks feed quickly and usually at night, people are seldom aware of being bitten, and this can be another reason for misdiagnosis of relapsing fever.

Three Fascinating Biological Aspects of Relapsing Fever Borrelia

Although many intriguing aspects of relapsing fever Borrelia biology can be found in other organisms, it is in this group of bacteria that these qualities evolved together to produce a highly effective pathogen. Therefore, relapsing fever Borrelia can serve as a model to understand the biological mechanisms employed by other infectious disease microbes.

  1. Antigenic variation: The microbes that cause relapsing fever have evolved an elaborate strategy to circumvent the immune system of mammals. As the infected animal’s immune system develops an antibody response to fight the infection of this pathogen, the bacteria generate a slightly different protein on its surface, allowing it to temporarily “hide.” Each time the infected host produces another immune response, the bacteria repeat this process. This mechanism is known as antigenic variation, and similar systems are used by the parasites that cause malaria and African trypanosomiasis. A recent molecular genetic study demonstrated that without the antigenic variation system, relapsing fever Borrelia do not generate relapses.
  2. Vector specificity: TBRF bacteria possess a fascinating vector specificity where each bacterial species can only be transmitted by a specific tick species. For example, B. duttonii is transmitted only by the tick Ornithodoros moubata, while B. hermsii is transmitted only by the O. hermsi tick. How this occurs is still a mystery, but a similar relationship exists between sandfly species that can only transmit an associated Leishmania species (causative agents of Leishmaniasis).
  3. Linear and circular DNA molecules: The genomes of all Borrelia species (including those that cause Lyme disease) are unique in the bacterial world, consisting of many linear and circular DNA molecules. Does this unusual genome structure provide an advantage for these bacteria to be transmitted by ticks or lice? Research continues to study the genome biology of this genus to answer this question, while continuing to decipher the mechanisms involved in DNA replication.

Legacy of Relapsing Fever Research

The legacy of relapsing fever research continues to benefit contemporary medicine, including the discovery of the agent of Lyme disease by Dr. Willy Burgdorfer and colleagues. Further insights into the biology of the Lyme disease agent were facilitated because they were first characterized in the relapsing fever Borrelia, which uses a similar mechanism for immune evasion and has the same genome architecture.

More recently, a novel relapsing fever species, B. miyamotoi, was identified and shown to be transmitted by the same tick species that carry B. burgdorferi. This new microbe was capable of causing human disease as well. Yet many aspects of relapsing fever Borrelia biology are not fully understood, and continued research into these bacteria promises to provide even more benefit to populations under threat from other vector-borne diseases.

Today, vector-borne diseases, most of which are preventable, continue to result in the loss of an estimated 700,000 lives annually around the world. In July 2022, ASM held a Congressional Briefing to evaluate this evolving threat in a changing climate.

Author: Philip Stewart, Ph.D.

Philip Stewart, Ph.D.
Philip Stewart, Ph.D., is a staff scientist at the Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, NIH in Hamilton, MT where he studies tick-transmitted diseases.