Relapsing Fever (Borrelia): Why the Fever Comes Back, and How It Is Diagnosed

A patient develops a sudden high fever with headache and muscle aches that lasts a few days, then breaks and disappears. A week later, just as the patient seems to have recovered, the fever returns. Then it happens again. This pattern of fever that comes, goes, and comes back is the signature of relapsing fever, and it points to a single mechanism: a bacterium that keeps changing its disguise to stay ahead of the immune system.

Relapsing fever is caused by Borrelia species, spread by lice or ticks. This page is about why the fever relapses, how the two forms (louse-borne and tick-borne) differ, and how the diagnosis is made by catching the organism in a blood smear at the right moment.

Introduction

Relapsing fever is an infection caused by Borrelia species, marked by repeated episodes of fever separated by fever-free intervals. It is spread by insect vectors, and there are two main forms distinguished by the vector.

Louse-borne (epidemic) relapsing fever (LBRF). Caused by Borrelia recurrentis and spread by the human body louse. Because it depends on lice and person-to-person spread, it occurs in epidemics under conditions of overcrowding, poverty, and social disruption (war, refugee settings). It is now mainly seen in East Africa (Ethiopia, Sudan).

Tick-borne (endemic) relapsing fever (TBRF). Caused by other Borrelia species (B. duttonii, B. hermsii, B. turicatae) and spread by soft ticks (Ornithodoros). It is endemic in specific regions, with rodents as the reservoir, and occurs as sporadic cases rather than large outbreaks.

A newer form, hard-tick relapsing fever caused by Borrelia miyamotoi (spread by the same Ixodes ticks that transmit Lyme disease), is increasingly recognized.

Borrelia also causes Lyme disease, a very different illness; the two are compared at the end and on the Lyme disease page.

Why the fever relapses: antigenic variation

The defining feature of relapsing fever, and the reason it has its name, comes from one elegant mechanism. Understanding it explains the entire disease.

The organism enters and multiplies. After a louse or tick exposure, Borrelia spreads into the blood and multiplies, producing large numbers of organisms. This heavy bacteremia causes the first fever episode.

The immune system fights back, and wins the first round. The body makes antibodies against the surface proteins of the Borrelia, and these antibodies clear most of the organisms from the blood. The fever breaks, and the patient feels better. This is the first fever-free interval.

But the organism changes its coat. A small number of Borrelia survive by switching to a new surface protein the existing antibodies do not recognize. This is antigenic variation: the organism has a large set of genes for different surface proteins and can switch which one it displays. The surviving, disguised organisms multiply again, causing a second bacteremia and a second fever before the immune system can catch up and make new antibodies.

The cycle repeats. Each time the immune system catches up, the organism changes its coat again, producing another relapse. Over successive episodes the immune system gradually gets ahead of the variation, so the relapses become shorter and milder and eventually stop.

Putting it together

The clinical course is a direct readout of this immune-versus-disguise race. Each fever = a wave of bacteria in the blood; each fever-free interval = the immune system having cleared the current coat; each relapse = the organism switching to a new coat. This also explains the key diagnostic rule below: you can only see the organism in the blood during a fever, when the bacteremia is high, not in the intervals, when it has been cleared.

How the two forms are transmitted

• Louse-borne: the body louse (Pediculus humanus) carries B. recurrentis. The organism is not injected by a bite; it is released when the louse is crushed (for example by scratching), and the organisms enter through broken skin or mucous membranes. Humans are the reservoir, which is why it spreads person to person and causes epidemics.
• Tick-borne: the soft tick (Ornithodoros) transmits the organism through its bite. Rodents are the reservoir. Soft ticks feed quickly and painlessly at night, so patients often do not recall a bite.

Clinical features

After an incubation period of about a week, the illness begins with a sudden high fever, headache, muscle and joint pains, and often nausea. The first febrile episode lasts about 3 to 5 days, then ends abruptly. A fever-free interval of about a week follows, then the fever relapses. Each successive episode tends to be shorter and milder than the one before, as the immune system gains ground.

Other features can include an altered mental state, abdominal pain, and vomiting. Bleeding (petechiae, nosebleeds, blood-tinged sputum) and neurological features (meningitis, seizures, focal deficits) can occur, and both are more common and more severe in the louse-borne (epidemic) form, which is the more dangerous of the two.

The louse-borne vs tick-borne comparison

Laboratory Diagnosis

The key rule: catch it during a fever

The single most important diagnostic point follows directly from the antigenic-variation mechanism: Borrelia is present in the blood only during the febrile episodes, when bacteremia is high. During the fever-free intervals the organism has been cleared from the blood and the smear is negative. So a blood smear must be taken while the patient is febrile. This is the practical payoff of understanding the relapse mechanism.

Figure: Approaches for the diagnosis of Relapsing fever (Image source: Aurélien Fotso Fotso and Michel Drancourt)

Microscopy: the mainstay

Relapsing fever is one of the few spirochetal infections you can diagnose by seeing the organism on a routine blood smear, because, unlike other spirochetes, relapsing-fever Borrelia stain well with ordinary blood stains (Wright or Giemsa stain). The spirochetes are seen between the red cells. As with malaria, both thick and thin films should be made, because in light infections the organism may show up only on the thick film.

Other microscopy options include dark-field microscopy (low sensitivity) and the quantitative buffy coat (QBC) method (higher sensitivity).

When microscopy is negative

Because the smear is only positive during fever, other methods help in the intervals or for species identification:

• Culture of Borrelia from blood is possible but difficult and slow, and is mainly a reference or research method.
• Serology (ELISA, IFA (indirect fluorescence assay) detects antibodies, but is limited: it cross-reacts with other spirochetes (false positives), and requires cultured organisms as antigen, so few laboratories offer it. The GlpQ immunoblot is the most reliable serological method and can distinguish relapsing fever from Lyme disease.
• PCR (Multiplex Real-time PCR targeting several Borrelia genes) can identify the species and is increasingly used. It targets 16SrRNA, flagellar B protein (flaB), gyrase B (gyrB) and GlpQ genes to identify the various species of Borrelia.

Treatment

Relapsing fever is treated with an antibiotic such as doxycycline (or erythromycin), and it responds well. The louse-borne form often clears with a short course; the tick-borne form usually needs a longer one.

One warning is genuinely important here: starting treatment commonly triggers a Jarisch-Herxheimer reaction, a sudden worsening of fever, chills, and a drop in blood pressure as large numbers of spirochetes are killed at once. In relapsing fever this reaction can be severe, even life-threatening, more so than in other spirochetal infections, because the bacterial load in the blood is so high. Patients are monitored closely when treatment begins. Specific doses and durations are clinical decisions and are not covered here.

How to remember

The fever relapses because the coat changes. Picture the Borrelia wearing a disguise. The immune system learns the disguise and clears it (fever breaks), so the organism puts on a new one and comes back (fever relapses). Antigenic variation is the whole story: each relapse is a new disguise. The name, the course, and the diagnosis all follow from this one idea.

Smear during the fever, not between. The organism is in the blood only when the patient is febrile. Take the blood smear during a fever spike. In the fever-free interval the smear is negative because the current coat has been cleared. This is the direct practical consequence of the relapse mechanism.

Louse = epidemic = worse; tick = endemic = milder. The louse-borne form (B. recurrentis) spreads person to person, causes epidemics in crowded settings, and has more bleeding and neurological complications. The tick-borne form is endemic, sporadic, from rodents, and generally milder. Louse is the dangerous one.

Crushed, not bitten (for lice). The body louse does not inject Borrelia by biting. The organism is released when the louse is crushed against the skin, so scratching drives it into broken skin. A useful contrast with the tick, which does transmit by biting.

Herxheimer hits hardest here. Of all the spirochetal infections, relapsing fever is the one where the Jarisch-Herxheimer reaction on starting treatment can be severe, because the blood is so full of organisms.

Key exam facts in one table

Where students get confused

Why the fever relapses. It is not reinfection or treatment failure. The same organism changes its surface protein (antigenic variation) to escape the antibodies each time, so it returns in waves until the immune system finally catches up. One organism, many disguises.

When to take the blood smear. The smear is only positive during a fever, when the organism is in the blood. Taking it during a fever-free interval gives a false negative. Time the smear to the fever spike.

Louse-borne is transmitted by crushing, not biting. The body louse does not inoculate Borrelia through a bite. The organism is released when the louse is crushed (by scratching), entering through broken skin. This is different from tick-borne, which is a true bite.

Relapsing fever Borrelia stain well; other spirochetes do not. Unlike Treponema and Leptospira, which are too thin for ordinary stains, relapsing-fever Borrelia are seen on a routine Giemsa or Wright blood smear. This is what makes microscopy the mainstay here.

Jarisch-Herxheimer is expected, and dangerous here. The worsening after the first antibiotic dose is the reaction to dying organisms, not an allergy or treatment failure. In relapsing fever it can be severe because the organism load is so high, so treatment is started with monitoring.

It is a different disease from Lyme. Both are Borrelia, but relapsing fever (recurrent fevers, antigenic variation, blood-smear diagnosis) is clinically and mechanistically distinct from Lyme disease (rash, arthritis, two-tier serology).

References

1. Fotso Fotso, A., & Drancourt, M. (2015). Laboratory diagnosis of tick-borne African relapsing fevers: latest developments. Frontiers in Public Health, 3, 254. https://doi.org/10.3389/fpubh.2015.00254
2. Procop, G. W., et al. (2017). Koneman's Color Atlas and Textbook of Diagnostic Microbiology (7th ed.). Wolters Kluwer.
3. Tille, P. M. (2022). Bailey & Scott's Diagnostic Microbiology (15th ed.). Elsevier.
4. Centers for Disease Control and Prevention. (current). Relapsing Fever. https://www.cdc.gov/relapsing-fever/