RELAPSING FEVER

RELAPSING FEVER

Current Diagnosis

• There are two forms of relapsing fever: epidemic and endemic.

• Epidemic relapsing fever is transmitted from person to person by the body louse Pediculus humanus.

• Endemic relapsing fever is transmitted from rodent reservoirs to humans exposed to endemic areas by soft-bodied ticks of the genus Ornithodoros.

• The hallmark of relapsing fever is two or more febrile episodes separated by periods of relative well-being.

• The diagnosis is confirmed by visualization of the etiologic spirochetes in thin peripheral blood smears prepared at times of febrile peaks by phase-contrast or darkfield microscopy or light microscopy after Wright or Giemsa staining.

Current Therapy

• The antibiotic of choice for treatment of relapsing fever is doxycycline (Doryx) except in children or pregnant women. In children <8 y, erythromycin (E-Mycin)1 or oral penicillin1 is used instead of tetracycline (Table 3).

• Relapsing fever, if severe or complicated with neuroborreliosis, requires treatment with the intravenous antibiotics ceftriaxone (Rocephin) or penicillin G (Table 3).

• The louse-borne epidemic form is treated with a single dose, whereas the endemic tick-borne form is treated with multiple doses for at least 1 week (Table 3).

• Antibiotic treatment of relapsing fever results in the Jarisch- Herxheimer reaction (JHR) in as many as 60% of cases, more often in the epidemic than in the endemic form. It is characterized by the sudden onset of tachycardia, hypotension, chills, rigors, diaphoresis, and high fever. To reduce the risk of JHR, antibiotics should be started between but not at times of febrile peaks.

1 Not FDA approved for this  indication.

Relapsing fever is one of several diseases caused by spirochetes. Other human spirochetal diseases are syphilis, Lyme disease, and leptospirosis. Notable features of spirochetes are wavy and helical shapes, length-to-diameter ratios of as much as 100 to 1, and flagella that lie between the inner and outer cell membranes. The spirochetes that cause relapsing fever are in the genus Borrelia. Other Borrelia species cause Lyme disease, avian spirochetosis, and epidemic bovine abortion. Table 1 shows the main Borrelia species of relapsing fever, their vectors, and an estimate of their geographic ranges. In the United States, relapsing fever was considered a disease endemic only in the West. However, the recent finding of relapsing fever–like Borrelia in ticks and dogs in the eastern United States suggests that the risk of relapsing fever may extend into the East.

Table 1

Relapsing Fever Borrelia Species Pathogenic to Humans

Epidemiology

There are two forms of relapsing fever: epidemic transmitted to humans by the body louse Pediculus humanus (louse-borne relapsing fever, LBRF) and endemic transmitted to humans by soft-bodied ticks of the genus Ornithodoros (tick-borne relapsing fever, TBRF). In LBRF, itching caused by skin infestation with lice leads to scratching, which may result in crushing of lice and release of infected hemolymph into areas of skin abrasion. Louse infestation is associated with cold weather and a lack of hygiene. Migrant workers and soldiers at war are particularly susceptible to this infection. Historically, massive outbreaks of LBRF occurred in Eurasia, Africa, and Latin America, but currently the disease is found only in Ethiopia and neighboring countries. However, immigrants can spread LBRF to other parts of the world.

The main risk factor for TBRF is exposure to endemic areas (Table 1). The risk of infection increases with outdoor activities in areas where rodents nest, like entering caves or sleeping in rustic cabins. Ornithodoros ticks are soft-bodied and feed for short periods of time (minutes), usually at night. They can live many years between blood meals and may transmit spirochetes to their offspring transovarially. Infection is produced by regurgitation of infected tick saliva into the skin wound during tick feeding. There are several natural vertebrate reservoirs for TBRF, but most common are rodents (deer mice, chipmunks, squirrels, and rats). In contrast, the body louse Pediculus humanus is a strict human parasite, living and multiplying in clothing.

Clinical Diagnosis

Relapsing fever should be suspected in any patient presenting with two or more episodes of high fever and constitutional symptoms spaced by periods of relative well-being. The index of suspicion increases if the patient has been exposed to endemic areas for TBRF or to countries where LBRF still occurs (Table 1). Whereas LBRF is usually associated with a single febrile relapse, TBRF usually has multiple relapses (up to 13). In LBRF the second episode of fever is typically milder than the first; in TBRF the multiple febrile periods are usually of equal severity. The febrile periods last from 1 to 3 days, and the intervals between fevers last from 3 to 10 days. During the febrile periods, numerous spirochetes are circulating in the blood. This is called spirochetemia and is sometimes unexpectedly detected during routine blood smear examinations. Between fevers, spirochetemia is not observed because the numbers are low. The fever pattern and recurrent spirochetemia are the consequences of antigenic variation of abundant outer membrane lipoproteins of relapsing fever Borrelia species that are the target for serotype-specific antibodies.

The mean latency between exposure to ticks in the endemic form or to lice in the epidemic form and onset of symptoms is 6 days (range, 3–18 days). Because Ornithodoros ticks feed briefly and painlessly at night, patients with TBRF may not be able to recall having been bitten by a tick. The clinical manifestations of TBRF and LBRF are similar, although some differences do exist. Table 2 lists the frequency of the most common manifestations of TBRF. The usual initial presentation is sudden onset of chills followed by high fever, tachycardia, severe headache, vomiting, myalgia and arthralgia, and often delirium. In the early stages, a reddish rash may be seen over the trunk, arms, or legs. The fever remains high for 3 to 5 days, and then it clears abruptly.

After an asymptomatic period of 7 to 10 days, the fever and other constitutional symptoms can reappear suddenly. The febrile episodes gradually become less severe, and the person eventually recovers completely. As the disease progresses, fever, jaundice, hepatosplenomegaly, cardiac arrhythmias, and cardiac failure may occur, especially with LBRF. Jaundice is more common at times of relapses. Patients with LBRF are more likely to develop petechiae on the trunk, extremities, and mucous membranes; epistaxis; and blood- tinged sputum. Rupture of the spleen may rarely occur. Multiple neurologic complications can occur as a result of disseminated intravascular coagulation in LBRF and as a result of infection of the meninges and cranial and spinal nerve roots by spirochetes in TBRF. The most common neurologic complications of TBRF are aseptic meningitis and facial palsy. Relapsing fever in pregnant women can cause abortion, premature birth, and neonatal death. Sometimes patients can have nonfebrile relapses, consisting of periods of severe headache, backache, weakness, and other constitutional symptoms without fever that occur at the time of expected relapses. Delirium may persist for weeks after the fever resolves, and, rarely, symptoms may be protracted.

Table 2

Frequent Clinical Manifestations of Tick-Borne Relapsing Fever

Sign or Symptom Frequency (%)
Headache 94
Myalgia 92
Chills 88
Nausea 76
Arthralgia 73
Vomiting 71
Abdominal pain 44
Confusion 38
Dry cough 27
Ocular pain 26
Diarrhea 25
Dizziness 25
Photophobia 25
Neck pain 24
Rash 18
Dysuria 13
Jaundice 10
Hepatomegaly 10
Splenomegaly 6

Relapsing fever may be confused with many diseases that are relapsing or cause high fevers. These include typhoid fever, yellow fever, dengue, African hemorrhagic fevers, African trypanosomiasis, brucellosis, malaria, leptospirosis, rat-bite fever, intermittent cholangitis, cat-scratch disease, and echovirus 9 infection, among others. Relapsing fever Borrelia spp. have antigens that are cross reactive with Lyme disease Borrelia spp. and inasmuch as the endemic areas of relapsing fever and Lyme disease overlap to some extent, confusion between the two infections can be expected.

Laboratory Diagnosis

Although the pattern of recurring fever is the clue to diagnosing relapsing fever, confirmation of the diagnosis requires demonstration of spirochetes in peripheral blood taken during an episode of fever.

The comparatively large number of spirochetes in the blood during relapsing fever provides the opportunity for the simplest method for laboratory diagnosis of the infection, light microscopy of Wright- or Giemsa-stained thin blood smears or darkfield or phase-contrast microscopy of a wet mount of plasma. The blood should be obtained during or just before peaks of body temperature. Between fever peaks, spirochetes often can be demonstrated by inoculation of blood or cerebrospinal fluid (CSF) into special culture medium (BSK-H with 6% rabbit serum available from Sigma) or experimental animals.

Enrichment for spirochetes is achieved by using the platelet-rich fraction of plasma or the buffy coat of sedimented blood. In the United States the most common causes of relapsing fever are Borrelia hermsii and Borrelia turicatae; both grow in BSK-H medium and in young mice or rats. Whereas direct visual detection of organisms in the blood is the most common method for laboratory confirmation of relapsing fever, immunoassays for antibodies are the most common means of laboratory confirmation for Lyme disease. Although serologic assays have been developed for the agents of relapsing fever, these are not widely available and of dubious utility. The antigenic variation displayed by the relapsing fever species means there are hundreds of different “serotypes.” If a different serotype or species is used for preparing the antigen, only antibodies to conserved antigens may be detected. For this reason, a standardized enzyme-linked immunosorbent assay (ELISA) with Lyme disease Borrelia as antigen may be the best available serologic assay for relapsing fever. ELISA for Borrelia burgdorferi antibodies is routinely done across the United States and Europe. If a positive result for IgM or IgG antibodies is obtained, the Western blot for antibodies to B. burgdorferi antigens would be expected to discriminate current or past Lyme disease from relapsing fever, as well as from syphilis, another cause of false- positive Lyme disease ELISA results. Other frequent laboratory abnormalities can occur in relapsing fever but are not diagnostic. These include elevated white blood cell count with increased neutrophils, thrombocytopenia, increased serum bilirubin, proteinuria, microhematuria, prolongation of the prothrombin time (PT) and partial thromboplastin time (PTT), and elevation of fibrin degradation products.

Treatment

Relapsing fever Borrelias are very sensitive to several antibiotics, and antimicrobial resistance is rare. Table 3 summarizes the treatment options for adults and children younger than 8 years. Children older than 8 years can be treated with the same antibiotics as adults, but the doses should be adjusted by weight. Before antibiotics are given, the possibility of causing the Jarisch-Herxheimer reaction (JHR) should be considered (see later). The tetracycline antibiotics are most commonly used for treatment of LBRF and TBRF. The first antibiotic of choice in adults and children older than 8 years is doxycycline (Doryx). In general, shorter treatments are needed for LBRF than for TBRF.

Single-dose therapy is usually recommended for LBRF. In contrast, in TBRF even multiple doses of tetracyclines for up to 10 days may fail to prevent relapses, and retreatment can be required.

Table 3

Treatment Options for Tick-Borne Relapsing Fever*

Adults

Nonsevere forms

1.   Doxycycline (Doryx oral), 100 mg PO bid for 1–2 wk†

2.   Tetracycline (Sumycin), 500 mg PO qid for 1–2 wk

3.   Erythromycin (Erythrocin),1 500 mg PO tid for 1–2 wk

Severe forms

1.   Ceftriaxone (Rocephin),1 2 g IV qd for 1–2 wk

2.   Penicillin G parenteral aqueous (Pfizerpen),1 4 million U IV q4h for 1–2 wk

Children (≤8 y)

Nonsevere forms

1. Erythromycin suspension oral (EryPed),1  30–50 mg/kg/d divided tid for 1–2 wk

2.   Azithromycin oral suspension (Zithromax),1  20 mg/kg on the first day followed by 10 mg/kg/d for 4 more days

3.   Penicillin V (Pen-Vee K),1  25–50 mg/kg/d divided qid for 1–2 wk

4.   Amoxicillin (Amoxil),1  50 mg/kg/d divided tid for 1– 2 wk

Severe forms

1.   Ceftriaxone (Rocephin),1  75–100 mg/kg/d IV for 1–2 wk

2.   Penicillin G parenteral aqueous (Pfizerpen),1

300,000 U/kg/d given IV in divided doses q4h for 1–2 wk

Abbreviations: IV = intravenous; PO = orally.

1  Not FDA approved for this indication.

*  The same oral agents are used for treatment of louse-borne (epidemic) relapsing fever but given as a single dose.

†  In general, treatment for 1 wk is recommended in early/milder cases and for up to 2 wk for more severe cases.

Alternative oral antibiotics to the tetracyclines are erythromycin (E- Mycin),1 azithromycin (Zithromax),1 amoxicillin (Amoxil),1 penicillin,1 and chloramphenicol (Chloromycetin).1 However, oral chloramphenicol is no longer available in the United States.

Erythromycin, azithromycin, and penicillin do not appear as effective as the tetracyclines; however, they are recommended for children younger than 8 years and for pregnant women. Amoxicillin is another alternative for young children with early Lyme disease; however, it is ineffective for human granulocytic ehrlichiosis, which sometimes occurs as a co-infection with Lyme disease.

Although treatment with antibiotics is usually given orally, they may need to be given intravenously if severe vomiting makes swallowing impractical. If there are symptoms and signs of meningitis or encephalitis without clinical and/or radiologic signs of increased intracranial pressure, the CSF should be examined to rule out central nervous system (CNS) infection. The finding of elevation of CSF cells and protein demands the use of parenteral antibiotics, such as penicillin G or ceftriaxone (Rocephin). Optimally, antibiotic treatment should be started during afebrile periods when the spirochetemia is low. Starting therapy near the peak of a febrile period may induce JHR, in which high fever and a rise and subsequent fall in blood pressure, sometimes to dangerously low levels, may occur.

Dehydration should be treated with fluids given intravenously. Severe headache can be treated with pain relievers such as codeine, and nausea or vomiting can be treated with prochlorperazine.

Jarisch-Herxheimer Reaction

Antibiotic treatment of relapsing fever causes JHR in as many as 60% of cases. JHR is more common in LBRF than in TBRF. It is characterized by the sudden onset of tachycardia, hypotension, chills, rigors, diaphoresis, and high fever. Patients with JHR have said that they felt as if they were going to die. JHR is caused by the rapid killing of circulating spirochetes 1 to 4 hours after the first dose of antibiotic, which results in the release of large amounts of Borrelia lipoproteins in the circulation followed by massive release of tumor necrosis factor and other cytokines. If possible, patients with JHR should be transferred to an intensive care unit for close monitoring and treatment. Over several hours, the temperature declines and the patient feels better. Large amounts of intravenous fluids (0.9% sodium chloride solution) may be required to treat hypotension. Steroids and nonsteroidal antiinflammatory agents have no effect on the frequency or severity of the JHR. One study found that pretreatment with anti- TNF-alpha monoclonal antibody (Humira)1 suppressed JHR after penicillin treatment for LBRF and reduced the associated increases in plasma cytokines. Death can occur as a result of JHR secondary to cardiovascular collapse in up to 5% of patients with treated LBRF and much less frequently in TBRF.

Outcome

Complete recovery occurs in 95% or more of adequately treated patients. The prognosis for untreated cases or if treatment is delayed varies. Mortality as high as 40% is reported in untreated epidemics of LBRF. Relapsing fever also has a high mortality in neonates. Some neurologic sequelae can occur in patients with TBRF complicated with neuroborreliosis.

Prevention

Prevention of TBRF involves avoidance of rodent- and tick-infested dwellings such as animal burrows, caves, and abandoned cabins.

Wearing clothing that protects skin from tick access (e.g., long pants and long-sleeved shirts) is also helpful. Repellents and acaricides provide additional protection. Diethyltoluamide (DEET) repels ticks when applied to clothing or skin, but it must be used with caution. It loses its effectiveness within 1 to several hours when applied to skin and must be reapplied; it is absorbed through the skin and may cause CNS toxicity if used excessively. Picaridin (KBR 3023), which has been used as an insect repellent for years in Europe and Australia, is now available in the United States in 7% solution as Cutter Advanced Repellent (Spectrum Brands). The U.S. Centers for Disease Control and Prevention (CDC) is recommending it as an alternative to DEET.

Permethrin Insect Repellent, an acaricide, is more effective than DEET but should not be applied directly to skin. When applied to clothing, it provides good protection for 1 day or more. In LBRF, prevention can be achieved by promoting personal hygiene and by dusting undergarments and the inside of clothing with malathion1,2 or lindane powder2 when available. Widespread antibiotic use may be necessary to control epidemics of LBRF, using one or two doses of 100 mg doxycycline given within 1 week of exposure.

References

1.     Barbour A.G., Hayes S.F. Biology of Borrelia species. Microbiol Rev. 1986;50:381–400.

2.     Bryceson A.D., Parry E.H., Perine P.L., et al. Louse-borne relapsing fever. Q J Med. 1970;39:129–170.

3.     Cadavid D., Barbour A.G. Neuroborreliosis during relapsing fever: Review of the clinical manifestations, pathology, and treatment of infections in humans and experimental animals. Clin Infect Dis. 1998;26:151–164.

4.     Fekade D., Knox K., Hussein K., et al. Prevention of Jarisch- Herxheimer reactions by treatment with antibodies against tumor necrosis factor alpha. N Engl J Med. 1996;335:311–315.

5.     Kazragis R.J., Dever L.L., Jorgensen J.H., Barbour A.G. In vivo activities of ceftriaxone and vancomycin against Borrelia spp. in the mouse brain and other sites. Antimicrob Agents Chemother. 1996;40:2632–2636.

6.     Melkert P.W. Fatal Jarisch-Herxheimer reaction in a case of relapsing fever misdiagnosed as lobar pneumonia. Trop Geogr Med. 1987;39:92–93.

7.     Southern P., Sanford J. Relapsing fever. Medicine. 1969;48:129– 149.

8.     Taft W., Pike J. Relapsing fever. Report of a sporadic outbreak including treatment with penicillin. JAMA. 1945;129:1002– 1005.

1  Not FDA approved for this  indication.

2  Not available in the United  States.

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