Continuing Education Activity

Relapsing fever typically refers to malaria-like illnesses caused by various spirochetes belonging to Borrelia species and characterized by recurrent fevers, chills, and malaise. The causative organism and associated vector vary based on the geographic area of exposure. Borrelia recurrentis is the cause of epidemic relapsing fever, which is reported most frequently in northern and eastern Africa. Tick-borne relapsing fever is reported in the United States and can be caused by several species, including Borrelia hermsii, Borrelia turicatae, and Borrelia parkeri. Regardless of the specific causative organism, relapsing fever is treated with doxycycline 100 milligrams (mg) twice a day for seven to ten days. In children under eight years of age, penicillin or erythromycin may be preferred agents due to the concern of dental staining with doxycycline use. It is important to observe patients for several hours after the initiation of antibiotic therapy, as Jarisch-Herxheimer reaction is common. Jarisch-Herxheimer reaction is a sepsis-like response to the release of inflammatory contents from within the bacteria after lysis by antibiotics. It is rarely fatal and managed with supportive care. This reaction is more common in adolescents than in younger children. Borrelia infections may also be self-limited and resolve without treatment in some cases.

Objectives:

• Review the typical presentation of relapsing fever.
• Describe the Jarisch-Herxheimer reaction.
• Describe the treatment of relapsing fever.
• Describe how enhanced coordination of the interprofessional team can lead to more rapid detection of relapsing fever and subsequently enhance the detection of pathology and allow for prompt initiation of treatment.

Introduction

Relapsing fever typically refers to malaria-like illnesses, characterized by recurrent fevers, chills, and malaise, caused by various spirochetes belonging to Borrelia species. The causative organism and associated vector vary based on the geographic area of exposure.[1][2][3]

Etiology

Borrelia recurrentis is the cause of epidemic relapsing fever, which is reported most frequently in northern and eastern Africa. Tick-borne relapsing fever, reported in the United States, can be caused by several species, including Borrelia hermsii, Borrelia turicatae, and Borrelia parkeri.[4]

Epidemiology

Borrelia recurrentis, or epidemic relapsing fever, is reported most commonly in areas of overcrowding and poor personal hygiene. It generally causes epidemics and has previously been associated with war, poverty, and famines. It is transmitted via lice and has decreased in frequency, substantially, since the first half of the 20th century. However, it is still commonly seen in the Horn of Africa, and among people who emigrated from Africa to Europe, in recent years. Other species causing relapsing fever in Africa include Borrelia duttonii, Borrelia hispanica, and Borrelia crocidurae. Borrelia hermsii, or tick-borne relapsing fever, is reported in the United States in Colorado, near Lake Tahoe, and near the Grand Canyon. Other species that cause tick-borne relapsing fever in the United States include Borrelia turicatae and Borrelia parkeri. Borrelia miyamotoi causes relapsing fever similar to Lyme disease. It is reported in the northeastern United States, Japan, and Russia, with slight variations in presentation depending on geography.[5]

Pathophysiology

Borrelia species are fastidious spirochetes. They are large with irregular spirals and readily stain with aniline dyes. Although Borrelia is technically gram-negative, they are most readily identified by Giemsa or Wright staining.

Borrelia recurrentis is transmitted when an infected human body louse, Pediculosis humanus corporis, is crushed and Borrelia recurrentis present in the hemocoel penetrate through intact skin and mucosal surfaces. Epidemic relapsing fever is not transmitted by intact lice. A louse is infected when it feeds on a febrile patient with relapsing fever. Humans are the only known host and reservoir of Borrelia recurrentis. On the contrary, small rodents and other mammals(birds, bats) serve as a reservoir for tick-borne Borrelia species. Borrelia hermsii, Borrelia parkeri, and Borrelia turicatae are transmitted via the bite of soft-bodied night-feeding Ornithodoros ticks. As the ticks feed at night, patients are often unaware of the bite. Exposure to these ticks has been associated with sleeping in mountain cabins and spelunking. Borrelia miyamotoi is transmitted via the Ixodes tick, similar to Lyme disease.

The clinical manifestations of relapsing fever, including fever, myalgias, chills, and arthralgias, are caused by an endotoxin-like substance produced by the spirochete. The initial febrile episode in relapsing fever resolves due to the development of antibodies directed at surface proteins of the organism. However, a reservoir of organisms in reticuloendothelial organs undergo genetic reassortment to alter the expression of surface proteins. This allows for an escape from immune clearance and re-emergence of spirochetemia and clinical symptoms. The typical recurrence pattern of Borrelia symptoms in relapsing fever is due to repeated cycles of reassortment of surface proteins followed by antibody-mediated suppression of infection. This characteristic variation of the outer-membrane lipoprotein is known as the relapse phenomenon. Infection is not associated with long-term immunity and patients may be reinfected as soon as six months after the initial infection.[3]

History and Physical

The incubation period is typically 4 to 18 days following exposure to Borrelia. The symptoms of relapsing fevers are characterized by the abrupt onset of fever and chills, often accompanied by malaise, arthralgias, myalgias. Other symptoms occurring early include anorexia, nausea, vomiting, and diarrhea. The patient is extremely exhausted accompanied by confusion. A petechial rash on the skin and mucous membranes if often seen.

Hepatic tenderness is the most common sign(60% of the patients). 40% of patients can have signs of meningism. Epistaxis and subconjunctival hemorrhage are more common compared to hemoptysis and retinal bleeds. Hepatic dysfunction and jaundice, enlargement of the spleen and liver may also occur.

Neurological issues like limb paralysis, cranial nerve palsies, mononeuritis multiplex, and focal convulsions are comparatively more frequent in tick-borne disease.

An increased risk of mortality is attributed to cerebral hemorrhage and myocarditis.

After the resolution of the first episode, which typically lasts one week, patients will experience several recurrences of fever that are shorter and less severe. Episodes occur every five to ten days and may persist for several cycles before resolution. In an epidemic or louse-borne relapsing fever, there are typically only one or two episodes of fever. However, in endemic, tick-borne relapsing fever, three to seven recurrences may occur before the resolution of symptoms.

Relapsing fever is associated with an increased risk of abortion and stillbirth in pregnant women.[3][6][3]

Evaluation

Diagnosis of relapsing fever requires a careful history with attention to travel history and other geographic information, living conditions, and the temporal pattern of the symptoms. Laboratory evaluation may include neutrophil leukocytosis, as well as thrombocytopenia. Jarisch-Herxheimer reaction occurring in response to antibiotics is associated with leukopenia. Elevated liver function tests are seen with hepatic impairment. Mild renal dysfunction can occur. Cerebral involvement is associated with cerebrospinal fluid pleocytosis without the presence of spirochetes.

Diagnosis is confirmed by detection of Borrelia in Giemsa-stained blood films, serologic analysis, or via PCR detection of the organism. These organisms are not identifiable in routine laboratory cultures. The diagnostic yield is highest with the earlier febrile episodes and decreases with each recurrence. Early in the course of illness, the number of spirochetes visible in the blood can reach 100,000/mm3. Between episodes and in later recurrences, the spirochetes may not be visible at all. Serology may also be used to diagnose tick-borne relapsing fever, particularly in situations in which diagnosis is suspected later in the course of illness. In that case, repeated testing with a rise in Immunoglobulin G (IgG) is suggestive of recent infection. However, these serologic tests cross-react with other spirochetes such as Leptospirosis and syphilis and must be interpreted in the setting of clinical symptoms.[3][7]  

Treatment / Management

Relapsing fever is treated with doxycycline 100 mg twice a day for seven to ten days. In pregnant women and children under eight years of age, penicillin or erythromycin are the preferred agents due to the concern of dental staining with doxycycline use. It is important to observe patients for several hours after initiation of antibiotic therapy, as Jarisch-Herxheimer reaction is common. Jarisch-Herxheimer reaction is a flu-like response to the release of inflammatory contents from within the bacteria after lysis by antibiotics. It is rarely fatal and managed with supportive care. This reaction is more common in adolescents than in younger children.

Improving the patient's nutritional status can go a long way in improving patient outcomes. Borrelia infections may also be self-limited and resolve without treatment in some cases.[8][9][10][6]

Differential Diagnosis

• Falciparum Malaria
• Leptospirosis
• Trench fever
• Yellow fever
• Dengue fever
• Brucellosis
• Ehrlichiosis
• Anaplasmosis
• Rat-bite fever
• Ascending cholangitis
• Viral hemorrhagic fever

Prognosis

With antibiotic treatment, the mortality of epidemic relapsing fever decreases from 10% to 40% to 2% to 4%. Fatalities are lower in tick-borne disease compared to louse-borne disease, with treatment.

Complications

• Hyperpyrexia
• Meningitis
• Focal neurological deficits
• Acute Respiratory Distress Syndrome ( ARDS)
• Perivascular interstitial histiocytic myocarditis
• Acute Pulmonary Edema from myocarditis
• Gastrointestinal Bleed
• Cerebral bleed
• Splenic Rupture
• Liver failure
• Disseminated Intravascular Coagulation ( DIC)

Deterrence and Patient Education

• Improving personal hygiene.
• Sterilization of the patient's clothing and bedding to kill the lice.

Pearls and Other Issues

There is currently no vaccine available for any of the Borrelia species associated with relapsing fever. Avoidance of louse and tick exposure through proper hygiene, environmental cleaning to remove rodent nesting material and insect repellant can decrease the risk of infection. As transmission is typically vector-borne, standard precautions are recommended, and isolation is not required other than the eradication of body lice.[11]

Enhancing Healthcare Team Outcomes

The diagnosis of relapsing fever can be challenging and is best managed by an interprofessional team that includes the emergency department physician, nurse practitioner, infectious disease expert, and a laboratory specialist. Once the diagnosis is made, the treatment is straightforward and most patients have no sequelae.