Pel-Ebstein Fever

Synonyms and related keywords: Pel-Ebstein fever, periodic fever of lymphomas, Hodgkin disease, Hodgkin's disease, HD, Hodgkin's episodic fever, Hodgkin episodic fever, B symptoms, B-type symptoms, Hodgkin lymphoma, Hodgkin's lymphoma, HL, lymphoma, lymphoma-related fever, relapsing fever, hemolysis, hemolytic anemia, periodic fever spikes


INTRODUCTION

Background: Hodgkin lymphoma (HL) is an unusual lymphoma that can manifest with constitutional symptoms (eg, fever, weight loss, night sweats) termed B-type symptoms. The periodic fever associated with HL is known as the Pel-Ebstein fever.

The criteria for B-type symptoms include fever (ie, temperature >38°C [>100.4°F]) for 3 consecutive days, weight loss exceeding 10% of body weight in 6 months, and night sweats. Pruritus, previously considered an important systemic symptom, does not by itself have prognostic importance and is not sufficient on its own to classify a patient as possessing B-type symptoms.

Pathophysiology: The pathophysiologic mechanism of the Pel-Ebstein fever is unknown; however, it is presumed to be due to cyclic cytokine release.

Frequency:

• In the US: No reliable objective data are known regarding the occurrence rate of classic Pel-Ebstein fever in a series of patients with HL. Anecdotally, some authorities estimate a 5-10% occurrence rate.

• Internationally: US and international rates of Pel-Ebstein fever are not known to differ.

Mortality/Morbidity:

• The Pel-Ebstein fever is not an independent cause of either morbidity or mortality, although the high fevers can be quite uncomfortable.

• The episodic hemolysis sometimes associated with Pel-Ebstein fever has been suggested to be due to increased susceptibility of older erythrocytes to temperature-induced hemolysis. Two cases of Pel-Ebstein fever temporally associated with pancytopenia have been reported, which would seem to suggest a cytokine-mediated etiology.

Race: No evidence indicates that Pel-Ebstein fever manifests differently or with different frequencies according to race.

Sex: Pel-Ebstein fever is not known to be sex-linked.

Age: No frequency differences by age group are known.

CLINICAL

History:

• Pel-Ebstein fever was described by 2 physicians in the late 1800s.

• Wilhelm Ebstein, a German internist who was a professor of medicine in Göttingen, described a patient with relapsing fever in "Das chronische Rückfallsfieber, eine neue Infektionskrankheit." Berliner klinische Wochenschrift, 1887, 24: 565-8, 837.

• Pieter Pel was a physician in Amsterdam who noted a similar finding years earlier in "Zur Symptomatologie der sogenannten Pseudo-Leukämie." Berliner klinische Wochenschrift, 1885, 22: 3-7.

• Pel-Ebstein fever has been used as an example of a disease that exists only because it has a name.

Physical:

• The diagnosis of Pel-Ebstein fever is made by examining a patient's temperature over several weeks.

• The classic description is of a relapsing, high-grade fever that can reach 40-40.5°C (105-106°F) and has a periodicity of 7-10 days. The fever spikes are abrupt in onset and resolution. The fever spikes overlie a temperature baseline that never quite reaches normal.

• Multiple, evenly spaced Beau lines in the nailbeds have been described as indicative of relapsing fever.

Causes:

• The etiology of Pel-Ebstein fever is thought to be cytokine release. Cytokines known to be released by Reed-Sternberg cells include interleukin 13, macrophage colony-stimulating factor, transforming growth factor-alpha, interleukin 10, and the T cell–directed CC chemokine thymus- and activation-regulated chemokine. Monocyte chemotactic protein 1 and interleukin 8 have also been detected at increased levels in HL tissues.

DIFFERENTIALS

Abdominal Abscess
Amebiasis
Arenaviruses
Bronchitis
Carcinoid Lung Tumors
Carcinoid Tumor, Intestinal
Catscratch Disease
Cellulitis
Chagas Disease (American Trypanosomiasis)
Chronic Bronchitis
Coxsackieviruses
Cryptococcosis
Dengue Fever
Echoviruses
Enterobacter Infections
Enterococcal Infections
Factitious Disorder
Fever of Unknown Origin
Human Herpesvirus Type 6
Hypersensitivity Reactions, Delayed
Hypersensitivity Reactions, Immediate
Inflammatory Bowel Disease

Other Problems to be Considered:

Pancreatic carcinoid tumor

WORKUP

Lab Studies:

• In a patient with true Pel-Ebstein fever, the diagnosis is established by the histologic finding of HL or another lymphoma. (Other lymphomas and malignancies may be associated with fevers, but only the fever associated with HL is named Pel-Ebstein.)

• No laboratory tests are particularly useful in persons with Pel-Ebstein fever.

• In rare cases, Pel-Ebstein fever has been associated with episodic hemolysis. In these cases, hemolysis laboratory studies may be helpful in making a diagnosis.

Imaging Studies:

• Imaging studies are not useful in the diagnosis of the fever; however, CT scans of the neck, chest, abdomen, and pelvis, as well as PET or gallium scans, can be useful in the diagnosis of the underlying Hodgkin lymphoma.

Procedures:

• No diagnostic procedures are particularly useful in persons with Pel-Ebstein fever beyond the biopsy used to diagnose the HL or causative lymphoma.

TREATMENT

Medical Care:

• Therapy for Pel-Ebstein fever involves the following 2 concepts:

• Standard antipyretic regimens, including aspirin and nonsteroidal anti-inflammatory drugs

• Most importantly, chemotherapy for the underlying lymphoma

• Pel-Ebstein fever reportedly responds to chemotherapy within as short as 2 days.

Surgical Care: Surgery is not indicated.

Consultations: Consulting a hematologist or oncologist for the management of the underlying HL is mandatory.

Diet: Diet modification is ineffective in the therapy for Pel-Ebstein fever.

Activity: Activity restriction does not play a role in treatment of Pel-Ebstein fever.

MEDICATION

Antipyretic therapy and chemotherapy for the underlying lymphoma are the 2 mainstays of medical therapy for Pel-Ebstein fever. Treatment of the underlying lymphoma or Hodgkin lymphoma (HL) is beyond the scope of this discussion (see Hodgkin Disease).

Drug Category: Antipyretic agents -- These agents are used to reduce uncomfortable fevers.

Drug Name	Acetaminophen (Tylenol) -- Reduces fever by acting directly on hypothalamic heat-regulating centers, which increases dissipation of body heat via vasodilation and sweating.
Adult Dose	325-1000 mg PO q4h prn; not to exceed 4 g/d
Pediatric Dose	10-15 mg/kg/dose PO q4-6h; not to exceed 5 doses/d
Contraindications	Documented hypersensitivity
Interactions	Rifampin can reduce analgesic effects; barbiturates, carbamazepine, hydantoins, and isoniazid may increase hepatotoxicity
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Hepatotoxicity possible in chronic alcoholism following various dose levels; severe or recurrent pain or high or continued fever may indicate serious illness; acetaminophen is contained in many OTC products, and combined use with these products may result in cumulative doses exceeding recommended maximum dose

FOLLOW-UP

Further Inpatient Care:

• No particular inpatient requirements are indicated for the management of Pel-Ebstein fever.

Further Outpatient Care:

• No particular outpatient therapy is warranted.

In/Out Patient Meds:

• Antipyretics are a mainstay of therapy, along with chemotherapy for HL.

Complications:

• Several reported cases of hemolysis have been associated with Pel-Ebstein fever. Whether the degree of hemolysis is inappropriate for the degree of fever or whether this is merely a temperature-related hemolytic reaction has not been determined. Additionally, 2 cases of cyclic pancytopenia have been reported.

Prognosis:

• B-type symptoms are a negative prognostic factor for HL.

Patient Education:

• Patients should be educated on the appropriate timing of antipyretic therapy.

MISCELLANEOUS

Medical/Legal Pitfalls:

• The differential diagnosis of relapsing fever is a possible source of malpractice liability.