Introduction
Fever of unknown origin (FUO) presents a significant diagnostic challenge in medicine. First defined in 1961 by Dr. Petersdorf and Dr. Beesom, FUO was initially characterized by a temperature exceeding 101 degrees Fahrenheit (38.3 degrees Centigrade) for at least three weeks, without a clear diagnosis even after a week of intensive hospital investigations. Advancements in outpatient diagnostic capabilities have since rendered the mandatory week-long inpatient investigation obsolete. This article delves into the complexities of Fever Differential Diagnosis in cases of FUO, exploring its causes, clinical presentation, and the crucial role of a collaborative healthcare team in effective management.
Etiology: Broadening the Fever Differential Diagnosis
The fever differential diagnosis for FUO is extensive, encompassing a wide array of conditions. Often, FUO arises from common illnesses manifesting in atypical ways, making diagnosis particularly challenging. The etiological landscape of FUO is broadly categorized into infectious, noninfectious inflammatory, malignant/neoplastic, and miscellaneous causes, each requiring careful consideration in the differential diagnosis.
Noninfectious Inflammatory Causes in Fever Differential Diagnosis
Inflammatory conditions represent a significant portion of the fever differential diagnosis in FUO. These include:
- Giant cell (temporal) arteritis
- Adult Still disease (juvenile rheumatoid arthritis)
- Systemic lupus erythematosus (SLE)
- Periarteritis nodosa/microscopic polyangiitis (PAN/MPA)
- Rheumatoid arthritis (RA)
- Antiphospholipid syndrome (APS)
- Gout
- Pseudogout
- Behçet disease
- Sarcoidosis
- Felty syndrome
- Takayasu arteritis
- Kikuchi disease
- Periodic fever adenitis pharyngitis aphthous ulcer (PFAPA) syndrome
Infectious Causes in Fever Differential Diagnosis
Infections remain a prominent category in the fever differential diagnosis of FUO. The range of infectious agents and sites is vast:
- Tuberculosis (TB)
- Q fever
- Brucellosis
- HIV infection
- Abdominopelvic abscesses
- Cat scratch disease (CSD)
- Epstein-Barr virus (EBV) infection
- Cytomegalovirus (CMV) infection
- Enteric (typhoid) fever
- Toxoplasmosis
- Extrapulmonary TB
- Organ-based infectious causes:
- Subacute bacterial endocarditis (SBE)
- Chronic sinusitis/mastoiditis
- Chronic prostatitis
- Discitis
- Vascular graft infections
- Whipple disease
- Multicentric Castleman disease (MCD)
- Cholecystitis
- Lymphogranuloma venereum (LGV)
- Tickborne infections:
- Babesiosis, Ehrlichiosis
- Anaplasmosis
- Tickborne relapsing fever (rodent-infested cabins)
- Regional infections:
- Histoplasmosis
- Coccidioidomycosis
- Leptospirosis
- Visceral leishmaniasis
- Rat-bite fever
- Louse-borne relapsing fever
Malignant and Neoplastic Causes in Fever Differential Diagnosis
Malignancies constitute a serious aspect of the fever differential diagnosis in FUO, although proportionally less frequent than infectious or inflammatory causes:
- Lymphoma
- Renal cell carcinoma
- Myeloproliferative disorder
- Acute myelogenous leukemia
- Multiple myeloma
- Breast/liver/pancreatic/colon cancer
- Atrial myxoma
- Metastases to brain/liver
- Malignant histiocytosis
Miscellaneous Causes in Fever Differential Diagnosis
A collection of miscellaneous conditions also contribute to the fever differential diagnosis of FUO:
- Cirrhosis (due to portal endotoxins)
- Drug fever
- Thyroiditis
- Crohn disease
- Pulmonary emboli
- Hypothalamic syndrome
- Familial periodic fever syndromes
- Cyclic neutropenia
- Factitious fever
Epidemiology: Contextualizing the Fever Differential Diagnosis
The epidemiology of FUO is highly variable, influenced by the underlying cause, patient age, geographical location, environmental exposures, and immune status. Notably, in developing nations, infectious etiologies are more commonly identified in FUO cases. Conversely, in developed countries, non-infectious inflammatory diseases are increasingly recognized as the cause of FUO. These epidemiological factors are crucial to consider when formulating a fever differential diagnosis.
History and Physical Examination: Guiding the Fever Differential Diagnosis
There is no single algorithm for diagnosing FUO. A meticulous history and physical examination, tailored to the patient’s specific symptoms, are paramount in narrowing down the fever differential diagnosis. Gathering information about past illnesses, symptom localization, alcohol consumption, medications (including over-the-counter), occupational and travel history, pet ownership, and familial medical history is essential.
Patient-reported symptoms can provide valuable clues. For example, B-symptoms (fever, night sweats, weight loss), early satiety, and significant weight loss may suggest a malignancy, directing the fever differential diagnosis towards neoplastic causes. Rigors point towards an infectious etiology, while joint involvement is a hallmark of rheumatologic disorders, shifting the fever differential diagnosis accordingly.
Key Historical Aspects for Fever Differential Diagnosis
- Family history of fever syndromes or relevant conditions
- Immunization history to rule out vaccine-preventable illnesses
- Dental history, as dental infections can be a source of FUO
- Occupational exposures to infectious agents or toxins
- Travel history to areas with endemic infections
- Nutritional and weight history changes
- Drug history, including prescription, OTC, and illicit drugs
- Sexual history, considering risk factors for HIV and STIs
- Recreational habits and hobbies
- Animal contacts, potential zoonotic exposures
- History of surgeries, trauma, or medical procedures
Fever Patterns: Clues in Fever Differential Diagnosis
Documenting and analyzing fever patterns can offer further insights in the fever differential diagnosis, particularly for infectious etiologies:
- Tertian or quartan fever (every third or fourth day): suggests malaria
- Undulant fever (evening fevers and sweats resolving by morning): points towards brucellosis
- Tick-borne relapsing fever (week-long fevers with week-long remissions): indicative of borreliosis
- Pel-Ebstein fever (week-long high fevers with week-long remissions): seen in Hodgkin lymphoma
- Periodic fevers: associated with cyclic neutropenia
- Double quotidian fever (two fever spikes daily): observed in adult Still disease, malaria, and typhoid
Historical and Physical Clues for Specific Etiologies in Fever Differential Diagnosis
Infectious Causes:
- History of invasive procedures/surgeries, dental work, TB exposure, pet contacts, mosquito/tick bites, rodent exposure, blood transfusions, immunosuppressive drugs.
- Abdominal surgery, trauma, peritonitis, endoscopy, urologic or gynecologic procedures may suggest intraabdominal, perinephric, or psoas abscess.
- Exposure to unpasteurized dairy: consider brucellosis, Q fever, Yersinia enterocolitica.
- Bird exposure: Chlamydia psittaci infection.
- Cat exposure: toxoplasmosis or cat scratch disease.
- Travel and unprotected sex: HIV, disseminated gonorrhea.
- Daycare center exposure: Epstein-Barr virus (EBV) infection.
Physical exam findings: New heart murmur (bacterial endocarditis), spinal tenderness (vertebral osteomyelitis), splenomegaly (miliary TB, EBV, CMV), epididymal nodule (extrapulmonary TB).
Malignant Causes:
- Unintentional weight loss, cancer screening history, family cancer history, smoking, alcohol use.
- Relative bradycardia (lymphoma/CNS malignancy), new heart murmur (atrial myxoma), sternal tenderness (myeloproliferative disorder), isolated hepatomegaly (hepatoma/liver metastases).
Non-Infectious Inflammatory Causes:
- Muscle/joint pain/stiffness, oral ulcers, family history of autoimmune conditions. Rigors/chills are less common.
- Fever distribution (morning fevers in periarteritis nodosa, double quotidian in adult Still disease).
- Oral ulcers (Behcet disease, SLE), unequal pulses (Takayasu arteritis), lymphadenopathy (SLE, RA, sarcoidosis), rashes (sarcoidosis, SLE, adult Still disease), epididymal nodule (periarteritis nodosa, SLE, sarcoidosis), hepatomegaly without splenomegaly (less likely rheumatologic).
Miscellaneous Causes:
- History of alcohol intake, IV drug use, NASH, hepatitis (cirrhosis), past medical history (Crohn disease).
- Splenomegaly (Crohn disease, liver cirrhosis).
Evaluation: A Systematic Approach to Fever Differential Diagnosis
When evaluating FUO, it is crucial to remember that the underlying cause is more often an atypical presentation of a common condition than a rare disease. Establishing a fever differential diagnosis requires a systematic and iterative approach, starting with thorough history and physical examination.
Non-invasive Tests in Fever Differential Diagnosis
Initial non-invasive diagnostic testing should include:
- Complete blood count (CBC) with differential
- Complete metabolic panel
- Urinalysis with microscopy and urine culture
- Three sets of blood cultures (from different sites, several hours apart, before antibiotics)
- Chest radiograph
- Erythrocyte sedimentation rate (ESR)
- C-reactive protein (CRP)
- Lactate dehydrogenase (LDH)
- Creatinine phosphokinase
- Antinuclear antibodies (ANA)
- Rheumatoid factor
- Cytomegalovirus IgM/PCR
- Heterophile antibody test
- Tuberculin skin test or interferon-gamma release assay
- HIV immunoassay
- CT scan of the abdomen
- CT scan of the chest
- Cardiac echocardiography (if endocarditis or atrial myxoma suspected)
If these tests are inconclusive, consider surreptitious thermometer manipulation and medication-induced fever as part of the fever differential diagnosis.
Nuclear Medicine Tests in Fever Differential Diagnosis
Fluorodeoxyglucose positron emission tomography (FDG-PET)/CT scan is increasingly utilized earlier in FUO workup to localize infectious, inflammatory, or neoplastic processes. While non-specific, it can guide further invasive tests like biopsies.
Labeled leukocyte studies (Gallium- and Indium-labeled) are alternatives if FDG-PET is unavailable, helpful for localization but less diagnostically specific. Positron emission tomography can aid in detecting obscure infections or malignancies in challenging fever differential diagnosis cases.
Invasive Tests in Fever Differential Diagnosis
Invasive tests are considered if clinical findings or initial tests suggest specific pathologies. Common invasive tests include biopsies of lymph nodes, liver, bone marrow, epididymal nodule, and temporal artery. These are particularly useful for diagnosing malignancy, certain infections, myeloproliferative disorders, and inflammatory conditions within the fever differential diagnosis.
Temporal artery biopsy is indicated in patients over 60 with elevated ESR and giant cell arteritis suspicion. Lymph node biopsy is recommended for patients with lymphadenopathy and FUO. Endoscopic examinations of the upper and lower GI tract, including retrograde cholangiography, may be necessary, especially when considering Crohn’s disease or biliary tract pathology in the fever differential diagnosis.
Treatment / Management: Targeting the Fever Differential Diagnosis
FUO management is etiology-dependent. Once a diagnosis is established from the fever differential diagnosis, specific treatment should be initiated. Empiric antibiotics are generally avoided unless the patient is neutropenic, as they can mask occult infections. Empiric glucocorticoids are also not routinely recommended unless there is strong suspicion for a specific rheumatologic condition in the fever differential diagnosis. However, in deteriorating patients, empiric trials of antibiotics, steroids, or anti-tuberculosis agents may be considered.
Exceptions to withhold empiric therapy include culture-negative endocarditis, cryptic disseminated TB, and temporal arteritis with vision loss risk. Surgical intervention is rarely needed in FUO management.
Specific Treatment Examples Based on Fever Differential Diagnosis
- Hepatic granulomas: Corticosteroids can be effective in 50% of cases; others resolve spontaneously.
- Giant cell arteritis: High-dose steroids, with intravenous administration for severe cases or ocular compromise.
- Polymyalgia rheumatica: Steroid therapy.
- Drug fever: Discontinue the offending drug; fever should subside within two days.
The naproxen test, while not definitively validated, may help differentiate between infectious and neoplastic etiologies in the fever differential diagnosis. A substantial temperature decrease with naproxen suggests a neoplastic origin, while minimal change points towards infection.
In up to 51% of FUO cases, a definitive diagnosis remains elusive. Prognosis in these cases is generally favorable, with spontaneous resolution often occurring within weeks to months. Non-steroidal anti-inflammatory drugs can be used for symptomatic fever management in stable, undiagnosed patients.
Differential Diagnosis: Categorizing Potential Causes of Fever
The differential diagnosis for FUO is broad, categorized into infections, neoplasms, connective tissue diseases, and miscellaneous conditions.
Infections (approximately one-third of FUO cases):
- Miliary tuberculosis (TB)
- Brucellosis
- Q fever
- Intraabdominal, pelvic, intranephric, and perinephric abscesses
- Typhoid/enteric fever
- Actinomycosis
- Amebiasis
- Atypical mycobacterial infection
- Blastomycosis
- Brain abscess
- Campylobacter infections
- Cholangitis
- Cholelithiasis
- Chagas disease
- Candidiasis
- Dengue fever
- Diabetic ulcers
- Empyema thoracis
- Empyema gallbladder
- Toxoplasmosis
- Giardiasis
- Hepatitis A-E
- Liver abscess
- Lung abscess
- Leptospirosis
- Leishmaniasis
- Libman-Sacks endocarditis
- Cat scratch disease (CSD)
- Malaria
- Mycoplasma
- Mucormycosis
- SARS COVID 19
- Pelvic inflammatory disease
- HIV
- Cytomegalovirus
- Epstein-Barr virus
- Extrapulmonary (renal, central nervous system) TB
(In HIV patients, 75% of FUO cases are infectious but rarely due to HIV itself.)
Rheumatologic and Inflammatory Disorders (approximately one-third of FUO cases):
- Adult Still disease
- Giant cell/temporal arteritis
- Periarteritis nodosa
- Microscopic polyangiitis
- Rheumatoid arthritis (RA)
- Systemic lupus erythematosus (SLE)
- Takayasu arteritis
- Kikuchi disease
- Sarcoidosis
- Felty syndrome
- Gaucher disease
- Polyarticular gout
- Pseudogout
- Antiphospholipid syndrome (APS)
- Behcet disease
- Marshall syndrome
Neoplasms and Malignancies (up to 18% of FUO cases):
- Lymphoma
- Renal cell carcinoma
- Acute myeloid leukemia
- Myeloproliferative disorders
- Atrial myxoma
- Multiple myeloma
- Colon carcinoma
- Pancreatic carcinoma
- Hepatoma
- CNS metastasis
- Liver metastasis
- Systemic mastocytosis
Miscellaneous Etiologies (remainder of FUO cases):
- Drug-induced fevers
- Liver cirrhosis
- Subacute thyroiditis
- Crohn disease
- Deep vein thrombosis
- Pulmonary embolus
- Hematomas
- Familial Mediterranean fever
- Hypothalamic dysfunction
- Hypertriglyceridemia (type V)
- Fictitious fever
Prognosis: Variability in Fever Differential Diagnosis Outcomes
The prognosis of FUO is highly dependent on the underlying etiology identified through the fever differential diagnosis. Elderly patients and those diagnosed with malignancies tend to have poorer prognoses. Children with undiagnosed FUO generally fare better than adults.
Complications: Disease-Specific vs. Undiagnosed FUO
Complications are also dictated by the specific diagnosis derived from the fever differential diagnosis. Interestingly, patients with undiagnosed FUO tend to have favorable outcomes and typically do not experience complications after fever resolution.
Deterrence and Patient Education: Navigating the Fever Differential Diagnosis Process
Patients need to be informed about the complexities of diagnosing FUO and the often-protracted diagnostic process. Active patient participation through providing a detailed and accurate history is crucial to guide the fever differential diagnosis effectively.
Enhancing Healthcare Team Outcomes: Collaborative Approach to Fever Differential Diagnosis
FUO remains a challenging diagnostic entity due to its extensive fever differential diagnosis. Effective diagnosis necessitates a thorough history, repeated physical examinations, and judicious use of diagnostic testing. A “shotgun” approach to testing early in the FUO workup is discouraged; directed testing based on clinical findings is more efficient and cost-effective.
An interdisciplinary team approach is essential in FUO management. Effective communication between nursing staff, primary care providers, hospitalists, specialists (infectious disease, rheumatology, hematology/oncology), and pharmacists is vital to optimize the fever differential diagnosis process, ensure timely diagnosis, and initiate appropriate treatment.
Review Questions
(Original article includes review questions here – these are omitted as per instructions)
References
(References are kept as in the original article)
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Disclosure: Ilona Brown declares no relevant financial relationships with ineligible companies.
Disclosure: Nancy Finnigan declares no relevant financial relationships with ineligible companies.
