SECTION 3 Special Problems in Infectious
Disease Practice: Fever
68 
Fever of Unknown Origin (FUO)
CHESTON B. CUNHA  |  BURKE A. CUNHA
KEY CONCEPTS
• The workup for fever of unknown origin (FUO) should not be
a ‘shotgun’ approach. It must be tailored to the patient’s pre-
senting symptoms and physical findings.
• Treatment of FUO should not be empiric and depends entirely
on the underlying etiology.
• Certain types of FUO are more common among certain epide-
miologic groups. Diagnostic efforts should first be directed to
the more likely causes in these groups.
• Nonspecific laboratory tests must be interpreted in the correct
clinical context. Although each test may not provide the diag-
nosis on its own, when utilized along with a detailed history
and examination, they become important diagnostic clues.
• Although a diagnosis remains elusive in 10–15% of cases of
FUO, careful diagnostic consideration should be given to these
‘not to be missed’ FUO diagnoses.
Introduction and Definition
Prolonged fevers have always been a difficult diagnostic challenge.1–3
In 1961, Petersdorf and Beeson defined fever of unknown origin
(FUO) as fever >101 °F (38.3 °C) lasting for 3 or more weeks that
remains undiagnosed after 1 week of intensive testing in the hospital.4
Currently, the diagnosis has been redefined as >3 weeks of fever >101 °F
(38.3 °C) that remains undiagnosed after 3 days of inhospital testing
or during two or more outpatient visits. FUOs has been classified noninfectious (marantic) endocarditis, e.g., malignant/neoplastic, as
into four distinct categories, i.e. malignant/neoplastic, infectious,
rheumatologic/inflammatory and miscellaneous.5–9 The distribution of
disorders causing FUO has changed since it was first described.10–15
Initially, infection was the leading cause of FUO, but in the following
decades neoplastic disorders have become more common.12–14 While
the distribution of FUO causes has changed and continues to do so
with new diagnostics/therapies for various diseases, the etiology of
FUO remains unknown in 10–15% of cases.13–15 Infectious and
malignant/neoplastic are the most common FUOs, followed by
rheumatic/inflammatory miscellaneous causes.16–20 Appropriate diag-
nostics should be based on presenting symptoms, physical examina-
tion findings and initial nonspecific laboratory studies in the context
of frequencies of the disorders causing FUO21–23 (Table 68-1).
Clinical Categories
MALIGNANT/NEOPLASTIC
Lymphoma
Both Hodgkin’s (HL) and non-Hodgkin’s lymphomas (NHL) are
among the more common malignancies to present low grade but pro-
longed fever.11,12 Relatively few FUO patients presenting with lym-
phoma manifest with high, spiking fevers.17 With a malignant/
neoplastic FUO, an otherwise unexplained elevated alkaline phospha-
tase should suggest lymphoma.16
Renal Cell Carcinoma (RCC)
RCC or hypernephroma typically presents with high, spiking fevers.
RCC’s varied presentations can pose a significant diagnostic dilemma
and has garnered it the name ‘the internist’s tumor’.7–12 While not
always present, new onset hematuria, left-sided varicocele or a flank
mass should suggest possible RCC. Neoplastic lesions in other solid
organs occasionally present with FUO, particularly rapidly growing
tumors with areas of necrosis within them, or lesions that cause
obstruction of normal flow (e.g. blockage of airways, biliary drainage,
ureteral obstruction).
Leukemias
Acute leukemias often present with prolonged fever. Transformations
of chronic myeloproliferative disorders, i.e. chronic myelogenous leu-
kemia (CML) with blast transformation to acute myeloid leukemia
(AML) or chronic lymphocytic leukemia (CLL) with Richter’s trans-
formation to lymphoma are not uncommon FUO causes.11–13
COMMON INFECTIOUS DISORDERS TO
CONSIDER WITH FUO
Infectious Endocarditis (IE)
Subacute bacterial endocarditis (SBE) is now an uncommon cause of
FUO as rapid diagnostic capabilities have improved (echocardiology
and blood culture methods).16 FUO presentation of SBE is typically
indolent, with fevers usually <102 °F (38.9 °C).9,16 Peripheral manifesta-
tions, such as Osler’s nodes, splinter hemorrhages, etc. are more likely
to be present the longer the patient has unrecognized IE.12
Transthoracic (TTE) and even transesophageal (TEE) echocardiog-
raphy might miss small vegetations in the early phase of SBE. Not all
vegetations identified on TTE or TEE indicate IE.22,23 In the absence of
positive blood cultures, consider difficult to culture pathogens (fungi,
anaerobes, fastidious bacteria) or other valvular abnormalities such as
well as Libman–Sacks endocarditis or atrial myxoma.16,17
True culture-negative endocarditis (CNE) is relatively infrequent.
CNE may be defined as having negative blood cultures with vegeta-
tions visible on echocardiography and peripheral manifestations of
IE.22 Current blood culture methods allow relatively rapid isolation of
previously difficult to culture organisms, e.g., nutritionally deficient
streptococci, and HACEK organisms (Haemophilus, Actinobacillus,
Cardiobacterium, Eikenella and Kingella spp.). If CNE is suspected, the
microbiology laboratory should be alerted for possible Brucella, Histo-
plasma, Legionella or Bartonella spp. since special media are required
for cultivating these organisms. Coxiella burnetii and Tropheryma
whipplei are rare causes of CNE and require special diagnostics, i.e.
serum titers, 16S polymerase chain reaction (PCR), etc.23
Abscesses
While virtually any anatomic site is possible, the most common location
for an occult abscess presenting as FUO is in the abdomen or pelvis.
Usually patients have undergone prior sur­gery/invasive procedures or
have underlying abdominal/pelvic disorders.5,7 Abdominal abscesses
often complicate diverticulitis or appendicitis. When diverticulitis is
responsible, abscess formation may have occurred weeks/months previ-
ously.5,8,10 Elderly patients or those on immunosuppressive medications
may not present with typical symptoms, delaying diagnosis.
Tuberculosis (TB)
Suspicion for TB should be raised based on prior exposure/having
lived in a TB endemic area. Globally, extrapulmonary/miliary TB is a
common cause of FUO.6 A positive tuberculin skin test (TST) or
interferon-gamma release assay (IGRA) is helpful if positive, but is
611
612 SECTION 3  Special Problems in Infectious Disease Practice: Fever

TABLE
68-1  Classic Causes of Fever of Unknown Origin (FUO)
Type of Disorder Common Uncommon Rare

MALIGNANCY/NEOPLASTIC • Lymphoma* • Preleukemia (AML)* • Atrial myxoma

DISORDERS • Hypernephroma (RCC) • MPDs* • Multiple myeloma
• Waldenström’s macroglobulinemia
• Colon carcinoma
• Pancreatic carcinoma
• Hepatoma
• CNS metastases
• Liver metastases
• Systemic mastocytosis*
• Angioimmunoblastic lymphadenopathy*
• Intravascular large B-cell lymphoma*

INFECTIOUS DISEASES • Miliary TB • Intra-abdominal/pelvic abscess† • SBE† (culture +ve, culture−ve)

• Brucellosis*† • Intra/perinephric abscess† • Periapical dental abscess*
• Q fever* • Typhoid/enteric fevers*† • Chronic sinusitis/mastoiditis
• Toxoplasmosis*† • Subacute vertebral osteomyelitis
• CSD*† • Aortic graft infection*†
• EBV • Aorto-enteric fistula†
• CMV* • Relapsing fever* (Borrelia recurrentis)
• HIV • Rat bite fever*† (Streptobacillus moniliformis
• Extrapulmonary TB (renal TB, or Spirillum minus)
CNS TB) • Leptospirosis
• Histoplasmosis
• Coccidioidomycosis
• Visceral leishmaniasis (kala-azar)
• LGV
• Whipple’s disease*
• Castleman’s disease (MCD)*
• Malaria*
• Babesiosis*
• Ehrlichiosis/anaplasmosis*
• Chronic prostatitis*
• Legionnaire’s disease
• Recurrent cholangitis*† (with Caroli’s disease)

RHEUMATOLOGIC/ • Adult Still’s disease (JRA)* • PAN/MPA* • Takayasu’s arteritis*

INFLAMMATORY • GCA/TA* • LORA • Kikuchi’s disease*
DISORDERS • SLE* • Sarcoidosis*
• Felty’s syndrome
• Fabry’s disease
• Gaucher’s disease
• Polyarticular gout*
• Pseudogout
• APS*
• Behçet’s disease*
• FAPA syndrome* (Marshall’s syndrome)
MISCELLANEOUS • Drug fever* • Subacute thyroiditis* • Pulmonary emboli (small/multiple)
DISORDERS • Cirrhosis* • Regional enteritis* (Crohn’s • Dissecting aortic aneurysm
disease) • Pseudolymphomas*
• Rosai–Dorfman disease*
• ECD*
• Cyclic neutropenia*
• Familial periodic fever syndromes
FMF*
Hyper-IgD syndrome*
TRAPS*
Schnitzler’s syndrome*
Muckle–Wells syndrome*
• Hypothalamic dysfunction
• Hypertriglyceridemia (type V)*
• Ulcerative colitis
• Habitual hyperthermia
• Retroperitoneal hematomas
• Psychogenic fever
• Factitious fever*

*May present as recurrent FUO.

†
If bacteremia suspected, obtain blood cultures.
Abbreviations for Tables 68-1 to 68-9:
ALL, acute lymphocytic leukemia; AML, acute myelogenous leukemia; APS, antiphospholipid syndrome; CLL, chronic lymphocytic leukemia; CMV, cytomegalovirus;
CNS, central nervous system; CSD, cat scratch disease; CT, computed tomography; EBV, Epstein–Barr virus; ECD, Erdheim–Chester disease; ESR, erythrocyte
sedimentation rate; FAPA, fever, aphthous ulcers, pharyngitis, adenitis; FMF, familial Mediterranean fever; FMH, family medical history; GCA, giant cell arteritis; HIV,
human immunodeficiency virus; LGV, lymphogranuloma venereum; LORA, late onset rheumatoid arthritis; MCD, multicentric Castleman’s disease; MPA, microscopic
polyangiitis; MPDs, myeloproliferative disorders; PAN, periarteritis nodosa; PET, positron emission tomography; RA, rheumatoid arthritis; RCC, renal cell carcinoma;
SBE, subacute bacterial endocarditis; SLE, systemic lupus erythematosus; SPEP, serum protein electrophoresis; TA, temporal arteritis; TB, tuberculosis; TNF, tumor
necrosis factor; TRAPS, TNF receptor-1-associated periodic syndrome.
Table 68-1 adapted from Cunha B.A.: Fever of unknown origin (FUO). In: Gorbach S.L., Bartlett J.B., Blacklow N.R., ed. Infectious diseases in medicine and surgery,
3rd ed. Philadelphia, PA: WB Saunders; 2004:1568–1577; Cunha B.A.: Fever of unknown origin: clinical overview and perspective. In: Cunha B.A., ed. Fever of
unknown origin. New York: Informa Healthcare; 2007:1–8; Cunha C.B., Cunha B.A.: Fever of unknown origin (FUO). In: Schlossberg D., ed. Clinical infectious
disease, 2nd ed. Cambridge: Cambridge University Press; 2015:1–9.

negative in half of TB FUOs. Latent TB in patients receiving steroids,
other immunosuppressive agents or underlying immunodeficiency can
reactivate TB. Miliary TB has few localizing signs and morning tem-
perature spikes can be the only clue.7,9,12
Typhoid Fever
Typhoid fever is an important cause of FUO in those with an appropri-
ate travel/contaminated food exposure history. Rose spots and spleno-
megaly can easily be missed.12 Typhoid fever is usually accompanied
by morning fever spikes, and relative bradycardia; both are important
clinical clues.16
Epstein–Barr Virus (EBV) Infectious Mononucleosis
Younger patients with EBV develop a typical mononucleosis illness,
but older adults often lack sore throat and cervical lymphadenopathy.
Older patients often present with prolonged fevers and fatigue with
right upper quadrant discomfort.7,11,14,16 In organ transplant recipients
EBV can reactivate with fever and a polyclonal B-cell proliferative state
known as post-transplant lymphoproliferative disorder.
Cytomegalovirus (CMV)
As with EBV, CMV is an important cause of FUO in normal and
immunocompromised hosts. Organ-specific disease, i.e., pneumonia,
colitis, etc., often requires biopsy for diagnosis as positive CMV PCR
often indicates CMV reactivation in peripheral WBCs rather than
infection.20–22 CMV can reactivate during systemic illnesses (e.g. SLE
flare, severe sepsis), bone marrow transplant (BMT), or from certain
high-risk chemotherapy regimens. As the presentation of CMV is often
limited to fatigue and fever, CMV is often overlooked, particularly in
normal hosts. CMV should be considered in obscure FUOs in immu-
nocompromised patients.
Cat-Scratch Disease (CSD)
CSD typically develops 1–2 weeks following the initial scratch from a
kitten. Prominent regional lymphadenopathy develops depending on
the site of inoculation. The site of entry is usually completely healed
when the patient presents with an FUO. In some cases, disseminated
CSD may occur, e.g., meningitis, endocarditis, Parinaud’s ocular glan-
dular syndrome, or isolated ocular involvement (macular star may be
the only finding).13,17 Cat exposure is the key historical element in dif-
ferentiating CSD from other causes of regional lymphadenopathy such
as toxoplasmosis or lymphoma.
Visceral Leishmaniasis (Kala-azar)
Visceral leishmaniasis (kala-azar) is often accompanied by double quo-
tidian fever (two temperature spikes/day). Leishmaniasis remains a
significant pathogen with human immunodeficiency virus (HIV) coin-
fection. Leishmania are detectable in liver, spleen and bone marrow.19,22
A history of travel to an endemic area may be the only initial clue; bone
marrow biopsy is the principal diagnostic method.
Histoplasmosis
FUO cases from endemic regions should be evaluated for histoplasmo-
sis. Histoplasmosis may mimic miliary TB. Unlike TB, renal and SLE may present with prolonged fevers during an SLE flare. While
central nervous system (CNS) involvement are uncommon in histo-
plamosis.20 Eosinophilia favors histoplasmosis over TB. Histoplasmo-
sis serology/urinary antigen may be helpful, but bone marrow biopsy
is diagnostic.13
Brucellosis
FUO cases from brucellosis endemic areas, e.g., Mediterranean, Persian
Gulf and India, patients with animal contact (sheep, cattle, goats, or
pigs) or ingestion of unpasteurized dairy products, should be evaluated
for brucellosis. Animal or milk/cheese exposure may have occurred
weeks/months prior to fever onset. The most common zoonotic infec-
tion worldwide, brucellosis has a predilection for bone, central nervous
system, or genitourinary (GU) tract (epididymo-orchitis).6–8 The diag-
nosis rests upon serologies and/or culture of this fastidious, slow-
growing bacterium.
Chapter 68  Fever of Unknown Origin (FUO) 613
Q Fever
Q fever should be considered in FUO cases with a cattle, sheep or goat
exposure. Exposure (often a parturient animal) may be remote as
infection becomes chronic; FUO often presents much later.11–13 Endo-
carditis, vascular infection or less frequently granulomatous hepatitis
are important manifestations of FUO due to chronic Q fever.22,23
Toxoplasmosis
While toxoplasmosis is an important cause of FUO in immunocom-
promised hosts, particularly solid organ transplant recipients and HIV
infections, toxoplasmosis should not be overlooked in normal hosts
with FUO. Regional/generalized lymphadenopathy may be the only
manifestation, mimicking lymphoma or CSD.15 Lymph node or bone
marrow biopsy has a characteristic appearance on staining, but often
the diagnosis is made by toxoplasma serologies.22,23
Trichinosis
Trichinosis should be considered in FUO patients with myositis fol-
lowing exposure/ingestion of undercooked meat, e.g., pork, bear
meat.12 Eosinophils are high and erythrocyte sedimentation rate (ESR)
is classically low, near zero in trichinosis.23
Lymphogranuloma Venereum (LGV)
LGV is the only sexually transmitted disease (STD) that may present
as FUO. To consider this as the cause of FUO a remote history (weeks
or even months) of sexual contact is required. LGV is typically accom-
panied by painful bilateral inguinal lymphadenopathy that can become
fluctuant and drain, forming fistulae/strictures.22
Whipple’s Disease
Whipple’s disease is a rare cause of FUO and difficult to recognize.
Diagnosis should be considered in FUO cases with subacute mental
status changes, arthritis, diarrhea and weight loss. Darkening of the
skin can accompany gastrointestinal (GI) or CNS symptoms.23
Babesiosis
Babesiosis FUOs present with fever and malaise. Intraeythrocytic
inclusions, with classic ‘Maltese cross’ on peripheral smear, along with
PCR, are diagnostic.22 Babesiosis as a cause of FUO should be consid-
ered in patients with endemic area exposures or blood transfusions.
Anemia, thrombocytopenia and elevated ferritin/lactate dehydroge-
nase (LDH) are babesiosis clues.17
RHEUMATOLOGIC/INFLAMMATORY DISORDERS
Giant Cell Arteritis (GCA)/Temporal Arteritis (TA)
The most common rheumatologic cause of FUO is GCA/TA. Although
it is classically associated with headache, jaw pain, or tenderness over
the temporal artery, prolonged fevers may be the only sign of GCA/
TA.9 The fever of GCA/TA is often high and without a specific pattern.6
GCA/TA occurs in patients over the age of 50 with elevated ESR.5 A
temporal artery biopsy is diagnostic.
Systemic Lupus Erythematosus (SLE)
leukopenia is a key feature of SLE flare, leukocytosis may be reflective
of superimposed infection. Liver involvement, e.g., elevated transami-
nases or eosinophilia, argues against an SLE diagnosis.22,23
Adult Onset Still’s Disease
Adult onset Still’s disease, i.e., adult juvenile rheumatoid arthritis
(JRA), is an important cause of FUO in adults, and the only rheuma-
tologic FUO associated with marked leukocytosis (>20 x109/L). Classi-
cally, a double quotidian fever is present and often precedes arthritis.
An evanescent ‘salmon’-colored truncal rash may precede or accom-
pany fever and arthralgias.6–8 Eye findings, pauciarticular arthritis and
hepatosplenomegaly in an FUO should suggest JRA. Lymphadenopa-
thy may also be present. Rheumatoid factor and antineutrophil anti-
body (ANA) are notably negative while markedly elevated ferritin
levels are a key clue.14,22
614 SECTION 3  Special Problems in Infectious Disease Practice: Fever
Polyarteritis Nodosa (PAN)
Excluding sarcoidosis, classic ANCA-negative PAN is the only rheu-
matologic FUO with eosinophilia.22 PAN involves branch points of
medium size arteries of the heart, kidneys and mesentery but not the
CNS. PAN is more common with concurrent hepatitis B virus. Defini-
tive diagnosis is via sural nerve or kidney biopsy.15
Familial Mediterranean Fever (FMF)
FMF should be considered in patients with FUO who have a family
history of FMF. Fever episodes may be separated by weeks/months;
typically, the first episode occurs in childhood.11 While fever may be
the only clinical feature, FMF attacks are typically accompanied by
abdominal/chest pain (serositis), arthritis (large joints), or episcleri-
tis.7,8 Diagnosis rests upon genotyping for mutations in the pyrin gene
or favorable response to colchicine.
FMF is caused by one of a series of possible loss of function muta-
tions of the MEFV gene on the short arm of chromosome 16. The gene
product is called pyrin (or marenostrin) and is primarily expressed in
neutrophils. MEFV mutations are rather common in many regions of
Italy, Israel, Turkey, Armenia and the Arabian Peninsula. A pyrin/
marenostrin mutation impairs its principal function, which is to shut
off excessive activation of inflammation and cellular apoptosis initi-
ated by the inflammasome pathway.24 Unchecked inflammation arises
when ASC (the apoptosis-associated, speck-like protein with a caspase
activation and recruitment domain) is not adequately controlled by
pyrin leading to severe episodes of fever, polyserositis, lymphadenitis,
joint pain and prolonged release of acute phase protein synthesis by
the liver. Symptoms usually arise by the first decade of life and if
unrecognized and not treated with colchicine, FMF can lead to amyloid
deposition in the kidney parenchyma with progressive chronic kidney
disease.25
Kikuchi’s Disease
Histiocytic necrotizing lymphadenitis (Kikuchi’s disease) should be
considered in FUO patients with otherwise unexplained cervical
lymphadenopathy. The etiology of this disease remains unknown.
Kikuchi’s disease typically occurs in young adults predominantly of
Japanese ancestry.22 Usually self-limited, Kikuchi’s disease may mimic
TB, CSD, toxoplasmosis, or lymphoma. Cervical lymph node biopsy
is diagnostic.20
Takayasu’s Arteritis
Takayasu’s arteritis presenting as FUO has signs referable to the aortic
arch, e.g., reduced pulses or evidence of subclavian steal syndrome.16
Takayasu’s arteritis FUO may be accompanied by malaise, night
sweats, weight loss, or Raynaud’s phenomenon.22 Diagnosis is based
upon imaging/biopsy.
MISCELLANEOUS DISORDERS
Drug Fever
Drug fever is often missed as a cause of FUO due to lack of localizing
signs. Drug fever is a diagnosis of exclusion and is diagnosed by dis-
continuing the responsible medication. Drug fever patients will appear
relatively well despite fevers.12 Physical signs are lacking, often the only
clue to suggest drug fever is relative bradycardia. Nonspecific tests may
provide diagnostic clues, e.g., mild elevations in serum transaminases
and the ESR. Atypical lymphocytes (<5%) or eosinophils are often
present.22,23 After the offending drug is discontinued, fevers usually
resolve within 72 hours.
Sulfa-containing medications such as stool softeners (e.g., docu-
sate), diuretics (e.g. furosemide), antiepileptics (e.g. phenytoin), H2-
blockers, or narcotics have a high likelihood of causing drug fevers.
Among antimicrobials, β-lactams (excluding monobactams and car-
bapenems), and TMP-SMX, are frequent causes of drug fever.23 Drug
fevers are most often due to medications taken for months or years
rather than recent/new drugs.22
Alcoholic Cirrhosis and Hepatocellular Carcinoma
Patients with cirrhosis commonly have low grade fevers (<102 ° F).7,12
Serum transaminases are relatively normal but gamma-glutamyl trans-
peptidase is typically elevated. While cirrhosis itself may present as an
FUO, such patients are at risk for developing hepatoma/hepatocellular
carcinoma (HCC).23 HCC is suggested by an elevated alpha-fetoprotein
(AFP), accompanied by typical imaging and histologic findings.
Crohn’s Disease
Crohn’s disease with a paucity of GI symptoms can be an obscure FUO
diagnosis.9 Extraintestinal manifestations of Crohn’s may be the only
presenting clues, e.g., arthritis, ankylosing spondylitis, or uveitis. Such
findings may predate GI symptoms in Crohn’s disease.12
Subacute Thyroiditis
Subacute thyroiditis is frequently accompanied by low grade fever. In
an FUO the only symptom of subacute thyroiditis may be anterior neck
pain and thyroid function tests may be deceptively normal. With thy-
roiditis, the throat is normal on examination but the thyroid isthmus
is tender to palpation.11,17
Pseudolymphoma
Drug-induced pseudolymphomas may present as fever and lymph­
adenopathy. An antecedent exposure to a drug known to cause
pseudolymphoma is required.12 Phenytoin and carbamazepine are
the most frequent causes, but other drugs including antiarrhythmics
and antipsychotics have been implicated. Lymphomas must be
excluded.5,17
Factitious Fever
Factitious fever occurs typically in young adults in or having knowl-
edge of the medical field. A history of psychiatric problems is not
always present. Patients appear well, and typically do not have chills
and have relative bradycardia. Temperature curves are often erratic,
particularly if due to thermometer manipulations by the patient.12,16
Injection of nonsterile material/bacteria may accompany factitious
fevers. A detailed discussion of this cause of FUO is presented in Prac-
tice Point 21.
Cyclic Neutropenia
Cyclic neutropenia is a rare cause of FUO, and patients are symptom-
free between episodes. Fever and neutropenia recur in multiples of 7
days (most commonly 21 days). This unique fever pattern should
point to the diagnosis.22
Hereditary Periodic Fever Syndromes
Schnitzler’s syndrome should be considered in patients with monoclo-
nal gammopathy who present with fever, chronic hives, arthralgias and
hepatosplenomegaly. It is a rare disorder and may be accompanied by
intermittent bone pain.20 Hyperimmunoglobulinemia D (HIDS) is one
of the periodic fever syndromes characterized by episodes, of fever,
arthralgias, diarrhea and oral ulcerations. Highly elevated ESR with
elevation of IgD and IgA are diagnostic of HIDS.11
TNF receptor-associated periodic syndrome (TRAPS) is an autoso-
mal dominant condition formerly known as familial Hibernian fever
and occurs in patients of Scottish and Irish ancestry. These FUO
patients typically present at an early age (age 3) with abdominal pain,
pleuritic pain and arthritis. Periorbital edema and conjunctivitis help
distinguish TRAPS from other periodic fevers.15,20
The underlying etiology of TRAPS is related to point mutations
within the gene responsible for the TNF receptor TNFRF1A. Reduced
shedding of the extracellular domain of the TNF receptor in TRAPS
impairs control over TNF activity upon early activation of the innate
immune response.26 The TNF inhibitor etanercept is highly effective
in terminating periodic fever and synovitis in TRAPS patients, impli-
cating a central role of excess TNF activity in the pathogenesis of this
syndrome.27
A number of other periodic fever syndromes with onset at infancy
or early childhood have been described which are largely attributable

to gain of function mutations capable of driving uncontrolled activa-
tion of the inflammasome. These syndromes are collectively referred
to as cyropyrin-associated periodic syndromes (CAPS) as the underly-
ing defect is excess inflammation driven by cyropyrin interactions with
ASC (apoptosis-associated, speck-like protein with a caspase activation
and recruitment domain). ASC induces formation of inflammasomes
for interleukin-1 processing, apoptosis and NFkB activation.28 Some
of these syndromes have devastating clinical consequences such as
NOMID (neonatal onset multisystem inflammatory disease) in which
chronic fever, skin lesions, arthritis, chronic meningitis and cerebral
atrophy can occur.
Other cyropyrin-associated diseases include Muckle-Wells syn-
drome (fevers, synovitis, urticaria, and amyloidosis) and familiar
cold auto-inflammatory syndrome (acute onset urticaria, fever, con-
junctivitis and synovitis after exposure to cold). All these cyropyrin-
related syndromes are auto-inflammatory in nature and are driven Because there are so many causes of FUO, a focused diagnostic
by endogenous, excess interleukin-1 beta release into the circulation.
Interleukin-1 inhibitors such as IL-1 receptor antagonists (anakinra FUO workup, the clinician should be sure FUO criteria are met.17–19
or canakinumab) are specific therapies for these syndromes and All too often, the clinical approach to FUO cases is not based on clinical
can improve quality of life and prevent amyloidosis in afflicted
patients.29
FUO in Specific Populations
FUO in an immunocompromised host is best approached based on
the type/effect of the immunosuppressive medications as well as the
underlying risk factors. Patients on TNF-alpha inhibitors have a greater
risk of TB, viral hepatitis flare, listeriosis or Pneumocystis (carinii)
jirovecii pneumonia (PJP). Decreased cell-mediated immunity (CMI)
has also been associated with lymphoma.30 B-cell directed agents such
as rituximab predispose to a number of infections, typically reactiva-
tion of viruses including CMV, HBV6 JC/BK viruses.
FUO in patients having had solid organ transplant (SOT) have
several factors to be considered. Net immunosuppression and underly-
ing disease/risk factors are key elements to directing the workup. Sero-
logic status of herpes simplex virus (HSV), CMV and EBV help predict
potential post-transplant causes of FUO. FUO is most likely >6 months
post-SOT. Prior/current travel history must also be considered as this
will dictate potential reactivation infections (strongyloidiasis, coccidi-
oidomycosis, etc.).31
In the era of antiretroviral therapy (ART), FUO in the HIV popula-
tion is less common in areas where ART is available. Causes of FUO
in HIV are dictated by the CD4 count. Most HIV FUOs have a CD4
count <100/µL and are caused by opportunistic infections.32–34 HIV
itself may be responsible for the FUO. Travel and prior exposure
history is also important as it may point to endemic infections (e.g.
histoplasmosis, TB, etc).
Febrile Neutropenia
In these patients, venous catheters or ports are the common sources
of fevers. If the patient remains febrile and neutropenic after one week
of appropriate empiric antibiotic therapy, invasive fungal infection
from Candida or Aspergillus spp. should be considered.35 Serum testing
for galactomannan or 1,3 beta-D-glucan may be helpful in identifying
systemic fungal infections. Malignancies themselves may cause FUO
and predispose to thrombophlebitis.35
FUO Based on Patient Age and Travel History
In children, FUO is often associated with acute viral syndromes due
to EBV or CMV. CSD is also frequent in children with cat exposure.36
Patients presenting with arthritis/sacroiliac joint pain should be evalu-
ated for JRA. Malignancies, e.g., lymphomas, leukemias, or Wilm’s
tumor, in children are common causes of FUO. Several of the rare
periodic fever syndromes may also present initially in the pediatric
population.37
Certain FUO etiologies are more common in the elderly, including
drug fever and malignancies that increase in incidence as patients
age.38–40 GCA/TA should only be considered in older patients.41
Chapter 68  Fever of Unknown Origin (FUO) 615
In the returning traveler, the diagnostic approach is focused on
endemic disease exposures indigenous to the region travelled.42 A
careful review of food and insect exposure guides the FUO workup.43
Additionally, immunization history and prophylactic medications
should be considered.44,45
Recurrent FUOs
Patients with ≥2 episodes of prolonged fever separated by ≥2 weeks of
fever-free interval are classified as displaying recurrent FUO. Recurrent
FUO is less likely to be infectious or neoplastic and more often rheu-
matologic or FUO of a miscellaneous cause.46
Clinical Approach to FUO
CLINICAL PERSPECTIVE
approach is required for effective diagnosis.16–21 Before initiating an
clues and instead consists of a comprehensive test battery resulting in
unnecessary and misdirected laboratory testing and imaging
studies.10,13,17 The ‘history is key to the diagnosis’ principle remains the
cornerstone of the focused FUO approach.5–9,8,9,22,23 The clinician
should carefully look for helpful diagnostic clues, often present in
nonspecific laboratory tests, as the basis for further selective diagnostic
testing.47–50 Specific diagnostic tests should be used to confirm or rule
out narrowed differential diagnostic possibilities.
DETERMINING THE FUO CATEGORY
Initially, FUOs are best approached by determining the likely FUO
category, i.e., malignant/neoplastic, rheumatic/inflammatory, infec-
tious or miscellaneous causes.47,51 Excluding miscellaneous FUOs,
other FUOs nearly always present with clinical or nonspecific labora-
tory findings that narrow diagnostic possibilities.5–18,22,23,52,53 While
there may be overlap of some signs or symptoms, there are character-
istic features associated with each FUO category: e.g., malignancy/
neoplastic FUOs frequently present with early anorexia and progres-
sive weight loss (>1 kg/week).48 While weight loss may accompany
rheumatic/inflammatory or infectious FUOs, weight loss is not so
pronounced/severe and early anorexia is not a feature of infectious or
rheumatic/inflammatory FUOs. Some clinical features, i.e., ‘diagnostic
eliminators’ are helpful in ruling out some FUO categories, e.g., the
presence of chills effectively eliminates a rheumatic/inflammatory
FUO and arthralgias/myalgias argue against a malignant/neoplastic
FUO.53
Before excessive testing for unusual diagnoses, consider common/
treatable causes of FUO that present in an atypical fashion.16,17,20,21
Within the FUO category, particular attention should be given to
characteristic clinical and nonspecific laboratory features that will
increase or decrease diagnostic possibilities, e.g., an infectious disease
FUO with night sweats should suggest an occult abscess, miliary
TB, SBE or HIV.7–9,22,23 In contrast, night sweats in a patient with a
malignant/neoplastic FUO does not narrow diagnostic possibilities
since night sweats are common with many malignant/neoplastic
disorders.54–56 Night sweats argue strongly against the category of
rheumatic/inflammatory FUO.47-50,57 The narrowed diagnostic possi-
bilities are the basis of selectively ordering imaging and specific diag-
nostic tests58 (Table 68-2).
Miscellaneous FUOs are a diagnosis of exclusion.6–8,10,17 The most
common causes of miscellaneous FUOs are drug fever and cirrho-
sis.50,59,60 These entities are important to recognize not only because
of their frequency, but to avoid an extensive workup looking for
other FUO causes.18,20 Subacute thyroiditis, sarcoidosis and regional
enteritis (Crohn’s disease) are common causes of miscellaneous
FUOs in young/middle-aged adults in contrast to multiple/small
pulmonary emboli and cirrhosis which are common miscellaneous
FUO causes in the elderly.59,61 With miscellaneous FUOs, clinical
findings rather than tests provide the clues to important diagnoses,
616 SECTION 3  Special Problems in Infectious Disease Practice: Fever

TABLE
68-2  Determining the Category of FUO to Direct the Diagnostic Workup
Diagnostic Eliminators that Argue Against the
Category Suggested by Clinical Features FUO Category

MALIGNANT/NEOPLASTIC

History

• Fatigue (any neoplastic disorder) • No fatigue

• Decreased appetite/weight loss (any neoplastic disorder) • No anorexia/weight loss
• Headache (primary CNS neoplasms) • Rigors (without antipyretics)
• Night sweats (any neoplastic disorder) • Arthralgias/myalgias
• Early satiety (any malignancy with splenomegaly)
• Pruritis (after hot bath/shower)

Physical Findings

• Relative bradycardia (lymphomas) • Morning (a.m.) temperature spikes

• Sternal tenderness (preleukemias, MPDs/lymphoreticular malignancies) • Double quotidian fever
• Pleural effusion (lymphomas, pulmonary neoplasms, pulmonary or liver metastases) • Synovitis
• Heart murmur (atrial myxoma) • Costochondral tenderness
• Hepatomegaly (hematoma, metastases, lymphomas)
• Splenomegaly (leukemias, lymphomas)
• Lymphadenopathy (lymphomas, ALL)
• Epididymitis/epidymal nodule (lymphomas)

Nonspecific Laboratory Tests

• Leukocytosis (MPDs, CLL) • Atypical lymphocytes (reactive/viral lymphocytes)

• Leukopenia (lymphoreticular malignancies) • Repeatedly normal ESRs (except for
• Anemia (any malignancy) hypernephromas)
• Myelocytes /metamyelocytes, ‘teardrop RBCs’ (neoplastic bone marrow involvement) • Eosinopenia (not on steroids)
• Abnormal (small/uniform) lymphocytes (CLL) • Increased serum transaminases
• Eosinophilia (MPDs, leukemias, lymphomas) • Polyclonal gammopathy
• Basophilia (MPDs, leukemias, lymphomas)
• Thrombocytopenia (any malignancy with bone marrow involvement)
• Thrombocytosis (any malignancy)
• Highly elevated ESR >100 mm/h (any malignancy)
• Increased alkaline phosphatase (hepatoma/lymphoma, liver metastases)
• Monoclonal gammopathy (multiple myeloma, Waldenström’s macroglobulinemia)
• Increased α1/α2 globulins (lymphomas)
• Increased ferritin levels (MPDs, any malignancy)

INFECTIOUS

History

• Previous surgical procedures (abscesses, SBE) • Early decreased appetite

• Recent insect exposure/bites, malaria, ehrlichiosis/anaplasmosis • Severe weight loss (>2 lb/week)
• IVDA/blood transfusions (CMV, HIV) • Pruritis (after hot bath/shower)
• Travel (typhoid/enteric fever, Legionnaire’s disease, brucellosis, HIV, malaria, Q fever)
• Fatigue (any chronic infection)
• Weight loss (abscesses, HIV, miliary TB, SBE)
• Night sweats (abscesses, HIV, miliary TB, SBE)
• Headaches (typhoid enteric fever, miliary TB, brucellosis, HIV)
• Mental confusion (brucellosis, miliary TB, Whipple’s disease, HIV, CSD)
• CVA (miliary TB, SBE)
• Tongue pain (relapsing fever)
• Arthralgias (LGV, Whipple’s disease, rat bite fever, brucellosis, HIV)
• Heart murmur (SBE)
• Back pain (miliary TB, brucellosis, SBE)
• Thigh pain (brucellosis)
• Early satiety (brucellosis, splenic abscess, typhoid/enteric fever)
• Animal contact (brucellosis, typhoid/enteric fever, Q fever, CSD, rat bite fever)

Physical Findings

• Relative bradycardia (typhoid/enteric fever, leptospirosis, brucellosis, malaria, Legionnaire’s disease, • Extreme hyperpyrexia (>106 °F [41.1 °C])
trichinosis) • Sternal tenderness (without recent sternotomy)
• Conjunctival suffusion (relapsing fever) • Monoclonal gammopathy (excluding CMV)
• Subconjunctival hemorrhage (SBE)
• Regional adenopathy (toxoplasmosis, CSD, HIV)
• Generalized (HIV, EBV, miliary TB, CMV, LGV, brucellosis)
• Heart murmur (SBE)
• Spinal tenderness (SBE, brucellosis, typhoid/enteric fever)
• Hepatomegaly (relapsing fever, typhoid/enteric fever, Q fever)
• Splenomegaly (miliary TB, SBE, brucellosis, EBV, CMV, relapsing fever, typhoid/enteric fever)
• Epididymitis/epididymal nodule (miliary TB, brucellosis, leptospirosis, EBV)
• Arthritis (rat bite fever, brucellosis, osteomyelitis, typhoid/enteric fever, Whipple’s disease)
 Chapter 68  Fever of Unknown Origin (FUO) 617

TABLE
68-2  Determining the Category of FUO to Direct the Diagnostic Workup (Continued)
Diagnostic Eliminators that Argue Against the
Category Suggested by Clinical Features FUO Category

Nonspecific Laboratory Findings

• Leukopenia (HIV, miliary TB, brucellosis, typhoid/enteric fever) • Myelocytes/metamyelocytes
• Lymphopenia (HIV, miliary TB) • Basophilia
• Lymphocytosis (miliary TB, EBV, CMV, toxoplasmosis) • Abnormal lymphocytes (not atypical/reactive viral
• Monocytosis (SBE, miliary TB, brucellosis, CMV) lymphocytes)
• Atypical lymphocytes (toxoplasmosis, CMV, EBV)
• Eosinophilia (trichinosis)
• Eosinopenia (typhoid/enteric fever)
• Thrombocytopenia (HIV, CMV, relapsing fever, malaria, babesiosis, ehrlichiosis/anaplasmosis)
• Thrombocytosis (abscess, osteomyelitis, SBE, miliary TB)
• Highly elevated ESR >100 mm/h (abscess, osteomyelitis, SBE)
• Subnormal ESR <10 mm/h (trichinosis)
• Rheumatoid factors (SBE)
• Polyclonal gammopathy (HIV)
• Increased serum transaminases (EBV, CMV, Q fever, toxoplasmosis, relapsing fever, brucellosis)
• Increased alkaline phosphatase (miliary TB)

RHEUMATIC/INFLAMMATORY

History
• Previous or FMH of arthritis • Rigors (without antipyretics)
• Dry eyes (LORA, SLE) • Anorexia (early)
• Watery eyes (PAN) • Severe weight loss (>2 lb/week)
• Vision disorders/eye pain (Takayasu’s arteritis, GCA/TA)
• Headache (GCA/TA)
• Neck/jaw pain (adult Still’s disease [JRA])
• Dry cough (GCA/TA)
• Abdominal pain (PAN, SLE)
• Myalgias/arthralgias (PAN, adult Still’s disease [JRA], LORA, SLE)

Physical Findings
• Band keratopathy (adult Still’s disease [JRA]) • Relative bradycardia
• Uveitis (adult Still’s disease [JRA], sarcoidosis, SLE)
• Dry eyes (LORA, SLE)
• Watery eyes (PAN)
• Cytoid bodies in fundus (SLE)
• Candle wax drippings fundi (sarcoidosis)
• Lymphadenopathy (Kikuchi’s disease, adult Still’s disease [JRA])
• Splenomegaly (SLE, LORA, adult Still’s disease [JRA], sarcoidosis, Kikuchi’s disease)
• Epididymitis/epididymal nodule (PAN)

Nonspecific Laboratory Tests

• Leukocytosis (adult Still’s disease [JRA]) • Atypical lymphocytes (reactive/viral lymphocytes)
• Eosinophilia (sarcoidosis, PAN) • Abnormal lymphocytes (not atypical/reactive viral
• Thrombocytopenia (SLE) lymphocytes)
• Highly elevated ESR >100 mm/h (any rheumatic disorder) • Eosinopenia (not on steroids)
• Increased serum transaminases (adult Still’s disease [JRA], Kikuchi’s disease) • Monoclonal gammopathy (excluding CMV)
• Increased alkaline phosphatase (PAN)
• Polyclonal gammopathy (SLE)
• Increased α1/α2 globulins (SLE)
• Increased ferritin levels (adult Still’s disease [JRA], SLE, GCA/TA)
MISCELLANEOUS CAUSES
History
• Alcoholism (cirrhosis) • Firm diagnosis in another FUO category
• Medications (drug fever, pseudolymphoma)
• Shortness of breath (pulmonary emboli)
• Abdominal pain (FMF, regional enteritis [Crohn’s disease], ulcerative colitis)
• Neck pain (subacute thyroiditis)
• Hyperlipidemia (hypertriglyceridemia)
• Always well appearing (factitious fever, drug fever)
• Well appearing [between attacks] (FMF, cyclic neutropenia)
• FMH positive for recurrent fevers (familial periodic fever syndromes)
Nonspecific Laboratory Tests
• Leukocytosis (drug fever, cirrhosis, pulmonary emboli)
• Leukepenia (cirrhosis)
• Leukopenia [during fever] (cyclic neutropenia)
• Eosinophilia (drug fever, pseudolymphoma, regional enteritis [Crohn’s disease], ulcerative colitis)
• Increased alkaline phosphatase (ulcerative colitis)
• Increased ESR (drug fever, pulmonary emboli, regional enteritis [Crohn’s disease], ulcerative colitis)
Physical Findings
• Relative tachycardia (pulmonary emboli)
• Relative bradycardia (drug fever, factitious fever)
• Thyroid tenderness (subacute thyroiditis)
• Wheezing (pulmonary emboli)
• Adenopathy (pseudolymphoma, Rosai–Dorfman disease, ECD disease)
• Splenomegaly (cirrhosis)

For abbreviations, see Table 68-1.

Adapted from Cunha C.B.: Infectious disease differential diagnosis. In: Cunha B.A., ed. Antibiotic essentials, 14th ed. New Delhi: Jaypee Brothers Medical Publishers;
2015:474–506.
618 SECTION 3  Special Problems in Infectious Disease Practice: Fever

e.g., factitious fever, habitual hyperthermia, cirrhosis and drug
fever.7–10,17,18,50,60 The antibiotics most often causing drug fevers are
β-lactams (not carbapenems) and sulfa-containing antibiotics (TMP-
SMX [trimethoprim–sulfamethoxazole]).22,23
DIAGNOSTIC APPROACH TO FUO WITH
LOCALIZING SIGNS
The workup priority in each FUO category should be given to diagno-
ses of serious disorders or potential reversible/curable disorders.5,11,12,17,18
Characteristic symptoms and physical findings and nonspecific labora-
tory tests determine the pattern of organ involvement.22,23,50 Since
all diseases have a characteristic pattern of organ involvement (POI),
determining the POI itself narrows diagnostic possibilities, e.g., (Table 68-3).
an FUO with conjunctival suffusion, muscle tenderness, with an
un-elevated ESR and eosinophilia, points to trichinosis.22,23
Diagnostic Significance of Physical
Examination Clues
The consultant should give attention to organ system manifestations
of FUO that may have been missed, were transient or were previously
undetectable. The high yield areas of FUO on physical examination
are the eyes, mouth, lymph nodes, liver, spleen and skin.62,63 The
cluster of abnormal findings determines the POI, thereby narrowing
diagnostic possibilities, e.g., an FUO with episcleritis, pauciarticular
arthritis and splenomegaly should suggest the possibility of JRA64

TABLE
68-3  Physical Finding Clues by FUO Category
General Appearance

Erythroderma Malignant/neoplastic: Lymphoma

Infectious: Leukemia (HTLV-1)
Miscellaneous: Drugs

Hyperpigmentation Infectious: Visceral leishmaniasis (kala-azar), Whipple’s disease, histoplasmosis

Miscellaneous: Drugs

Head Abnormalities

Long eyelashes Infectious: Visceral leishmaniasis (kala-azar), trypanosomiasis

Miscellaneous: HIV drugs

Lacrimal gland enlargement Infectious: Miliary TB

Rheumatic/inflammatory: RA, SLE, sarcoidosis

Parotid enlargement Infectious: Rat bite fever (Streptobacillus moniliformis)

Rheumatic/inflammatory: Sarcoidosis
Miscellaneous: Cirrhosis

Eye Abnormalities

Iritis Infectious: Relapsing fever

Rheumatic/inflammatory: SLE, Behçet’s syndrome, LORA

Conjunctivitis Infectious: LGV, relapsing fever

Rheumatic/inflammatory: Adult Still’s disease (JRA)

Conjunctival suffusion Infectious: Leptospirosis, relapsing fever, ehrlichiosis/anaplasmosis, trichinosis

Episcleritis Infectious: Miliary TB

Rheumatic/inflammatory: Sarcoidosis, LORA, adult Still’s disease (JRA), SLE, PAN, GCA/TA
Miscellaneous: Regional enteritis (Crohn’s disease)

Uveitis Infectious: Miliary TB, histoplasmosis, malaria, LGV, CMV, brucellosis, leptospirosis, CSD
Rheumatic/inflammatory: Adult Still’s disease (JRA), SLE, PAN, sarcoidosis, Behçet’s syndrome, LORA

Keratitis Infectious: Miliary TB, toxoplasmosis, histoplasmosis, CMV

Rheumatic/inflammatory: Behçet’s syndrome

Chorioretinitis Infectious: Toxoplasmosis, CMV, histoplasmosis, TB, coccidioidomycosis, leptospirosis

Rheumatic/inflammatory: Sarcoidosis, SLE, PAN

Cytoid bodies (cotton wool spots) Malignant/neoplastic: Atrial myxoma

Infectious: CSD, HIV, CMV, SBE
Rheumatic/inflammatory: SLE, GCA/TA, Adult Still’s disease (JRA), PAN

Roth spots Malignant/neoplastic: Leukemia, atrial myxoma

Infectious: SBE, malaria
Rheumatic/inflammatory: PAN, SLE, GCA/TA, Takayasu’s arteritis

Periphlebitis (candle wax drippings) Infectious: CMV, leptospirosis

Rheumatic/inflammatory: Sarcoidosis

Mouth Abnormalities

Oral ulcers Infectious: CMV, histoplasmosis, miliary TB, brucellosis

Rheumatic/inflammatory: SLE, Behçet’s syndrome, hyper-IgE syndrome
Miscellaneous: FAPA syndrome, cyclic neutropenia

Back Abnormalities

Spinal tenderness Malignant/neoplastic: Multiple myeloma

Infectious: Vertebral osteomyelitis, typhoid/enteric fever, miliary TB, brucellosis, SBE
 Chapter 68  Fever of Unknown Origin (FUO) 619

TABLE
68-3  Physical Finding Clues by FUO Category (Continued)

Heart Abnormalities

Pericardial effusion Infectious: Miliary TB

Rheumatic/inflammatory: SLE

Heart murmur Malignant/neoplastic: Atrial myxoma, marantic endocarditis

Infectious: SBE
Rheumatic/inflammatory: Takayasu’s arteritis, SLE (Libman–Sacks)

Abdominal Abnormalities

Hepatomegaly Malignant/neoplastic: Pancreatic cancer, hepatoma, liver metastases

Infectious: Liver abscess, ehrlichiosis/anaplasmosis, malaria, babesiosis, brucellosis, leptospirosis, typhoid/enteric fever,
Q fever, EBV, CMV, HIV
Miscellaneous: Cirrhosis

Splenomegaly Malignant/neoplastic: Systemic mastocytosis, angioblastic lymphadenopathy, lymphoma, MPDs

Infectious: Malaria, dengue fever, visceral leishmaniasis (kala-azar), SBE, ehrlichiosis/anaplasmosis, babesiosis, typhoid/
enteric fever, leptospirosis, EBV, CMV, relapsing fever, toxoplasmosis, brucellosis, Q fever, CSD, histoplasmosis,
miliary TB, HIV
Rheumatic/inflammatory: SLE, sarcoidosis, RA (Felty’s syndrome)
Miscellaneous: Regional enteritis (Crohn’s disease)

Hepatosplenomegaly Malignant/neoplastic: Hypernephroma (RCC)

Infectious: Malaria, typhoid/enteric fever, brucellosis, visceral leishmaniasis (kala-azar), EBV, CMV, HIV, toxoplasmosis,
relapsing fever, CSD, histoplasmosis, miliary TB, babesiosis, ehrlichiosis/anaplasmosis, Q fever
Rheumatic/inflammatory: Sarcoidosis

Lymph Node Abnormalities

Preauricular adenopathy Malignant/neoplastic: Lymphoma

Infectious: Rat bite fever (Spirillum minus), CSD

Occipital adenopathy Malignant/neoplastic: Lymphoma

Infectious: CSD

Anterior cervical adenopathy Malignant/neoplastic: Lymphoma

Infectious: Toxoplasmosis, CSD, brucellosis
Rheumatic/inflammatory: SLE, Kikuchi’s disease

Posterior cervical adenopathy Malignant/neoplastic: Lymphoma

Infectious: Toxoplasmosis, EBV, CMV
Rheumatic/inflammatory: Sarcoidosis

Supraclavicular adenopathy Malignant/neoplastic: Lymphoma

Infectious: Miliary TB, CSD

Epitrochlear adenopathy Infectious: CSD, brucellosis

Rheumatic/inflammatory: Sarcoidosis

Generalized lymphadenopathy Malignant/neoplastic: ALL

Infectious: Miliary TB, EBV, CMV, toxoplasmosis, CSD, LGV, brucellosis, HIV, visceral leishmaniasis (kala-azar),
Whipple’s disease
Rheumatic/inflammatory: SLE, RA, adult Still’s disease, Gaucher’s disease, sarcoidosis, Kikuchi’s disease
Miscellaneous: Pseudolymphoma (Dilantin)

Genitourinary Abnormalities

Epididymitis/epidymal nodule Malignant/neoplastic: Lymphoma

Infectious: Miliary TB, blastomycosis, brucellosis, leptospirosis, EBV, rat bite fever (Spirillum minus), relapsing fever
Rheumatic/inflammatory: SLE, PAN, sarcoidosis
Miscellaneous: FMF

Extremity Abnormalities

Splinter hemorrhages Malignant/neoplastic: Atrial myxoma, AML, ALL

Infectious: SBE, trichinosis
Rheumatic/inflammatory: LORA

Tender fingertips Infectious: SBE, typhoid/enteric fever

Rheumatic/inflammatory: SLE

Erythema nodosum Malignant/neoplastic: Lymphoma

Infectious: Miliary TB, EBV, LGV, histoplasmosis, CSD
Rheumatic/inflammatory: Sarcoidosis
Miscellaneous: Drugs, ulcerative colitis (UC), regional enteritis (Crohn’s disease)

Neurological Abnormalities

Mental confusion Malignant/neoplastic: CNS metastases

Infectious: Trichinosis, brucellosis, SBE, HIV, CSD, Whipple’s disease, Q fever
Rheumatic/inflammatory: Behçet’s syndrome, SLE
Optic nerve atrophy Infectious: Miliary TB, toxoplasmosis
Rheumatic/inflammatory: Sarcoidosis, GCA/TA, Behçet’s syndrome, SLE, PAN

For abbreviations, see Table 68-1.

Adapted from Cunha C.B.: Infectious disease differential diagnosis. In: Cunha B.A., ed. Antibiotic essentials, 14th ed. New Delhi: Jaypee Brothers Medical Publishers;
2015:474–506.
620 SECTION 3  Special Problems in Infectious Disease Practice: Fever

Diagnostic Significance of Nonspecific cultures are clinically irrelevant in malignant/neoplastic, rheumatic/

Laboratory Test Clues
Since patients with FUOs, by definition, have been undiagnosed for >3
weeks of comprehensive diagnostic testing, many nonspecific tests are
available for evaluation.63–66 Because nonspecific tests are, by defini-
tion, nonspecific, the diagnostic specificity of nonspecific tests is
enhanced by the degree of abnormality.47,50 A mild/moderately ele-
vated ESR is not very helpful diagnostically, but if the ESR is highly
elevated (>100 mm/h), then diagnostic possibilities are narrowed to
relatively few disorders.23,63 Diagnostic specificity of nonspecific tests
is also increased by the company they keep: in the infectious disease
FUO category, an elevated ESR and alkaline phosphatase should
suggest the possibility of miliary TB, whereas the same findings in a
malignant/neoplastic FUO suggest hepatoma, lymphoma, hyperne-
phroma or liver metastases.63,65 The pattern of nonspecific test abnor-
malities, not the individual nonspecific tests, has diagnostic significance.
The more key nonspecific findings present, the more probable the
diagnosis suggested by the constellation of abnormal nonspecific labo-
ratory findings.22,23,63–66 ESR is of most diagnostic benefit if highly
elevated (>100 mm/h).63 However, an un-elevated ESR may rarely
occur with malignancies, e.g., RCC.54 In a lymphoma with a normal
ESR, other clues are present, e.g., elevated alkaline phosphatase, ele-
vated ferritin, B12 and LDH may point to the diagnosis.63 Some non-
specific laboratory tests have exclusionary diagnostic value, e.g., an
FUO due to possible typhoid/enteric fever is diagnostically eliminated
by eosinophilia.63,64
Since there are so many causes of FUO, diagnostic algorithms place in the FUO workup, particularly when the differential diagnosis
are unhelpful and often misleading.17,18,22 Comprehensive/excessive
laboratory testing, usually justified on the basis of completeness,
should be avoided. There are no specific tests that should be routinely
ordered in all FUOs.16,22,50 SBE remains common in clinical practice,
yet has become a rare cause of FUO.11,13,15,67 For this reason,
blood cultures should not be routinely obtained in all FUOs. Blood
inflammatory or miscellaneous FUOs. With infectious FUOs,
blood cultures document bacteremia, e.g., typhoid fever, brucellosis
(Table 68-4).
Imaging Studies
Imaging studies are no substitute for an FUO-focused history
and physical examination and carefully considered nonspecific labora-
tory tests based on likely diagnostic possibilities. However, imaging
tests may be helpful in several ways. First, each FUO disorder has a
characteristic POI and imaging studies are helpful in determining the
POI, which often limits differential diagnostic possibilities.68–70 If
rheumatic/inflammatory FUO clues include lymph nodes, spleen and
kidneys, but spares the liver, this POI in the rheumatic/inflammatory
FUO category suggests systemic lupus erythematosus (SLE).17,18
Imaging tests are helpful in localizing organ involvement for definitive
pathologic diagnosis on biopsy.68 Imaging studies also have an exclu-
sionary role in the FUO workup, e.g., hypernephromas or intra-
abdominal abscesses are effectively ruled out by negative imaging
studies. An FUO with increased splenic uptake of gallium or indium
may suggest an otherwise unsuspected EBV, CMV or lymphoma.69,70
If osteomyelitis is suspected, a bone or gallium scan is preferred.
Indium scans should be avoided because of false-negative results in
osteomyelitis. Unlike gallium scans, indium scans may also be falsely
negative with malignancies.53,69,70
Positron emission tomography (PET) scans have an important
is between infectious, malignant/neoplastic and rheumatic/
inflammatory disorders. PET scans may provide an otherwise unex-
pected clue in obscure FUOs, e.g., increased blood vessel uptake may
suggest an aortic graft infection, large vessel vasculitis, or intravascular
B-cell lymphoma. An increased cardiac uptake on PET scan may be
the only clue pointing to the diagnosis of Q fever endocarditis.71–75

TABLE
68-4  Laboratory Clues by FUO Category
WBC Abnormalities

Leukocytosis Infectious: Most infections

Rheumatic/inflammatory: Adult Still’s disease (JRA)
Miscellaneous: Drug fever

Leukopenia Malignant/neoplastic: Leukemias

Infectious: Miliary TB, typhoid/enteric fever, malaria, brucellosis, visceral leishmaniasis (kala-azar), EBV, CMV, histoplasmosis,
relapsing fever, ehrlichiosis/anaplasmosis
Rheumatic/inflammatory: RA (Felty’s syndrome), Gaucher’s disease, SLE, sarcoidosis
Miscellaneous: Cyclic neutropenia

Relative lymphocytosis Malignant/neoplastic: ALL, lymphomas, carcinomas, multiple myeloma

Infectious: Whipple’s disease, miliary TB, brucellosis, histoplasmosis, EBV, CMV, visceral leishmaniasis (kala-azar),
toxoplasmosis, typhoid/enteric fever
Rheumatic/inflammatory: LORA

Relative lymphopenia Malignant/neoplastic: Lymphoma, cirrhosis

Infectious: CMV, HIV, miliary TB, typhoid/enteric fever, Q fever, brucellosis, malaria, babesiosis, histoplasmosis, ehrlichiosis/
anaplasmosis, Whipple’s disease
Rheumatic/inflammatory: Sarcoidosis, SLE, LORA
Miscellaneous: Cirrhosis

Monocytosis Malignant/neoplastic: MPDs, lymphomas

Infectious: Miliary TB, SBE, histoplasmosis, brucellosis, visceral leishmaniasis (kala-azar), malaria, typhoid/enteric fever,
babesiosis, EBV, CMV
Rheumatic/inflammatory: Sarcoidosis, Gaucher’s disease, RA, SLE, PAN, GCA/TA
Miscellaneous: Regional enteritis (Crohn’s disease), ulcerative colitis

Atypical lymphocytes Infectious: EBV, CMV, toxoplasmosis, brucellosis, malaria, babesiosis, ehrlichiosis/anaplasmosis
Miscellaneous: Drug fever

Eosinophilia Malignant/neoplastic: Lymphomas, MPDs

Infectious: Trichinosis, histoplasmosis, coccidioidomycosis
Rheumatic/inflammatory: PAN, sarcoidosis
Miscellaneous: Hyper-IgE syndrome, drug fever, regional enteritis (Crohn’s disease), ulcerative colitis

Basophilia Malignant/neoplastic: Preleukemia (AML), acute leukemias, lymphomas, MPDs


TABLE
68-4  Laboratory Clues by FUO Category (Continued)
RBC Abnormalities
Erythrophagocytosis
Platelet Abnormalities
Thrombocytopenia
Thrombocytosis
Pancytopenia
Serum Test Abnormalities
Erythrocyte sedimentation
rate (highly elevated)
SPEP (polyclonal
gammopathy)
SPEP (monoclonal
gammopathy)
Elevated ferritin levels
(highly elevated)
Elevated cold agglutinins
Elevated lactate
dehydrogenase (LDH)
Liver Test Abnormalities
Elevated alkaline
phosphatase (AP) (mildly
elevated)
Elevated serum
transaminases (SGOT/
SGPT) (mildly elevated)
Elevated GGT (GGTP)
Rheumatic Test Abnormalities
Elevated rheumatoid
factors (RF)
Elevated antinuclear
antibody titers (ANA)
Elevated angiotensin-
converting enzyme
levels (ACE)
For abbreviations, see Table 68-1.
Adapted from Cunha C.B.: Infectious disease differential diagnosis. In: Cunha B.A., ed. Antibiotic essentials, 14th ed. New Delhi: Jaypee Brothers Medical Publishers;
2015:474–506.
Chapter 68  Fever of Unknown Origin (FUO) 621
Malignant/neoplastic: Lymphomas, acute leukemias, multiple myeloma, MPDs
Infectious: HIV, EBV, CMV, malaria, babesiosis, toxoplasmosis, visceral leishmaniasis (kala-azar), histoplasmosis, typhoid/enteric
fever, SBE, Q fever, miliary TB, brucellosis
Rheumatic/inflammatory: SLE, necrotic sarcoidosis, LORA, macrophage activation syndrome (MAS)
Malignant/neoplastic: Leukemias, lymphomas, carcinomas, MPDs, multiple myeloma
Infectious: EBV, CMV, ehrlichiosis/anaplasmosis, malaria, babesiosis, histoplasmosis, visceral leishmaniasis (kala-azar), HIV,
miliary TB, relapsing fever, brucellosis
Rheumatic/inflammatory: Gaucher’s disease
Miscellaneous: Drugs, cirrhosis
Malignant/neoplastic: Malignancies, MPDs, lymphomas
Infectious: Miliary TB, chronic infections (e.g., osteomyelitis, abscess), SBE, Q fever
Rheumatic/inflammatory: GCA/TA, PAN
Miscellaneous: Drugs
Infectious: Miliary TB, brucellosis, histoplasmosis, ehrlichiosis/anaplasmosis, MV, HIV
Rheumatic/inflammatory: Gaucher’s disease, sarcoidosis, SLE
Malignant/neoplastic: Malignancies
Infectious: SBE, osteomyelitis, abscess, Q fever
Rheumatic/inflammatory: GCA/TA, adult Still’s disease (JRA), PAN
Miscellaneous: Cirrhosis, drug fever
Malignant/neoplastic: Atrial myxoma
Infectious: HIV, malaria, visceral leishmaniasis (kala-azar), LGV, rat bite fever, Q fever
Rheumatic/inflammatory: SLE, PAN, Takayasu’s arteritis
Miscellaneous: Cirrhosis
Malignant/neoplastic: Multiple myeloma, Waldenström’s macroglobulinemia
Infectious: CMV, visceral leishmaniasis (kala-azar), typhoid/enteric fever
Malignant/neoplastic: Preleukemias (AML), lymphomas, multiple myeloma, Waldenström’s macroglobulinemia, hepatomas,
liver/CNS metastases
Infectious: EBV, CMV, malaria, ehrlichiosis/anaplasmosis, HIV, miliary TB
Rheumatic/inflammatory: RA, adult Still’s disease (JRA), SLE, GCA/TA, Kawasaki disease
Miscellaneous: Cirrhosis, macrophage activation syndrome (MAS) (see Practice Point 22)
Malignant/neoplastic: Lymphomas, multiple myeloma, Waldenström’s macroglobulinemia
Infectious: EBV, CMV, malaria, Q fever, HIV, Mycoplasma pneumoniae
Rheumatic/inflammatory: SLE
Malignant/neoplastic: Malignancies
Infectious: Malaria, babesiosis, ehrlichiosis/anaplasmosis, SBE, histoplasmosis, miliary TB, toxoplasmosis, trichinosis, CMV
Rheumatic/inflammatory: Adult Still’s disease (JRA)
Miscellaneous: Pulmonary emboli
Malignant/neoplastic: Multiple myeloma, pre-/acute leukemias, liver metastasis, lymphomas, carcinomas
Infectious: Liver abscess, EBV, CMV, Q fever, ehrlichiosis/anaplasmosis, malaria, histoplasmosis, HIV, miliary TB, relapsing fever
Rheumatic/inflammatory: Gaucher’s disease
Miscellaneous: Cirrhosis, ulcerative colitis, drug fever
Infectious: Q fever, relapsing fever, brucellosis, ehrlichiosis/anaplasmosis, liver abscess, EBV, CMV, malaria
Rheumatic/inflammatory: Adult Still’s disease (JRA)
Miscellaneous: Drug fever, cirrhosis, ulcerative colitis
Malignant/neoplastic: Hepatoma, liver metastases, hypernephroma (RCC)
Infectious: EBV
Miscellaneous: Cirrhosis
Malignant/neoplastic: Malignancy
Infectious: SBE, miliary TB, visceral leishmaniasis (kala-azar), EBV, typhoid/enteric fever
Rheumatic/inflammatory: Sarcoidosis, LORA, Behçet’s disease, SLE
Miscellaneous: Cirrhosis
Infectious: HIV, EBV, CMV, TB, SBE, visceral leishmaniasis (kala-azar), malaria
Rheumatic/inflammatory: SLE, LORA, sarcoidosis
Malignant/neoplastic: Multiple myeloma, lymphoma
Infectious: Miliary TB, coccidioidomycosis
Rheumatic/inflammatory: Gaucher’s disease
Miscellaneous: Cirrhosis
622 SECTION 3  Special Problems in Infectious Disease Practice: Fever

TABLE Differential Diagnosis of FUO with No TABLE Usual Diagnostic Fever Ranges by FUO
68-5  Localizing Signs 68-6  Category

Malignant/Neoplastic FUO Causes with Fevers Usually <101 °F (38.3 °C)

Lymphomas Intravascular Malignant/neoplastic Multiple myeloma, Waldenström’s
Hypernephromas Large B-cell lymphoma macroglobulinemia, systemic
Preleukemia (AML) mastocytosis, colon cancer (without
MPDs perforation/abscess), pancreatic cancer
(without perforation/abscess)
Infectious
Miliary TB Aortic graft infection Infectious Any infectious disease presenting as FUO
Brucellosis Whipple’s disease
Q fever Castleman’s disease (MCD) Rheumatic/inflammatory Sarcoidosis, RA (Felty’s syndrome), LORA,
Typhoid/enteric fever Malaria Gaucher’s disease
CMV Babesiosis
HIV Ehrlichiosis/anaplasmosis Miscellaneous Cirrhosis, ulcerative colitis,
hypertriglyceridemia (type V),
Rheumatic/Inflammatory hypothalamic dysfunction, habitual
hyperthermia
GCA/TA
PAN FUO Causes with Fevers Usually 101–102 °F (38.3–38.9 °C)
SLE
Sarcoidosis Malignant/neoplastic Hepatomas, liver metastases, CNS
APS metastases, atrial myxomas, MPDs,
AML, ALL, MCD, angioimmunoblastic
Miscellaneous lymphadenitis
Drug fever Cyclic neutropenia
Pulmonary emboli Hypertriglyceridemia (type V) Infectious Any infectious disease presenting as an
Factitious fever FUO
Regional enteritis (Crohn’s disease) Rheumatic/inflammatory GCA/TA, PAN/MPA, Takayasu’s arteritis,
Ulcerative colitis (UC) Kikuchi’s disease, Beçhet’s disease,
FAPA syndrome, APS, gout,
For abbreviations, see Table 68-1.
pseudogout
Adapted from Cunha C.B., Cunha B.A.: Fever of unknown origin (FUO). In:
Schlossberg D., ed. Clinical infectious disease, 2nd ed. Cambridge: Miscellaneous Subacute thyroiditis, regional enteritis
Cambridge University Press; 2015:1–9. (Crohn’s disease), pulmonary emboli
(small/multiple), pseudolymphomas,
cyclic neutropenia, Rosai–Dorfman
disease, ECD, familial periodic fevers
Additional Nonspecific Tests with FUO Relevance
It is difficult to differentiate infectious from malignant/neoplastic FUO Causes of Fevers Usually >102 °F (38.9 °C)
FUOs. In this differential diagnosis, the Naprosyn test may be useful Malignant/neoplastic Lymphoma, hypernephroma (RCC),
in the diagnostic workup.76,77 Naproxen 375 mg (PO) q12h given x3 preleukemia (AML)
days results in a prompt decrease in temperature if the underlying Infectious Typhoid/enteric fevers, intra/perinephric
cause is a malignant/neoplastic FUO (vs infection). However, the abscesses, intra-abdominal/pelvic
Naprosyn test has no differential diagnostic usefulness for other FUO abscesses, visceral leishmaniasis
causes. (kala-azar)
The incidence of SBE has decreased and SBE has become a rare Rheumatic/inflammatory SLE, adult Still’s disease (JRA)
cause of FUO. The role of echocardiography in FUO depends on the Miscellaneous Drug fever, factitious fever
probability of cardiac involvement in the FUO category being consid-
ered. In an FUO, cardiac echocardiology is indicated if bacteremia is For abbreviations, see Table 68-1.
present (due to an endocarditis pathogen) and/or if signs of SBE are Adapted from Cunha C.B., Cunha B.A.: Fever of unknown origin (FUO). In:
Schlossberg D., ed. Clinical infectious disease, 2nd ed. Cambridge:
present. If prosthetic valve endocarditis (PVE) is suspected, TEE is Cambridge University Press; 2015:1–9.
preferred. Diagnosis of SBE is based on the presence of a cardiac veg-
etation with bacteremia due to an SBE pathogen.17,18,22 A cardiac veg-
etation on TTE/TEE with negative blood cultures is not diagnostic of emboli) are <102 °F (38.9°C) (Table 68-6). Since nearly all infectious
culture-negative endocarditis (CNE). CNE may be defined as negative diseases manifest with evening/night temperature spikes, morning
blood cultures with a cardiac vegetation and signs of SBE. For clinical temperature spikes have important diagnostic significance. In an
purposes, CNE may be regarded as infectious or noninfectious. obscure FUO, morning temperature spikes limit diagnostic possibili-
Common causes of FUOs presenting as infectious CNE are Q fever ties to typhoid fever, TB, Whipple’s disease and PAN.50,63 Unusual fever
and brucellosis.22,23,50 patterns may be the only clue to obscure FUOs.78,79
More helpful in FUO diagnosis are characteristic fever curves.80,81
DIAGNOSTIC APPROACH TO FUO WITHOUT It is critical to recognize that adult Still’s disease (JRA) has a charac-
LOCALIZING SIGNS teristic double quotidian fever pattern (while also bearing an intermit-
The most diagnostically challenging FUOs are those without localizing tent fever, which is diagnostically unhelpful).64 A double quotidian
signs. Fever patterns should be carefully reviewed for fever height, fever (not antipyretic induced) limits FUO possibilities to very few
frequency, as well as diagnostic fever patterns5–9,12,14,22 (Table 68-5). disorders, e.g., malarial, infections, visceral leishmaniasis (kala-azar)
and adult Still’s disease (JRA)53,63 (Table 68-7). Since fever curves are
Diagnostic FUO Fever Curves diagnostically most helpful in obscure or diagnostically difficult FUOs,
The more obscure the cause of the FUO, the more diagnostically antimicrobials and antipyretics should be avoided until a definitive
helpful are fever patterns in suggesting or excluding certain FUO dis- diagnosis is made.22,53
orders, e.g., the lack of relative bradycardia effectively rules out typhoid/
enteric fever, excluding patients on beta-blockers, diltiazem, or vera- Key Nonspecific FUO Tests
pamil.60 The degree of fever elevation is also useful in excluding certain In FUOs without localizing signs four key FUO tests (ESR, serum fer-
FUO disorders, e.g., the fevers of bland pulmonary emboli (not septic ritin, alkaline phosphatase and rheumatoid factors) often prove
 Chapter 68  Fever of Unknown Origin (FUO) 623

helpful. These tests if abnormal, considered together, can be helpful in FUOs, antinuclear antibody, double-stranded DNA, cytoplasmic anti-
suggesting or narrowing diagnostic possibilities.22,23,36,46,82 Highly ele- neutrophil cytoplasmic antibodies, perinuclear antineutrophil cyto-
vated ESR with an elevated alkaline phosphatase suggests possible plasmic antibodies and antiphospholipid antibodies (APL) are useful.
PAN, but if ferritin levels are also highly elevated, then adult Still’s For miscellaneous FUOs, an elevated GGT may point to otherwise
disease (JRA) becomes a diagnostic consideration.57 unsuspected cirrhosis or a hypernephroma (RCC).83–85 In an FUO
Beside the nonspecific tests for FUO, B12, LDH, uric acid and without localizing signs, a gallium or indium scan may be helpful in
angiotensin-converting enzyme (ACE) levels often are helpful in the detecting otherwise unsuspected organ involvement, e.g., abscesses,
malignant/neoplastic FUO category. With rheumatic/inflammatory shunt/graft infections, or retroperitoneal adenopathy. Computed
tomography (CT) and magnetic resonance (MR) scans should not be
TABLE
done routinely as part of the FUO workup, but should be based on
68-7  Diagnostic Fever Patterns by FUO Category* clinical clues pointing to an anatomical region, e.g., if regional enteritis
(Crohn’s disease) is suspected. Scans are also useful to define the FUO
Fever Patterns FUO Associations pathology, i.e., location/extent of liver abnormalities. In FUO, PET
Morning (a.m.) Infectious: Miliary TB, typhoid/enteric fever, scans are most useful for malignancies, localized infections or
temperature Whipple’s disease rheumatic/inflammatory disorders77–80 (Table 68-8).
spikes Rheumatic/inflammatory: PAN
Miscellaneous: Factitious fever FUO Invasive Diagnostic Tests
Relative tachycardia Infectious: Trichinosis Invasive diagnostic tests for FUOs include abscess aspiration, and
Miscellaneous: Pulmonary emboli (multiple/small), biopsy of a mass, lymph node, liver or bone marrow75,83,84 (Table 68-9).
psychogenic fever In the FUO with hepatomegaly or hepatic mass lesions, liver biopsy
Relative bradycardia Malignant/neoplastic: Lymphoma may be diagnostic with an otherwise unexplained elevated alkaline
Infectious: Typhoid fever, leptospirosis, phosphatase. Lymph nodes likely to be diagnostic on biopsy are pos-
Legionnaire’s disease, Q fever, malaria, terior cervical, epitrochlear, supraclavicular, mediastinal or hilar
babesiosis, ehrlichiosis/anaplasmosis nodes. With obscure FUOs, bone marrow culture/biopsy may be
Miscellaneous: Drug fever, drugs (beta-blockers,
verapamil, diltiazem), factitious fever useful. In malignant/neoplastic FUOs, bone marrow biopsy may reveal
myelodysplastic states, preleukemic states, lymphoma, myeloma, etc.75
Double quotidian Infectious: Visceral leishmaniasis (kala-azar), miliary Bone marrow aspiration/biopsy and culture may be diagnostic when
fevers TB, mixed malarial infections
Rheumatic/inflammatory: Adult Still’s disease other tests are negative, e.g., typhoid fever, miliary TB, leishmaniasis,
(JRA) histoplasmosis, brucellosis, Q fever.86–88 Bone marrow biopsy in
Miscellaneous: Drugs (antipyretics) rheumatoid/inflammatory FUOs may provide a clue to unsuspected
Relapsing or Malignant/neoplastic: Hodgkin’s lymphoma (Pel– GCA/TA. With current diagnostic tests, exploratory laparotomy is no
‘camel-back’ fever Ebstein fever) longer in the FUO workup.89–96
pattern Infectious: Leptospirosis, brucellosis, rat bite fever
(Spirillum minus) THE FOCUSED DIAGNOSTIC APPROACH
Miscellaneous: Drugs (antipyretics)
Even with the best diagnostic efforts ~10–15% of FUOs will remain
*Diagnostic fever curves are particularly useful in suggesting a diagnosis with undiagnosed after a focused FUO workup.11,13,14,20,21 In each FUO cat-
difficult to diagnose FUOs without localizing signs. egory, there are important easily missed FUOs. Careful diagnostic
For abbreviations, see Table 68-1.
Adapted from Cunha C.B.: Infectious disease differential diagnosis. In: Cunha
consideration should be given to these ‘not to be missed’ important
B.A., ed. Antibiotic essentials, 14th ed. New Delhi: Jaypee Brothers Medical FUO diagnoses. (In some cases, PET scans or invasive diagnostic tests
Publishers; 2015: 474–506. may be the only way to diagnose some obscure FUOs.)

TABLE
68-8  Unusual Causes of FUO Suggested or Diagnosed by PET/CT Scan
Malignant/Neoplastic Disorders Infectious Diseases Rheumatic/Inflammatory Disorders Miscellaneous Disorders
• Intravascular large B-cell lymphoma • Aortic graft infection • Large vessel vasculitis • ECD
• Q fever endocarditis • GCA
• MCD • Takayasu’s arteritis
• CMV colitis

For abbreviations, see Table 68-1.

Adapted from Cunha C.B., Cunha B.A.: Fever of unknown origin (FUO). In: Schlossberg, D., ed. Clinical infectious disease, 2nd ed. Cambridge: Cambridge University
Press; 2015: 1–9.

TABLE
68-9  Unusual Causes of FUO Suggested or Diagnosed by Bone Marrow Biopsy or Culture
Malignant/Neoplastic Disorders Infectious Diseases Rheumatic/Inflammatory Disorders Miscellaneous Disorders
• Lymphomas • SBE* • GCA/TA • Drug related
• Leukemias • Miliary TB (pseudolymphoma)
• Myeloma • Disseminated Mycobacterium
• Pre-leukemia (AML) avium-intracellulare (MAI)
• MPDs • Disseminated histoplasmosis
• Systemic mastocytosis • MCD
• Metastatic carcinoma† • Whipple’s disease
• Typhoid/enteric fever

*Bone marrow cultures may be positive with negative blood cultures.

†
From stomach cancer, colon cancer, breast cancer, prostate cancer, bronchogenic carcinoma (small cell).
For abbreviations, see Table 68-1.
Adapted from Cunha C.B., Cunha B.A.: Fever of unknown origin (FUO). In: Schlossberg D., ed. Clinical infectious disease, 2nd ed. Cambridge: Cambridge University
Press; 2015: 1–9.
624 SECTION 3  Special Problems in Infectious Disease Practice: Fever

Recurrent FUOs Empiric Therapy of FUOs

Some FUO disorders have the potential to recur. Recurrent FUOs are
most often due to rheumatic/inflammatory or miscellaneous disor-
ders.46,97 The longer a recurrent FUO persists, the more likely it is not
infectious or malignant/neoplastic.92–101 The chances of diagnosing an
FUO persisting for >6 months is relatively low.98
Recurrent FUOs may also be due to inadequate therapy of disorders
that are prone to relapse, e.g., Whipple’s disease, Q fever, brucellosis,
adult Still’s disease (JRA), regional enteritis (Crohn’s disease), familial
Mediterranean fever (FMF), cyclic neutropenia and Behçet’s disease.
Infections that may present as a recurrent FUO are relatively limited,
e.g., most commonly EBV, CMV, TB. Additionally, chronic prostatitis,
recurrent cholangitis and apical dental abscesses may also present as
recurrent FUO. The most common malignant/neoplastic recurrent
FUOs are due to lymphomas or atrial myxomas.
The FUO category with the most disorders with the potential to
present as a recurrent FUO is miscellaneous disorders. Recurrent mis-
cellaneous FUOs typically persist for years, evading a definitive diag-
nosis. The diagnostic approach is based on eliminating the most
common diseases first, e.g., cirrhosis, drug fever. If suspected on the
basis of clinical clues, disorders such as Castleman’s disease (MCD),
cyclic neutropenia, FAPA syndrome, FMF, and hyper IgD syndrome
should be considered.98–102 If these miscellaneous disorders have been
eliminated, unusual hereditary recurrent FUOs should then be con-
sidered. Careful attention should be given to the family medical history
and ethnicity, which are key to suspecting these hereditary periodic
fevers. Before pursuing an extensive workup, the clinician should con-
sider psychogenic and factitious fever, particularly if the patient is well
appearing, with normal ESR and no other test abnormalities.103
Because fever patterns are diagnostically important, antipyretics
should be avoided. Prognostically, fevers reflect FUO disease activity
as well as the response to therapy. Antipyretics can mimic fever pat-
terns of a variety of disorders misleading the unwary clinician to
pursue irrelevant diagnoses based on antipyretic-induced fever
patterns.
In general, without a diagnosis, empiric antibiotic therapy with
FUOs should be avoided. Aside from masking signs and symptoms,
clinical improvement may not be due to antimicrobial effect (some
antibiotics have anti-inflammatory properties). Antibiotic therapy
may decrease the yield of cultures from a variety of body sites and
delay, blunt or eliminate diagnostic titer elevations.104,105
There are a few life-threatening FUO disorders which are difficult
to diagnose and that clearly benefit from early empiric therapy. Empiric
therapy may be life-saving with miliary TB. Empiric high-dose steroid
therapy may be sight-saving in GCA/TA with visual symptoms. For
CNE, every attempt should be made to make a definitive etiologic
diagnosis before initiating empiric CNE antibiotic therapy. CNE may
be infectious (bacterial or fungal) or noninfectious (marantic endo-
carditis).104,105 FUOs are primarily diagnostic, not therapeutic, prob-
lems. Once the definitive diagnosis of an FUO is determined, then
appropriate therapy may be given.
The prognosis in FUOs that remain undiagnosed after repeated
extensive workups is good, i.e., FUOs that remain undiagnosed are
usually benign.106
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