142 PART 2 Cardinal Manifestations and Presentation of Diseases

FIGURE 19-3 Confluent desquamative erythema in a patient with Staphylococcal scalded-skin syndrome.

Nikolsky sign evident as shearing of epidermis due to gentle, lateral pressure. (From K Wolff et al [eds]:

Fitzpatrick’s Color Atlas and Synopsis of Clinical Dermatology, 8th ed. New York, McGraw-Hill, 2017, p. 554,

Figure 25-42; with permission.)

in tropical and subtropical regions, is associated with a maculopapular

eruption (Fig. A1-54) and severe polyarticular small-joint arthralgias.

Hand-foot-and-mouth disease (Chap. 204), most commonly caused by

coxsackievirus A16 or enterovirus 71, is distinguished by tender vesicles distributed on the hands and feet and in the mouth (Fig. A1-22);

coxsackievirus A6 causes an atypical syndrome with more extensive

lesions. The classic target lesions of erythema multiforme (Fig. A1-24)

appear symmetrically on the elbows, knees,

palms, soles, and face. In severe cases, these

lesions spread diffusely and involve mucosal

surfaces. Lesions may develop on the hands and

feet in endocarditis (Fig. A1-23) (Chap. 128).

Pernio, tender violaceous lesions that are acral

(Fig. A1-57), occur most commonly on the feet,

in asymptomatic or mild COVID-19. Vesicles,

urticaria, or maculopapular eruptions, often pruritic, may occur on the trunk and extremities in

moderate or severe disease, while retiform purpura occurs on the extremities and buttocks in

severe COVID-19.

■ CONFLUENT DESQUAMATIVE

ERYTHEMAS

These eruptions consist of diffuse erythema frequently followed by desquamation. The eruptions

caused by group A Streptococcus or Staphylococcus

aureus are toxin-mediated. Scarlet fever (Chap.

148) (Fig. A1-25) usually follows pharyngitis;

patients have a facial flush, a “strawberry” tongue,

and accentuated petechiae in body folds (Pastia’s

lines). Kawasaki disease (Fig. A1-29) (Chaps. 58

and 363) presents in the pediatric population

as fissuring of the lips, a strawberry tongue,

conjunctivitis, adenopathy, and sometimes cardiac abnormalities. Streptococcal toxic shock

syndrome (Chap. 148) manifests with hypotension, multiorgan failure, and, often, a severe

group A streptococcal infection (e.g., necrotizing

fasciitis). Staphylococcal toxic shock syndrome

(Chap. 147) also presents with hypotension and

multiorgan failure, but usually only S. aureus

colonization—not a severe S. aureus infection—is

documented. Staphylococcal scalded-skin syndrome

(Fig. A1-28) (Chap. 147) is seen primarily in

children and in immunocompromised adults.

Generalized erythema is often evident during

the prodrome of fever and malaise; profound tenderness of the skin

is distinctive. In the exfoliative stage, the skin can be induced to form

bullae with light lateral pressure (Nikolsky’s sign) (Fig. 19-3). In a mild

form, a scarlatiniform eruption mimics scarlet fever, but the patient

does not exhibit a strawberry tongue or circumoral pallor. In contrast

to the staphylococcal scalded-skin syndrome, in which the cleavage

plane is superficial in the epidermis, toxic epidermal necrolysis (Chap.

60), a maximal variant of Stevens-Johnson syndrome, involves sloughing of the entire epidermis (Fig. A1-26), resulting in severe disease.

Exfoliative erythroderma syndrome (Chaps. 58 and 60) is a serious

reaction associated with systemic toxicity that is often due to eczema,

psoriasis (Fig. A1-27), a drug reaction, or mycosis fungoides. Drug

rash with eosinophilia and systemic symptoms (DRESS), often due to

antiepileptic and antibiotic agents (Chap. 60), initially appears similar

to an exanthematous drug reaction (Fig. A1-48) but may progress to

exfoliative erythroderma; it is accompanied by multiorgan failure and

has an associated mortality rate of ~10%.

■ VESICULOBULLOUS OR PUSTULAR ERUPTIONS

Varicella (Chap. 193) is highly contagious, often occurring in winter

or spring, and is characterized by pruritic lesions that, within a given

region of the body, are in different stages of development at any point

in time (Fig. 19-4; see also Fig. A1-30). In immunocompromised

hosts, varicella vesicles may lack the characteristic erythematous

base or may appear hemorrhagic. Lesions of Pseudomonas “hot-tub”

folliculitis (Chap. 164) are also pruritic and may appear similar to

those of varicella (Fig. A1-55). However, hot-tub folliculitis generally

occurs in outbreaks after bathing in hot tubs or swimming pools, and

lesions occur in regions occluded by bathing suits. Lesions of variola

(smallpox) (Chap. S3) also appear similar to those of varicella but are

FIGURE 19-2 Peripheral eruption on the wrist and palm exhibiting erythematous

macules in the process of evolving into petechial lesions in a patient with Rocky

Mountain spotted fever. (From K Wolff et al [eds]: Fitzpatrick’s Color Atlas and

Synopsis of Clinical Dermatology, 8th ed. New York, McGraw-Hill, 2017, p. 562,

Figure 25-50; with permission.)

143 Fever and Rash CHAPTER 19

FIGURE 19-4 Vesicular and pustular lesions on the chest in a patient with

varicella. (From K Wolff et al [eds]: Fitzpatrick’s Color Atlas and Synopsis of Clinical

Dermatology, 8th ed. New York, McGraw-Hill, 2017, p. 695, Figure 27-48; with

permission.)

FIGURE 19-5 Urticarial eruption. (From K Wolff et al [eds]: Fitzpatrick’s Color Atlas

and Synopsis of Clinical Dermatology, 8th ed. New York, McGraw-Hill, 2017, p. 299,

Figure 14-2; with permission.)

all at the same stage of development in a given region of the body

(Figs. A1-50B, A1-50C). Variola lesions are most prominent on the

face (Fig. A1-50A) and extremities, while varicella lesions are most

prominent on the trunk. Herpes simplex virus infection (Chap. 192) is

characterized by hallmark grouped vesicles on an erythematous base.

Primary herpes infection is accompanied by fever and toxicity, while

recurrent disease is milder. Rickettsialpox (Chap. 187) is often documented in urban settings and is characterized by vesicles followed by

pustules (Figs. A1-33B, A1-33C). It can be distinguished from varicella by an eschar at the site of the mouse-mite bite (Fig. A1-33A) and

the papule/plaque base of each vesicle. Acute generalized exanthematous

pustulosis (Fig. A1-49) should be considered in individuals who are

acutely febrile and are taking new medications, especially anticonvulsant or antimicrobial agents (Chap. 60). Disseminated Vibrio vulnificus

infection (Chap. 168) or ecthyma gangrenosum due to Pseudomonas

aeruginosa (Fig. A1-34) (Chap. 164) should be considered in immunosuppressed individuals with sepsis and hemorrhagic bullae. In children,

Mycoplasma pneumoniae–induced rash and mucositis (MIRM) (Fig.

A1-56) is characterized by a sparse, often vesiculobullous eruption

with prominent oral, ocular, or urogenital mucositis.

■ URTICARIA-LIKE ERUPTIONS

Individuals with classic urticaria (“hives”) (Fig. 19-5; see also Fig.

A1-35) usually have a hypersensitivity reaction without associated fever.

In the presence of fever, urticaria-like eruptions are most often due to

urticarial vasculitis (Chap. 363). Unlike individual lesions of classic urticaria, which last up to 24 h, these lesions may last 3–5 days. Etiologies

include serum sickness (often induced by drugs such as penicillins, sulfas, salicylates, or barbiturates), connective-tissue disease (e.g., systemic

lupus erythematosus or Sjögren’s syndrome), and infection (e.g., with

hepatitis B virus, enteroviruses, or parasites). Malignancy, especially lymphoma, may be associated with fever and chronic urticaria (Chap. 58).

■ NODULAR ERUPTIONS

In immunocompromised hosts, nodular lesions often represent disseminated infection. Patients with disseminated candidiasis (Fig. A1-37)

(often due to Candida tropicalis) may have a triad of fever, myalgias,

and eruptive nodules (Chap. 216). Disseminated cryptococcosis lesions

(Fig. 19-6; see also Fig. A1-36) (Chap. 215) may resemble molluscum contagiosum (Chap. 196). Necrosis of nodules should raise the

suspicion of aspergillosis (Fig. A1-38) (Chap. 217) or mucormycosis

FIGURE 19-6 Nodular eruption on the face due to disseminated Cryptococcus

in a patient with HIV infection. (From K Wolff et al [eds]: Fitzpatrick’s Color Atlas

and Synopsis of Clinical Dermatology, 8th ed. New York, McGraw-Hill, 2017, p. 641,

Figure 26-57. Used with permission from Loïc Vallant, MD.)

144 PART 2 Cardinal Manifestations and Presentation of Diseases

FIGURE 19-7 Purpura fulminans in a patient with acute meningococcemia. (From

K Wolff et al [eds]: Fitzpatrick’s Color Atlas and Synopsis of Clinical Dermatology,

8th ed. New York, McGraw-Hill, 2017, p. 568, Figure 25-59; with permission.)

FIGURE 19-8 Eschar with surrounding erythema at the site of a tick bite in a patient with African tick-bite fever. (From K Wolff et al [eds]: Fitzpatrick’s Color Atlas and

Synopsis of Clinical Dermatology, 8th ed. New York, McGraw-Hill, 2017, p. 561, Figure 25-49; with permission.)

(Chap. 218). Erythema nodosum presents with exquisitely tender nodules

on the lower extremities (Fig. A1-39). Sweet syndrome (Chap. 58) should

be considered in individuals with multiple nodules and plaques, often

so edematous (Fig. A1-40) that they give the appearance of vesicles or

bullae. Sweet syndrome may occur in individuals with infection, inflammatory bowel disease, or malignancy and can also be induced by drugs.

■ PURPURIC ERUPTIONS

Acute meningococcemia (Chap. 155) classically presents in children as a

petechial eruption, but initial lesions may appear as blanchable macules

or urticaria. Rocky Mountain spotted fever should be considered in the

differential diagnosis of acute meningococcemia. Echovirus 9 infection

(Chap. 204) may mimic acute meningococcemia; patients should be

treated as if they have bacterial sepsis because prompt differentiation of

these conditions may be impossible. Large ecchymotic areas of purpura

fulminans (Fig. 19-7; see also Fig. A1-41) (Chaps. 155 and 304) reflect

severe underlying disseminated intravascular coagulation, which may be

due to infectious or noninfectious causes. The lesions of chronic meningococcemia (Fig. A1-42) (Chap. 155) may have a variety of morphologies, including petechial. Purpuric nodules may develop on the legs and

resemble erythema nodosum but lack its exquisite tenderness. Lesions

of disseminated gonococcemia (Chap. 156) are distinctive, sparse, countable hemorrhagic pustules (Fig. A1-43), usually located near joints. The

lesions of chronic meningococcemia and those of gonococcemia may be

indistinguishable in terms of appearance and distribution. Viral hemorrhagic fever (Chaps. 209 and 210) should be considered in patients with

an appropriate travel history and a petechial rash. Thrombotic thrombocytopenic purpura (Chaps. 58, 100, and 115) and hemolytic-uremic

syndrome (Chaps. 115, 161, and 166) are closely related and are noninfectious causes of fever and petechiae. Cutaneous small-vessel vasculitis (leukocytoclastic vasculitis) typically manifests as palpable purpura

(Fig. A1-44) and has a wide variety of causes (Chap. 58).

■ ERUPTIONS WITH ULCERS OR ESCHARS

The presence of an ulcer or eschar (Fig. 19-8) in the setting of a more

widespread eruption can provide an important diagnostic clue. For example, an eschar may suggest the diagnosis of scrub typhus or rickettsialpox

(Fig. A1-33A) (Chap. 187) in the appropriate setting. In other illnesses

(e.g., anthrax) (Fig. A1-52) (Chap. S3), an ulcer or eschar may be the

only skin manifestation.

■ FURTHER READING

Cherry JD: Cutaneous manifestations of systemic infections, in

Feigin and Cherry’s Textbook of Pediatric Infectious Diseases, 8th ed.

JD Cherry et al (eds). Philadelphia, Elsevier, 2019, pp 539–559.

Juliano JJ et al: The acutely ill patient with fever and rash, in Mandell,

Douglas, and Bennett’s Principles and Practice of Infectious Diseases,

vol 1, 9th ed. JI Bennett et al (eds). Philadelphia, Elsevier, 2020,

pp 801–818.

Kang S et al (eds): Fitzpatrick’s Dermatology, 9th ed. New York,

McGraw-Hill, 2019.

Wolff K et al: Fitzpatrick’s Color Atlas and Synopsis of Clinical Dermatology, 8th ed. New York, McGraw-Hill, 2017.

145 Fever of Unknown Origin CHAPTER 20

■ DEFINITION

Clinicians commonly refer to any febrile illness without an initially

obvious etiology as fever of unknown origin (FUO). Most febrile illnesses either resolve before a diagnosis can be made or develop distinguishing characteristics that lead to a diagnosis. The term FUO should

be reserved for prolonged febrile illnesses without an established etiology despite intensive evaluation and diagnostic testing. This chapter

focuses on FUO in the adult patient.

FUO was originally defined by Petersdorf and Beeson in 1961 as an

illness of >3 weeks’ duration with fever of ≥38.3°C (≥101°F) on two

occasions and an uncertain diagnosis despite 1 week of inpatient evaluation. Nowadays, most patients with FUO are hospitalized only if their

clinical condition requires it, and not for diagnostic purposes alone;

thus the in-hospital evaluation requirement has been eliminated from

the definition. The definition of FUO has been further modified by the

exclusion of immunocompromised patients, whose workup requires

an entirely different diagnostic and therapeutic approach. For optimal

comparison of patients with FUO in different geographic areas, it has

been proposed that the quantitative criterion (diagnosis uncertain after

1 week of evaluation) be changed to a qualitative criterion that requires

the performance of a specific list of investigations. Accordingly, FUO

is now defined as follows:

1. Fever ≥38.3°C (≥101°F) on at least two occasions

2. Illness duration of ≥3 weeks

3. No known immunocompromised state

4. Diagnosis that remains uncertain after a thorough history-taking,

physical examination, and the following obligatory investigations:

determination of erythrocyte sedimentation rate (ESR) and C-reactive

protein (CRP) level; platelet count; leukocyte count and differential;

measurement of levels of hemoglobin, electrolytes, creatinine, total

protein, alkaline phosphatase, alanine aminotransferase, aspartate

aminotransferase, lactate dehydrogenase, creatine kinase, ferritin,

antinuclear antibodies, and rheumatoid factor; protein electrophoresis; urinalysis; blood cultures (n = 3); urine culture; chest x-ray;

abdominal ultrasonography; and tuberculin skin test (TST) or interferon γ release assay (IGRA).

Closely related to FUO is inflammation of unknown origin (IUO),

which has the same definition as FUO, except for the body temperature

20 Fever of Unknown Origin

Chantal P. Bleeker-Rovers,

Catharina M. Mulders-Manders,

Jos W. M. van der Meer

criterion: IUO is defined as the presence of elevated inflammatory

parameters (CRP or ESR) on multiple occasions for a period of at least

3 weeks in an immunocompetent patient with normal body temperature, for which a final explanation is lacking despite history-taking,

physical examination, and the obligatory tests listed above. It has been

shown that the causes and workup for IUO are the same as for FUO.

Therefore, for convenience, the term FUO will refer to both FUO and

IUO within the remainder of this chapter.

■ ETIOLOGY AND EPIDEMIOLOGY

Table 20-1 summarizes the findings of large studies on FUO conducted

over the past 20 years.

The range of FUO etiologies has evolved since its first definition

as a result of changes in the spectrum of diseases causing FUO, the

widespread use of antibiotics, and especially the availability of new

diagnostic techniques. The proportion of cases caused by intraabdominal abscesses and tumors, for example, has decreased because of earlier

detection by CT and ultrasound. In addition, infective endocarditis

is a less frequent cause because blood culture and echocardiographic

techniques have improved. Conversely, some diagnoses such as acute

HIV infection were unknown six decades ago.

Roughly comparable to 60 years ago, in non-Western cohorts

infections remain the most common cause of FUO. Up to half of all

infections in patients with FUO outside Western nations are caused

by Mycobacterium tuberculosis, which is a less common cause in

Western Europe and probably also in the United States. Recent data

from the latter, however, have not been reported. In Western cohorts,

noninfectious inflammatory diseases (NIIDs), including autoimmune,

autoinflammatory, and granulomatous diseases, as well as vasculitides,

form the most common cause of FUO. More than one-third of Western

patients with FUO have a diagnosis that falls within the category of

NIIDs. The number of FUO patients diagnosed with NIIDs probably

will not decrease in the near future, as fever may precede more typical

manifestations or laboratory evidence of these diseases by months.

Moreover, many NIIDs can be diagnosed only after prolonged observation and exclusion of other diseases.

In Western cohorts, FUO remains unexplained in more than onethird of patients. This is much higher than 60 years ago. This difference

can be explained by the fact that in patients with fever a diagnosis

is often established before 3 weeks have elapsed because these patients

tend to seek medical advice earlier, and because better diagnostic techniques, such as CT, MRI, and positron emission tomography (PET)/CT,

are now available. Therefore, only the cases that are most difficult to diagnose continue to meet the criteria for FUO. Furthermore, most patients

who have FUO without a diagnosis currently do well. A less aggressive

diagnostic approach may be used in clinically stable patients once diseases

with immediate therapeutic or prognostic consequences have been ruled

out. In patients with recurrent fever (defined as repeated episodes of fever

TABLE 20-1 Etiology of FUO: Pooled Results of Large Studies Published in the Past 20 Years (1999–2019)

GEOGRAPHIC

AREA

NO. OF COHORTS

(INCLUSION

PERIOD) NO. OF PATIENTS

INFECTIONS,

MEDIAN %

(RANGE)

NONINFECTIOUS

INFLAMMATORY

DISEASES, MEDIAN %

(RANGE)

MALIGNANCY,

MEDIAN %

(RANGE)

MISCELLANEOUS,

MEDIAN % (RANGE)

NO

DIAGNOSIS,

MEDIAN %

(RANGE)

Western Europe 10

(1990–2014)

1820 17

(11–32)

25

(12–32)

10

(3–20)

10

(0–15)

37

(26–51)

Other European

and Turkey

13

(1984–2015)

1316 38

(26–59)

25

(15–38)

14

(5–19)

6

(2–18)

16

(4–35)

Middle East 3

2009–2010 and ?a

1235 66

(42–79)

15

(7–17)

7

(1–30)

1

(0–12)

8

(2–12)

Asia 20

(1994–2017)

3802 42

(11–58)

20

(7–57)

13

(6–22)

9

(0–15)

18

(0–36)

a

One study (published in 2015) did not report the inclusion period.

Abbreviation: NIID, non-infectious inflammatory disease.

For references, see supplementary material at www.accessmedicine.com/harrisons.

146 PART 2 Cardinal Manifestations and Presentation of Diseases

interspersed with fever-free intervals of at least 2 weeks and apparent

remission of the underlying disease), the chance of attaining an etiologic

diagnosis is <50%.

■ DIFFERENTIAL DIAGNOSIS

The differential diagnosis for FUO is extensive. It is important to

remember that FUO is far more often caused by an atypical presentation of a rather common disease than by a very rare disease. Table 20-2

presents an overview of possible causes of FUO. Atypical presentations

of endocarditis, diverticulitis, vertebral osteomyelitis, and extrapulmonary tuberculosis are the more common infectious disease diagnoses.

TABLE 20-2 All Reported Causes of Fever of Unknown Origin (FUO)a

Infections

Bacterial, nonspecific Abdominal abscess, adnexitis, apical granuloma, appendicitis, cholangitis, cholecystitis, diverticulitis, endocarditis, endometritis, epidural

abscess, infected joint prosthesis, infected vascular catheter, infected vascular prosthesis, infectious arthritis, infective myonecrosis,

intracranial abscess, liver abscess, lung abscess, malakoplakia, mastoiditis, mediastinitis, mycotic aneurysm, osteomyelitis, pelvic

inflammatory disease, prostatitis, pyelonephritis, pylephlebitis, renal abscess, septic phlebitis, sinusitis, spondylodiscitis, xanthogranulomatous

urinary tract infection

Bacterial, specific Actinomycosis, atypical mycobacterial infection, bartonellosis, brucellosis, Campylobacter infection, Chlamydia pneumoniae infection, chronic

meningococcemia, ehrlichiosis, gonococcemia, legionellosis, leptospirosis, listeriosis, louse-borne relapsing fever (Borrelia recurrentis), Lyme

disease, melioidosis (Pseudomonas pseudomallei), Mycoplasma infection, nocardiosis, psittacosis, Q fever (Coxiella burnetii), rickettsiosis,

Spirillum minor infection, Streptobacillus moniliformis infection, syphilis, tick-borne relapsing fever (Borrelia duttonii), tuberculosis, tularemia,

typhoid fever and other salmonelloses, Whipple’s disease (Tropheryma whipplei), yersiniosis

Fungal Aspergillosis, blastomycosis, candidiasis, coccidioidomycosis, cryptococcosis, histoplasmosis, Malassezia furfur infection,

paracoccidioidomycosis, Pneumocystis jirovecii pneumonia, sporotrichosis, zygomycosis

Parasitic Amebiasis, babesiosis, echinococcosis, fascioliasis, malaria, schistosomiasis, strongyloidiasis, toxocariasis, toxoplasmosis, trichinellosis,

trypanosomiasis, visceral leishmaniasis

Viral Colorado tick fever, coxsackievirus infection, cytomegalovirus infection, dengue, Epstein-Barr virus infection, hantavirus infection, hepatitis (A,

B, C, D, E), herpes simplex, HIV infection, human herpesvirus 6 infection, parvovirus infection, West Nile virus infection

Noninfectious Inflammatory Diseases

Systemic rheumatic

and autoimmune

diseases

Ankylosing spondylitis, antiphospholipid syndrome, autoimmune hemolytic anemia, autoimmune hepatitis, Behçet’s disease, cryoglobulinemia,

dermatomyositis, Felty syndrome, gout, mixed connective-tissue disease, polymyositis, pseudogout, reactive arthritis, relapsing polychondritis,

rheumatic fever, rheumatoid arthritis, Sjögren’s syndrome, systemic lupus erythematosus, Vogt-Koyanagi-Harada syndrome

Vasculitis Allergic vasculitis, eosinophilic granulomatosis with polyangiitis, giant cell vasculitis/polymyalgia rheumatica, granulomatosis with polyangiitis,

hypersensitivity vasculitis, Kawasaki disease, polyarteritis nodosa, Takayasu arteritis, urticarial vasculitis

Granulomatous

diseases

Idiopathic granulomatous hepatitis, sarcoidosis

Autoinflammatory

syndromes

Adult-onset Still’s disease, Blau syndrome, CAPSb

 (cryopyrin-associated periodic syndromes), Crohn’s disease, DIRA (deficiency of the

interleukin 1 receptor antagonist), familial Mediterranean fever, hemophagocytic syndrome, hyper-IgD syndrome (HIDS, also known as

mevalonate kinase deficiency), juvenile idiopathic arthritis, PAPA syndrome (pyogenic sterile arthritis, pyoderma gangrenosum, and acne),

PFAPA syndrome (periodic fever, aphthous stomatitis, pharyngitis, adenitis), recurrent idiopathic pericarditis, SAPHO (synovitis, acne,

pustulosis, hyperostosis, osteomyelitis), Schnitzler syndrome, TRAPS (tumor necrosis factor receptor–associated periodic syndrome)

Neoplasms

Hematologic

malignancies

Amyloidosis, angioimmunoblastic lymphoma, Castleman’s disease, Hodgkin’s disease, hypereosinophilic syndrome, leukemia, lymphomatoid

granulomatosis, malignant histiocytosis, multiple myeloma, myelodysplastic syndrome, myelofibrosis, non-Hodgkin’s lymphoma,

plasmacytoma, systemic mastocytosis, vaso-occlusive crisis in sickle cell disease

Solid tumors Most solid tumors and metastases can cause fever. Those most commonly causing FUO are breast, colon, hepatocellular, lung, pancreatic,

and renal cell carcinomas.

Benign tumors Angiomyolipoma, cavernous hemangioma of the liver, craniopharyngioma, necrosis of dermoid tumor in Gardner’s syndrome

Miscellaneous Causes

ADEM (acute disseminated encephalomyelitis), adrenal insufficiency, aneurysms, anomalous thoracic duct, aortic dissection, aortic-enteral

fistula, aseptic meningitis (Mollaret’s syndrome), atrial myxoma, brewer’s yeast ingestion, Caroli disease, cholesterol emboli, cirrhosis,

complex partial status epilepticus, cyclic neutropenia, drug fever, Erdheim-Chester disease, extrinsic allergic alveolitis, Fabry’s disease,

factitious disease, fire-eater’s lung, fraudulent fever, Gaucher disease, Hamman-Rich syndrome (acute interstitial pneumonia), Hashimoto’s

encephalopathy, hematoma, hypersensitivity pneumonitis, hypertriglyceridemia, hypothalamic hypopituitarism, idiopathic normal-pressure

hydrocephalus, inflammatory pseudotumor, Kikuchi’s disease, linear IgA dermatosis, mesenteric fibromatosis, metal fume fever, milk protein

allergy, myotonic dystrophy, nonbacterial osteitis, organic dust toxic syndrome, panniculitis, POEMS (polyneuropathy, organomegaly,

endocrinopathy, monoclonal protein, skin changes), polymer fume fever, post–cardiac injury syndrome, primary biliary cirrhosis, primary

hyperparathyroidism, pulmonary embolism, pyoderma gangrenosum, retroperitoneal fibrosis, Rosai-Dorfman disease, sclerosing

mesenteritis, silicone embolization, subacute thyroiditis (de Quervain’s), Sweet syndrome (acute febrile neutrophilic dermatosis), thrombosis,

tubulointerstitial nephritis and uveitis syndrome (TINU), ulcerative colitis

Thermoregulatory Disorders

Central Brain tumor, cerebrovascular accident, encephalitis, hypothalamic dysfunction

Peripheral Anhidrotic ectodermal dysplasia, exercise-induced hyperthermia, hyperthyroidism, pheochromocytoma

a

This table includes all causes of FUO that have been described in the literature. b

CAPS includes chronic infantile neurologic cutaneous and articular syndrome (CINCA,

also known as neonatal-onset multisystem inflammatory disease, or NOMID), familial cold autoinflammatory syndrome (FCAS), and Muckle-Wells syndrome.

Q fever and Whipple’s disease (Tropheryma whipplei infection) are

quite rare but should always be kept in mind as a cause of FUO since

the presenting symptoms can be nonspecific. Serologic testing for Q

fever, which results from exposure to animals or animal products,

should be performed by immunofluorescence assay (IFA) when the

patient lives in a rural area or has a history of heart valve disease, an

aortic aneurysm, or a vascular prosthesis. In patients with unexplained

symptoms localized to the central nervous system, gastrointestinal

tract, or joints, polymerase chain reaction testing for Tropheryma

whipplei should be performed. Travel to or (former) residence in tropical countries or the American Southwest should lead to consideration

147 Fever of Unknown Origin CHAPTER 20

of infectious diseases such as malaria, leishmaniasis, histoplasmosis,

or coccidioidomycosis. Fever with signs of endocarditis and negative blood culture results poses a special problem. Culture-negative

endocarditis (Chap. 128) may be due to difficult-to-culture bacteria

such as nutritionally variant bacteria, HACEK organisms (including

Haemophilus parainfluenzae, H. paraphrophilus, Aggregatibacter actinomycetemcomitans, A. aphrophilus, A. paraphrophilus, Cardiobacterium hominis, C. valvarum, Eikenella corrodens, and Kingella kingae;

discussed below), Coxiella burnetii, T. whipplei, and Bartonella species.

Marantic endocarditis is a sterile thrombotic disease that occurs as a

paraneoplastic phenomenon, especially with adenocarcinomas. Sterile

endocarditis is also seen in the context of systemic lupus erythematosus

and antiphospholipid syndrome.

Of the NIIDs, adult-onset Still’s disease, large-vessel vasculitis, polymyalgia rheumatica, systemic lupus erythematodus (SLE), and sarcoidosis

are rather common diagnoses in patients with FUO. The hereditary autoinflammatory syndromes are very rare (with the exception of familial

Mediterranean fever in specific geographic regions) and usually present

in young patients. Schnitzler syndrome, which can present at any age, is

uncommon but can often be diagnosed easily in a patient with FUO who

presents with urticaria, bone pain, and monoclonal gammopathy.

Although most tumors can present with fever, malignant lymphoma

is by far the most common diagnosis of FUO among the neoplasms.

Sometimes the fever even precedes lymphadenopathy detectable by

physical examination.

Apart from drug-induced fever and exercise-induced hyperthermia,

none of the miscellaneous causes of fever is found very frequently in

patients with FUO. Virtually all drugs can cause fever, even after longterm use. Drug-induced fever, including DRESS (drug reaction with

eosinophilia and systemic symptoms; Fig. A1-48), is often accompanied by eosinophilia and also by lymphadenopathy, which can be

extensive. More common causes of drug-induced fever are allopurinol,

carbamazepine, lamotrigine, phenytoin, sulfasalazine, furosemide,

antimicrobial drugs (especially sulfonamides, minocycline, vancomycin, β-lactam antibiotics, and isoniazid), some cardiovascular drugs

(e.g., quinidine), and some antiretroviral drugs (e.g., nevirapine).

Exercise-induced hyperthermia (Chaps. 18 and 465) is characterized

by an elevated body temperature that is associated with moderate to

strenuous exercise lasting from half an hour up to several hours without an increase in CRP level or ESR. Unlike patients with fever, these

patients typically sweat during the temperature elevation. Factitious

fever (fever artificially induced by the patient—for example, by IV

injection of contaminated water) should be considered in all patients

but is more common among young women in health-care professions.

In fraudulent fever, the patient is normothermic but manipulates the

thermometer. Simultaneous measurements at different body sites (rectum, ear, mouth) should rapidly identify this diagnosis. Another clue

to fraudulent fever is dissociation between pulse rate and temperature.

Previous studies of FUO have shown that a cause is more likely to

be found in elderly patients than in younger age groups. In many cases,

FUO in the elderly results from an atypical manifestation of a common

disease, among which giant cell arteritis and polymyalgia rheumatica

are most frequently involved. Tuberculosis is the most common infectious disease associated with FUO in elderly patients, occurring much

more often than in younger patients. As many of these diseases are

treatable, it is well worth pursuing the cause of fever in elderly patients.

APPROACH TO THE PATIENT

Fever of Unknown Origin

FIRST-STAGE DIAGNOSTIC TESTS

Figure 20-1 shows a structured approach to patients presenting

with FUO. The most important step in the diagnostic workup is

the search for potentially diagnostic clues (PDCs) through complete and repeated history-taking and physical examination and

the obligatory investigations listed above and in the figure. PDCs

are defined as all localizing signs, symptoms, and abnormalities

potentially pointing toward a diagnosis. Although PDCs are often

misleading, only with their help can a concise list of probable

diagnoses be made. The history should include information about

the fever pattern (continuous or recurrent) and duration, previous

medical history, present and recent drug use, family history, sexual

history, country of origin, recent and remote travel, unusual environmental exposures associated with travel or hobbies, and animal

contacts. A complete physical examination should be performed,

with special attention to the eyes, lymph nodes, temporal arteries,

liver, spleen, sites of previous surgery, entire skin surface, and

mucous membranes. Before further diagnostic tests are initiated,

antibiotic and glucocorticoid treatment, which can mask many diseases, should be stopped. For example, blood and other cultures are

not reliable when samples are obtained during antibiotic treatment,

and the size of enlarged lymph nodes usually decreases during

glucocorticoid treatment, regardless of the cause of lymphadenopathy. Despite the high percentage of false-positive ultrasounds

and the relatively low sensitivity of chest x-rays, the performance

of these simple, low-cost diagnostic tests remains obligatory in all

patients with FUO in order to separate cases that are caused by

easily diagnosed diseases from those that are not. Abdominal ultrasound is preferred to abdominal CT as an obligatory test because

of relatively low cost, lack of radiation burden, and absence of side

effects.

Only rarely do biochemical tests (beyond the obligatory tests

needed to classify a patient’s fever as FUO) lead directly to a definitive diagnosis in the absence of PDCs. The diagnostic yield of

immunologic serology other than that included in the obligatory

tests is relatively low. These tests more often yield false-positive

rather than true-positive results and are of little use without PDCs

pointing to specific immunologic disorders. Given the absence of

specific symptoms in many patients and the relatively low cost of

the test, investigation of cryoglobulins appears to be a valuable

screening test in patients with FUO.

Multiple blood samples should be cultured in the laboratory long

enough to ensure ample growth time for any fastidious organisms,

such as HACEK organisms. It is critical to inform the laboratory of

the intent to test for unusual organisms. Specialized media should be

used when the history suggests uncommon microorganisms, such

as Histoplasma or Legionella. Performing more than three blood cultures or more than one urine culture is useless in patients with FUO

in the absence of PDCs (e.g., a high level of clinical suspicion of

endocarditis). Repeating blood or urine cultures is useful only when

previously cultured samples were collected during antibiotic treatment or within 1 week after its discontinuation. FUO with headache

should prompt microbiologic examination of cerebrospinal fluid

(CSF) for organisms including herpes simplex virus (especially type

2), Cryptococcus neoformans, and Mycobacterium tuberculosis. In

central nervous system tuberculosis, the CSF typically has elevated

protein and lowered glucose concentrations, with a mononuclear

pleocytosis. CSF protein levels range from 100 to 500 mg/dL in most

patients, the CSF glucose concentration is <45 mg/dL in 80% of

cases, and the usual CSF cell count is between 100 and 500 cells/μL.

Microbiologic serology should not be included in the diagnostic workup of patients without PDCs for specific infections.

A tuberculin skin test (TST) or interferon γ release assay (IGRA,

QuantiFERON test) is included in the obligatory investigations, but

it may yield false-negative results in patients with miliary tuberculosis, malnutrition, or immunosuppression. Although the IGRA is

less influenced by prior vaccination with bacille Calmette-Guérin

(BCG) or by infection with nontuberculous mycobacteria, its sensitivity is similar to that of the TST; a negative TST or IGRA therefore

does not exclude a diagnosis of tuberculosis. Miliary tuberculosis

is especially difficult to diagnose. Granulomatous disease in liver

or bone marrow biopsy samples, for example, should always lead

to a (re)consideration of this diagnosis. If miliary tuberculosis

is suspected, liver biopsy for acid-fast smear, culture, and polymerase chain reaction probably still has the highest diagnostic yield;

148 PART 2 Cardinal Manifestations and Presentation of Diseases

Stable condition:

Follow-up for new PDCs

Consider NSAID treatment

Deterioration:

Further diagnostic tests

Consider therapeutic trial

Fever ≥38.3° C (≥101° F) and illness lasting ≥3 weeks

and no known immunocompromised state

History and physical examination

Obligatory investigations:

ESR or CRP, hemoglobin, platelet count, leukocyte count and differential, electrolytes,

creatinine, total protein, protein electrophoresis, alkaline phosphatase, AST, ALT, LDH,

creatine kinase, antinuclear antibodies, rheumatoid factor, urinalysis, blood cultures (n = 3),

urine culture, chest x-ray, abdominal ultrasonography, and tuberculin skin test or IGRA

PDCs present PDCs absent or misleading

Exclude manipulation with thermometer

Stop or replace medication to exclude drug fever

Guided diagnostic tests

DIAGNOSIS

Stop antibiotic treatment and glucocorticoids

Cryoglobulin and funduscopy

NO DIAGNOSIS

FDG-PET/CT (or labeled leukocyte

scintigraphy or gallium scan); see Fig. 20-2

Scintigraphy abnormal Scintigraphy normal

Confirmation of abnormality

(e.g., biopsy, culture)

Repeat history and physical examination

Perform PDC-driven invasive testing

DIAGNOSIS NO DIAGNOSIS DIAGNOSIS NO DIAGNOSIS

Chest and abdominal CT

Temporal artery biopsy (≥55 years)

DIAGNOSIS NO DIAGNOSIS

FIGURE 20-1 Structured approach to patients with FUO. ALT, alanine aminotransferase; AST, aspartate aminotransferase; CRP, C-reactive protein; ESR, erythrocyte

sedimentation rate; FDG-PET/CT, 18F-fluorodeoxyglucose positron emission tomography combined with low-dose CT; IGRA, interferon γ release assay; LDH, lactate

dehydrogenase; NSAID, nonsteroidal anti-inflammatory drug; PDCs, potentially diagnostic clues (all localizing signs, symptoms, and abnormalities potentially pointing

toward a diagnosis).

however, biopsies of bone marrow, lymph nodes, or other involved

organs also can be considered.

The diagnostic yield of echocardiography, sinus radiography,

radiologic or endoscopic evaluation of the gastrointestinal tract,

and bronchoscopy is very low in the absence of PDCs. Therefore,

these tests should not be used as screening procedures.

After identification of all PDCs retrieved from the history, physical examination, and obligatory tests, a limited list of the most

probable diagnoses should be made. Since most investigations are

helpful only for patients who have PDCs for the diagnoses sought,

further diagnostic procedures should be limited to specific investigations aimed at confirming or excluding diseases on this list. In

FUO, the diagnostic pointers are numerous and diverse but may

be missed on initial examination, often being detected only by a

very careful examination performed subsequently. In the absence

of PDCs, the history and physical examination should therefore

be repeated regularly. One of the first steps should be to rule out

factitious or fraudulent fever, particularly in patients without signs

149 Fever of Unknown Origin CHAPTER 20

of inflammation in laboratory tests. All medications, including

nonprescription drugs and nutritional supplements, should be discontinued early in the evaluation to exclude drug fever. If fever

persists beyond 72 h after discontinuation of the suspected drug,

it is unlikely that this drug is the cause. In patients without PDCs

or with only misleading PDCs, fundoscopy by an ophthalmologist

may be useful in the early stage of the diagnostic workup to exclude

retinal vasculitis. When the first-stage diagnostic tests do not lead

to a diagnosis, 18F-fluorodeoxyglucose (18F-FDG) positron emission

tomography combined with computed tomography (PET/CT) or,

if the former is not available, radiolabeled leukocyte scintigraphy

should be performed, especially when the ESR or the CRP level is

elevated.

Recurrent Fever In patients with recurrent fever, the diagnostic

workup should consist of thorough history-taking, physical examination, and obligatory tests. The search for PDCs should be directed

toward clues matching known recurrent syndromes (Table 20-3).

Patients should be asked to return during a febrile episode so that the

history, physical examination, and laboratory tests can be repeated

during a symptomatic phase. Further diagnostic tests, such as PET/CT

or scintigraphic imaging (see below), should be performed only during a febrile episode or when inflammatory parameters are abnormal

because abnormalities may be absent between episodes. In patients

with recurrent fever lasting >2 years, it is very unlikely that the fever

is caused by infection or malignancy. Further diagnostic tests in that

direction should be considered only when PDCs for infections, vasculitis syndromes, or malignancy are present or when the patient’s

clinical condition is deteriorating.

Fluorodeoxyglucose Positron Emission Tomography 18F-FDG

PET/CT has become an established imaging procedure in FUO.

FDG accumulates in tissues with a high rate of glycolysis, which

occurs not only in malignant cells but also in activated leukocytes

and thus permits the imaging of acute and chronic inflammatory

processes. Compared with conventional scintigraphy (see below),

FDG-PET/CT offers the advantages of higher resolution, greater

sensitivity in chronic low-grade infections, and a high degree of

accuracy in the central skeleton. Furthermore, vascular uptake of

FDG is increased in patients with vasculitis (Fig. 20-2). The mechanisms responsible for FDG uptake do not allow differentiation

among infection, sterile inflammation, and malignancy. However,

since all of these disorders are causes of FUO, FDG-PET/CT can

be used to guide additional diagnostic tests (e.g., targeted biopsies)

that may yield the final diagnosis. It is important to realize that

physiologic uptake of FDG may obscure pathologic foci in the

brain, heart, bowel, kidneys, and bladder. FDG uptake in the heart,

which obscures endocarditis, may be prevented by consumption of

a low-carbohydrate diet before the PET investigation. In patients

with fever, bone marrow uptake is frequently increased in a nonspecific way due to cytokine activation, which upregulates glucose

transporters in bone marrow cells.

TABLE 20-3 All Reported Causes of Recurrent Fevera

Infections

Bacterial, nonspecific Apical granuloma, diverticulitis, prostatitis, recurrent bacteremia caused by colonic neoplasia or persistent focal infection,

recurrent cellulitis, recurrent cholangitis or cholecystitis, recurrent pneumonia, recurrent sinusitis, recurrent urinary tract

infection

Bacterial, specific Bartonellosis, brucellosis, chronic gonococcemia, chronic meningococcemia, louse-borne relapsing fever (Borrelia

recurrentis), melioidosis (Pseudomonas pseudomallei), Q fever (Coxiella burnetii), salmonellosis, Spirillum minor infection,

Streptobacillus moniliformis infection, syphilis, tick-borne relapsing fever (Borrelia duttonii), tularemia, Whipple’s disease

(Tropheryma whipplei), yersiniosis

Fungal Coccidioidomycosis, histoplasmosis, paracoccidioidomycosis

Parasitic Babesiosis, malaria, toxoplasmosis, trypanosomiasis, visceral leishmaniasis

Viral Cytomegalovirus infection, Epstein-Barr virus infection, herpes simplex

Noninfectious Inflammatory Diseases

Systemic rheumatic and autoimmune

diseases

Ankylosing spondylitis, antiphospholipid syndrome, autoimmune hemolytic anemia, autoimmune hepatitis, Behçet’s disease,

cryoglobulinemia, gout, polymyositis, pseudogout, reactive arthritis, relapsing polychondritis, systemic lupus erythematosus

Vasculitis Churg-Strauss syndrome, giant cell vasculitis/polymyalgia rheumatica, hypersensitivity vasculitis, polyarteritis nodosa,

urticarial vasculitis

Granulomatous diseases Idiopathic granulomatous hepatitis, sarcoidosis

Autoinflammatory syndromes Adult-onset Still’s disease, Blau syndrome, CANDLE (chronic atypical neutrophilic dermatitis with lipodystrophy and elevated

temperature syndrome), CAPSb

 (cryopyrin-associated periodic syndrome), CRMO (chronic recurrent multifocal osteomyelitis),

Crohn’s disease, DIRA (deficiency of the interleukin 1 receptor antagonist), familial Mediterranean fever, hemophagocytic

syndrome, hyper-IgD syndrome (HIDS, also known as mevalonate kinase deficiency), juvenile idiopathic arthritis, NLRC4-

activating mutations, PAPA syndrome (pyogenic sterile arthritis, pyoderma gangrenosum, and acne), PFAPA syndrome

(periodic fever, aphthous stomatitis, pharyngitis, adenitis), recurrent idiopathic pericarditis, SAPHO (synovitis, acne, pustulosis,

hyperostosis, osteomyelitis), SAVI (stimulator of interferon genes [STING]–associated vasculopathy with onset in infancy),

Schnitzler syndrome, TRAPS (tumor necrosis factor receptor–associated periodic syndrome)

Neoplasms

Angioimmunoblastic lymphoma, Castleman’s disease, colon carcinoma, craniopharyngioma, Hodgkin’s disease, malignant

histiocytosis, mesothelioma, non-Hodgkin’s lymphoma

Miscellaneous Causes

Adrenal insufficiency, aortic-enteral fistula, aseptic meningitis (Mollaret’s syndrome), atrial myxoma, brewer’s yeast ingestion,

cholesterol emboli, cyclic neutropenia, drug fever, extrinsic allergic alveolitis, Fabry’s disease, factitious disease, fraudulent

fever, Gaucher disease, hypersensitivity pneumonitis, hypertriglyceridemia, hypothalamic hypopituitarism, inflammatory

pseudotumor, metal fume fever, milk protein allergy, polymer fume fever, pulmonary embolism, sclerosing mesenteritis

Thermoregulatory Disorders

Central Hypothalamic dysfunction

Peripheral Anhidrotic ectodermal dysplasia, exercise-induced hyperthermia, pheochromocytoma

a

This table includes all causes of recurrent fever that have been described in the literature. b

CAPS includes chronic infantile neurologic cutaneous and articular syndrome

(CINCA, also known as neonatal-onset multisystem inflammatory disease, or NOMID), familial cold autoinflammatory syndrome (FCAS), and Muckle-Wells syndrome.

150 PART 2 Cardinal Manifestations and Presentation of Diseases

FIGURE 20-2 FDG-PET/CT in a patient with FUO. This 72-year-old woman presented with a low-grade fever and severe fatigue of almost 3 months’ duration. An extensive

history was taken, but the patient had no specific complaints and had not traveled recently. Her previous history was unremarkable, and she did not use any drugs. Physical

examination, including palpation of the temporal arteries, yielded completely normal results. Laboratory examination showed normocytic anemia, a C-reactive protein level

of 43 mg/L, an erythrocyte sedimentation rate of 87 mm/h, and mild hypoalbuminemia. Results of the other obligatory tests were all normal. Since there were no potentially

diagnostic clues, FDG-PET/CT was performed. This test showed increased FDG uptake in all major arteries (carotid, jugular, and subclavian arteries; thoracic and abdominal

aorta; iliac, femoral, and popliteal arteries) and in the soft tissue around the shoulders, hips, and knees—findings compatible with large-vessel vasculitis and polymyalgia

rheumatica. Within 1 week after the initiation of treatment with prednisone (60 mg once daily), the patient completely recovered. After 1 month, the prednisone dose was

slowly tapered.

In recent years, many cohort studies and several meta-analyses

have focused on the diagnostic yield of PET and PET/CT in FUO.

These studies are highly variable in terms of the selection of patients,

the follow-up, and the selection of a gold-standard reference. Indirect comparisons of test performance suggested that FDG-PET/CT

outperformed stand-alone FDG-PET, gallium scintigraphy, and leukocyte scintigraphy. Similarly, indirect comparisons of diagnostic

yield suggested that FDG-PET/CT was more likely than alternative

tests to correctly identify the cause of FUO. Meta-analyses report a

high diagnostic yield for PET and PET/CT in the workup of FUO

patients, with pooled sensitivity and specificity figures of ~85% and

~50%, respectively, and a total diagnostic yield of ~50% for PET/

CT and ~40% for PET.

As many patients with FUO present with periodic fever, correct

timing of PET/CT increases its diagnostic value. Few studies on the

use of biomarkers such as elevated CRP or ESR for a contributory

outcome of PET/CT have been performed. When both CRP and

ESR are normal at the time of FDG-PET/CT, outcome may only be

contributory when a patient does have fever at the time of the scan.

Although PET/CT and other scintigraphic techniques do not

directly provide a definitive diagnosis (with the exception of some

patients with, for instance, large vessel vasculitis), they often identify the anatomic location of a particular ongoing metabolic process. With the help of other techniques such as biopsy and culture,

a timely diagnosis and treatment can be facilitated. Pathologic FDG

uptake is quickly eradicated by treatment with glucocorticoids in

many diseases, including vasculitis and lymphoma; therefore, glucocorticoid use should be stopped or postponed until after FDGPET/CT is performed.

FDG-PET/CT is a relatively expensive procedure whose availability is still limited compared with that of CT and conventional

scintigraphy. Nevertheless, FDG-PET/CT can be cost-effective in

the FUO diagnostic workup if used at an early stage, helping to

establish an early diagnosis, reducing days of hospitalization for

diagnostic purposes, and obviating unnecessary and unhelpful

tests. When FDG-PET/CT has been made under the right conditions (i.e., when elevated CRP or ESR or fever were present during

the scan) but has not contributed to the final diagnosis, repeating

PET/CT is probably of little value, unless new signs or symptoms

appear.

Conventional scintigraphic imaging other than PET/CT

Conventional scintigraphic methods used in clinical practice are

67Ga-citrate scintigraphy and 111In- or 99mTc-labeled leukocyte scintigraphy. Sensitivity and specificity of conventional scintigraphic

studies are lower than for PET/CT: the diagnostic yield of gallium

scintigraphy ranges from 21% to 54%, and on average the location

of a source of fever can correctly be localized in approximately onethird of patients. The diagnostic value of leukocyte scintigraphy

ranges from 8% to 31%, and overall the cause of FUO can correctly

be identified in one-fifth of patients. When PET/CT is not available,

these techniques are the only alternative.

LATER-STAGE DIAGNOSTIC TESTS

In some cases, more invasive tests are appropriate. Abnormalities

found with imaging often need to be confirmed by pathology and/

or culture of biopsy specimens. If lymphadenopathy is found, lymph

node biopsy is necessary, even when the affected lymph nodes are

hard to reach or when previous biopsies were inconclusive. In the

case of skin lesions, skin biopsy should be undertaken.

If no diagnosis is reached despite PET/CT and PDC-driven

histologic investigations or culture, second-stage screening diagnostic tests should be considered (Fig. 20-1). In three studies, the

diagnostic yield of screening chest and abdominal CT in patients

with FUO was ~20%. The specificity of chest CT was ~80%, but

that of abdominal CT varied between 63% and 80%. Despite the

151 Fever of Unknown Origin CHAPTER 20

relatively limited specificity of abdominal CT and the probably limited additional value of chest CT after normal FDG-PET/CT, chest

and abdominal CT may be used as screening procedures at a later

stage of the diagnostic protocol because of their noninvasive nature

and high sensitivity. Bone marrow aspiration is seldom useful in

the absence of PDCs for bone marrow disorders. With addition of

FDG-PET/CT, which is highly sensitive in detecting lymphoma,

carcinoma, and osteomyelitis, the value of bone marrow biopsy as

a screening procedure is probably further reduced. Several studies

have shown a high prevalence of giant cell arteritis among patients

with FUO, with rates up to 17% among elderly patients. Giant cell

arteritis often involves large arteries and in most cases can be diagnosed by FDG-PET/CT. However, temporal artery biopsy is still

recommended for patients ≥55 years of age in a later stage of the

diagnostic protocol: FDG-PET/CT will not be useful in vasculitis

limited to the temporal arteries because of the small diameter of

these vessels and the high levels of FDG uptake in the brain. In the

past, liver biopsies were often performed as a screening procedure

in patients with FUO. In each of two studies, liver biopsy as part

of the later stage of a screening diagnostic protocol was helpful in

only one patient. Moreover, abnormal liver tests are not predictive

of a diagnostic liver biopsy in FUO. Liver biopsy is an invasive procedure that carries the possibility of complications and even death.

Therefore, it should not be used for screening purposes in patients

with FUO except in those with PDCs for liver disease or miliary

tuberculosis.

In patients with unexplained fever after all of the above procedures, the last steps in the diagnostic workup—with only a marginal

diagnostic yield—come at an extraordinarily high cost in terms

of both expense and discomfort for the patient. Repetition of a

thorough history-taking and physical examination and review of

laboratory results and imaging studies (including those from other

hospitals) are recommended. Diagnostic delay often results from

a failure to recognize PDCs in the available information. In these

patients with persisting FUO, waiting for new PDCs to appear

probably is better than ordering more screening investigations.

Only when a patient’s condition deteriorates without providing new

PDCs should a further diagnostic workup be performed.

SECOND OPINION IN AN EXPERT CENTER

When despite the workup described above no explanation for FUO

is found, second opinion in an expert center on FUO should be

considered. The single study on the value of second opinion in

FUO reported that in 57.3% of patients with unexplained FUO, a

diagnosis could be found in an expert center. Additionally, of all

patients who remained without a diagnosis even after second opinion, 10.9% became fever-free upon empirical treatment, adding up

to a beneficial outcome in 68.2% of patients.

TREATMENT

Fever of Unknown Origin

Empirical therapeutic trials with antibiotics, glucocorticoids, or

antituberculous agents should be avoided in FUO except when a

patient’s condition is rapidly deteriorating after the aforementioned

diagnostic tests have failed to provide a definite diagnosis.

ANTIBIOTICS AND ANTITUBERCULOUS THERAPY

Antibiotic or antituberculous therapy may irrevocably diminish

the ability to culture fastidious bacteria or mycobacteria. However,

hemodynamic instability or neutropenia is a good indication for

empirical antibiotic therapy. If the TST or IGRA is positive or

if granulomatous disease is present with anergy and sarcoidosis

seems unlikely, a trial of therapy for tuberculosis should be started.

Especially in miliary tuberculosis, it may be very difficult to obtain

a rapid diagnosis. If the fever does not respond after 6 weeks of

empirical antituberculous treatment, another diagnosis should be

considered.

COLCHICINE, NONSTEROIDAL ANTI-INFLAMMATORY

DRUGS, AND GLUCOCORTICOIDS

Colchicine is highly effective in preventing attacks of familial Mediterranean fever (FMF) but is not always effective once an attack is

well under way. When FMF is suspected, the response to colchicine

is not a completely reliable diagnostic tool in the acute phase, but

with colchicine treatment most patients show remarkable improvements in the frequency and severity of subsequent febrile episodes

within weeks to months. Therefore, colchicine may be tried in

patients with features compatible with FMF, especially when these

patients originate from a high-prevalence region.

If the fever persists and the source remains elusive after completion of the later-stage investigations, supportive treatment with

nonsteroidal anti-inflammatory drugs (NSAIDs) can be helpful.

The response of adult-onset Still’s disease to NSAIDs is dramatic

in some cases.

The effects of glucocorticoids on giant cell arteritis and polymyalgia rheumatica are equally impressive. Early empirical trials with

glucocorticoids, however, decrease the chances of reaching a diagnosis for which more specific and sometimes life-saving treatment

might be more appropriate, such as malignant lymphoma. The ability of NSAIDs and glucocorticoids to mask fever while permitting

the spread of infection or lymphoma dictates that their use should

be avoided unless infectious diseases and malignant lymphoma

have been largely ruled out and inflammatory disease is probable

and is likely to be debilitating or threatening.

INTERLEUKIN 1 INHIBITION

Interleukin (IL) 1 is a key cytokine in local and systemic inflammation and the febrile response. The availability of specific IL-1-

targeting agents has revealed a pathologic role of IL-1-mediated

inflammation in a growing list of diseases. Anakinra, a recombinant

form of the naturally occurring IL-1 receptor antagonist (IL-1Ra),

blocks the activity of both IL-1α and IL-1β. Anakinra is extremely

effective in the treatment of many autoinflammatory syndromes,

such as FMF, cryopyrin-associated periodic syndrome, tumor

necrosis factor receptor–associated periodic syndrome, mevalonate

kinase deficiency (hyper IgD syndrome), Schnitzler syndrome, and

adult onset Still’s disease. There are many other chronic inflammatory disorders in which anti-IL-1 therapy is highly effective. A

therapeutic trial with anakinra can be considered in patients whose

FUO has not been diagnosed after later-stage diagnostic tests.

Although most chronic inflammatory conditions without a known

basis can be controlled with glucocorticoids, monotherapy with

IL-1 blockade can provide improved control without the metabolic,

immunologic, and gastrointestinal side effects of glucocorticoid

administration.

■ PROGNOSIS

In patients in whom FUO remains unexplained, prognosis is favorable.

Two large studies on mortality in these patients have been performed.

The first study included 436 patients of whom 168 remained without

a diagnosis. Of these, 4 (2.4%) died during follow-up. All 4 patients

died during the index admission, and in 2 of them a diagnosis was

made upon autopsy (1 had intravascular lymphoma and 1 had bilateral

pneumonia). The second study included 131 patients with unexplained

FUO. Of these patients, 9 (6.9%) died during a median follow-up of

5 years. In 6 of these patients the cause of death was known, and in 5

of them death was considered unrelated to the febrile disease. Overall,

FUO-related mortality rates have continuously declined over recent

decades. The majority of fevers are caused by treatable diseases, and the

risk of death related to FUO is, of course, dependent on the underlying

disease.