Chapter 17 - Fever of Unknown Origin

Question 1

any febrile illness without an initially

obvious etiology

Answer 1

fever of unknown origin (FUO)

Question 2

prolonged febrile illnesses without an established etiology

despite intensive evaluation and diagnostic testing

Answer 2

fever of unknown origin (FUO)

Question 3

Definition of FUO

Answer 3

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 Creactive
   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).

Question 4

accounts for about one-fifth of cases of FUO in Western countries

Answer 4

infection

Question 5

common causes of FUO

Answer 5

infection

noninfectious inflammatory diseases (NIIDS)

neoplasms

Question 6

diseases under NIIDS

Answer 6

collagen or rheumatic diseases, vasculitis

syndromes, granulomatous disorders, and autoinflammatory syndromes

Question 7

50% of cases caused by infections in patients with FUO outside Western
nations are due what?

Answer 7

tuberculosis

Question 8

repeated episodes
of fever interspersed with fever-free intervals of at least 2 weeks and
apparent remission of the underlying disease

Answer 8

recurrent fever

Question 9

more common infectious

disease diagnoses that serves as differential diagnosis for FUO

Answer 9

Atypical
presentations of endocarditis, diverticulitis, vertebral osteomyelitis,
and extrapulmonary tuberculosis

Question 10

quite rare but
should always be kept in mind as a cause of FUO since the presenting
symptoms can be nonspecific

Answer 10

Q fever and Whipple’s disease

Question 11

results from exposure to animals or animal products, should be performed
when the patient lives in a rural area or has a history of heart
valve disease, an aortic aneurysm, or a vascular prosthesis.

Answer 11

Q fever

perform serologic testing

Question 12

patients
with unexplained symptoms localized to the central nervous system,
gastrointestinal tract, or joints

Answer 12

Tropheryma whipplei (whipplei’s disease)

perform polymerase chain reaction test

Question 13

diseases that could obtained when you travel to or (former) residence
in tropical countries or the American Southwest

Answer 13

infectious diseases such as malaria, leishmaniasis,

histoplasmosis, or coccidioidomycosis

Question 14

disease that 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

Answer 14

Culture-negative endocarditis

Question 15

sterile thrombotic disease that occurs as a paraneoplastic

phenomenon, especially with adenocarcinomas

Answer 15

Marantic endocarditis

Question 16

seen in the context of systemic lupus erythematosus and antiphospholipid
syndrome

Answer 16

Sterile endocarditis

Question 17

Of the NIIDs, these diseases are the common diagnoses in patients with FUO

Answer 17

large-vessel vasculitis, polymyalgia rheumatica, sarcoidosis,
familial Mediterranean fever, and adult-onset Still’s disease

Question 18

of the NIIDs, this disease very is very rare and usually present in
young patients.

Answer 18

hereditary
autoinflammatory syndromes

HAS

Question 19

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

Answer 19

Schnitzler syndrome

Question 20

most common diagnosis of FUO among the neoplasms.

Answer 20

malignant lymphoma

Question 21

miscellaneous causes of fever

Answer 21

drug-induced fever and exercise-induced hyperthermia

Question 22

often accompanied by eosinophilia and also by lymphadenopathy,
which can be extensive

Answer 22

Drug-induced fever, including DRESS

(drug reaction with eosinophilia and systemic symptoms

Question 23

More common causes of drug-induced fever

Answer 23

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)

Question 24

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; typically these patients sweat during the
temperature elevation

Answer 24

Exercise-induced hyperthermia

Question 25

fever artificially induced by the patient—for example, by IV injection of contaminated water more common among young women in health care professions

Answer 25

Factitious fever

Question 26

patient is normothermic but manipulates the thermometer. dissociation between pulse rate and temperature.

Answer 26

fraudulent fever

Question 27

FUO | in the elderly results from an atypical manifestation of a common disease, such as?

Answer 27

giant cell arteritis and polymyalgia rheumatica

Question 28

most common infectious disease associated with FUO in elderly patients, occurring much more often than in younger patients.

Answer 28

Tuberculosis

Question 29

most important step in the diagnostic workup in FUO

Answer 29

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

Question 30

blood and other cultures are not reliable | when samples are obtained during when

Answer 30

during antibiotic treatment

Question 31

size | of enlarged lymph nodes usually decreases during when

Answer 31

glucocorticoid | treatment

Question 32

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.

Answer 32

ultrasounds and chest xrays

Question 33

preferred to abdominal CT as an obligatory test because of relatively low cost, lack of radiation burden, and absence of side effects.

Answer 33

Abdominal ultrasound

Question 34

Given the absence of specific symptoms in many patients and the relatively low cost of the test, investigation of _________ appears to be a valuable screening test in patients with FUO.

Answer 34

cryoglobulins

Question 35

Specialized media should | be used when the history suggests uncommon microorganisms, such as _________

Answer 35

Histoplasma or Legionella

Question 36

when is repeating blood or urine cultures useful?

Answer 36

previously cultured samples were collected during antibiotic treatment or within 1 week after its discontinuation

Question 37

FUO with headache should prompt microbiologic examination of cerebrospinal fluid (CSF) for organisms including ____________

Answer 37

herpes simplex virus (especially | type 2), Cryptococcus neoformans, and Mycobacterium tuberculosis

Question 38

In | central nervous system tuberculosis, the CSF typically has _________

Answer 38

``` -elevated protein -lowered glucose concentrations -mononuclear pleocytosis ```

Question 39

CSF protein level in CNS TB

Answer 39

100 to 500 mg/dL

Question 40

CSF glucose concentration level in CNS TB

Answer 40

<45 mg/dL in 80% of | cases

Question 41

usual CSF cell count

Answer 41

between 100 and 500 cells/μL.

Question 42

should not be included in the diagnostic | workup of patients without PDCs for specific infections

Answer 42

Microbiologic serology

Question 43

included in the obligatory investigations, but it may yield falsenegative results in patients with miliary tuberculosis, malnutrition, or immunosuppression.

Answer 43

TST

Question 44

diseases that could yield false-negative result

Answer 44

miliary tuberculosis, malnutrition, | or immunosuppression

Question 45

less influenced by prior vaccination with bacille Calmette-Guérin or by infection with nontuberculous mycobacteria, its sensitivity is similar to that of the TST

Answer 45

IGRA

Question 46

Granulomatous disease in liver or bone marrow biopsy samples, for example, should always lead to a (re)consideration of this diagnosis.

Answer 46

Miliary tuberculosis

Question 47

diagnostics to be done to have highest diagnostic yield for miliary tuberculosis

Answer 47

liver biopsy for | acid-fast smear, culture, and polymerase chain

Question 48

One of the first steps in diagnosing FUO, particularly in patients without signs of inflammation in laboratory tests.

Answer 48

rule out factitious or fraudulent | fever

Question 49

should be discontinued early in the | evaluation to exclude drug fever

Answer 49

medications, including nonprescription drugs | and nutritional supplements

Question 50

If fever persists beyond _____ after discontinuation of the suspected drug, it is unlikely that this drug is the cause

Answer 50

72 hr

Question 51

In patients without PDCs or with only misleading PDCs, __________ may be useful in the early stage of the diagnostic workup.

Answer 51

funduscopy

Question 52

When the first-stage diagnostic tests do not lead to a diagnosis, ________ should be performed, especially when the ESR or the CRP level is elevated.

Answer 52

scintigraphy

Question 53

In patients with recurrent fever lasting ______, | it is very unlikely that the fever is caused by infection or malignancy

Answer 53

>2 years

Question 54

noninvasive method allowing delineation of foci in all parts of the body on the basis of functional changes in tissues.

Answer 54

Scintigraphic imaging

Question 55

Conventional scintigraphic methods used in clinical practice

Answer 55

67Ga-citrate scintigraphy and 111In- or 99mTc-labeled leukocyte scintigraphy.

Question 56

diagnostic test that routinely | provide information on only part of the body

Answer 56

CT and MRI

Question 57

diagnostic test that readily allows whole-body imaging

Answer 57

scintigraphy

Question 58

established imaging procedure in FUO

Answer 58

18F-Fluorodeoxyglucose (FDG) positron emission tomography (PET) combined with CT

Question 59

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

Answer 59

FDG

Question 60

Normal uptake may obscure pathologic foci in the ________________

Answer 60

brain, | heart, bowel, kidneys, and bladder

Question 61

FDG uptake in the heart, which obscures endocarditis, may be prevented by consumption of a ___________ before the PET investigation

Answer 61

low-carbohydrate diet

Question 62

offers the advantages of higher resolution, greater sensitivity in chronic low-grade infections, and a high degree of accuracy in the central skeleton.

Answer 62

FDG-PET/CT

Question 63

they often identify the anatomic location of a particular ongoing metabolic process and, with the help of other techniques such as biopsy and culture, facilitate timely diagnosis and treatment

Answer 63

scintigraphic techniques

Question 64

Abnormalities found with scintigraphic techniques often need to be confirmed by ____________

Answer 64

pathology and/or culture of biopsy specimens

Question 65

If no diagnosis is reached despite scintigraphic and PDC-driven histologic investigations or culture, ____________________ should be considered

Answer 65

second-stage screening diagnostic | tests

Question 66

may be used as screening procedures at a later stage of the diagnostic protocol because of their noninvasive nature and high sensitivity.

Answer 66

chest | and abdominal CT

Question 67

Several studies have shown a high prevalence of _________ among patients with FUO, with rates up to 17% among elderly patients

Answer 67

giant cell arteritis

Question 68

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

Answer 68

temporal artery biopsy

Question 69

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

Answer 69

FDG-PET/CT

Question 70

good indication | for empirical antibiotic therapy

Answer 70

hemodynamic instability or neutropenia

Question 71

when does trial of therapy for TB should be started?

Answer 71

TST or IGRA is positive granulomatous disease is present with anergy and sarcoidosis seems unlikely

Question 72

If the fever does not respond after ______ of empirical antituberculous treatment, another diagnosis should be considered.

Answer 72

6 weeks

Question 73

highly effective in preventing attacks of familial Mediterranean fever but is not always effective once an attack is well under way.

Answer 73

Colchicine

Question 74

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

Answer 74

NSAIDS

Question 75

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

Answer 75

NSAIDs and glucocorticoids

Question 76

a recombinant form of the naturally occurring IL-1 receptor antagonist (IL-1Ra), blocks the activity of both IL-1α and IL-1β

Answer 76

Anakinra

Question 77

extremely effective in the treatment of many autoinflammatory syndromes, such as familial Mediterranean fever, cryopyrin-associated periodic syndrome, tumor necrosis factor receptor–associated periodic syndrome, mevalonate kinase deficiency (hyper IgD syndrome), and Schnitzler syndrome

Answer 77

Anakinra

Question 78

A therapeutic trial with _____ can be considered in patients whose FUO has not been diagnosed after later-stage diagnostic tests.

Answer 78

Anakinra

Question 79

can provide improved control without the metabolic, immunologic, and gastrointestinal side effects of glucocorticoid administration.

Answer 79

monotherapy with IL-1 blockade