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Perspective

TheNEW ENGLAND JOURNAL ofMEDICINE

january 17, 2013

n engl j med 368;3 nejm.org january 17, 2013197

as they define it a tempera-ture rising above 38.3C (101F)on several occasions over a peri-od of more than 3 weeks, forwhich no diagnosis has beenreached despite 1 week of inpa-tient investigation is con-sidered classic FUO. In the past60 years, clinician-scientists havetracked the changing causes ofthese problematic fevers, as dis-ease patterns and definitionshave changed and as improvedserologic and imaging technolo-

gies have begun revealing diag-noses more quickly. The standarddefinition of FUO no longer in-cludes the requirement for a weekof inpatient evaluation. And in theearly 1990s, Durack and Streetproposed dividing FUOs into fourgroups: classic, nosocomial, neu-tropenic, and HIV-associated.2

According to Petersdorf andBeesons original report, FUOs

were caused by infection (in 36%of patients), malignancy (19%),collagen vascular diseases (19%),and miscellaneous other causes(19%), such as drug fever.1 Nocause was determined in 7% ofpatients. It is paradoxical thatdespite the introduction of com-puted tomography (CT), magneticresonance imaging, improved cul-ture techniques, numerous newserologic assays, and polymerase-chain-reaction studies, in recentyears more FUOs have actually

eluded diagnosis. In 2003, Vander-schueren and colleagues reportedthat in nearly a third of 290 im-munocompetent patients in Bel-gium, no diagnosis was made,3and in 2007, Bleeker-Rovers et al.reported that among 73 immu-nocompetent patients from fivehospitals in the Netherlands, nocause of FUO was identified in51% of cases.4

As an infectious-disease physi-cian who has practiced at academ-ic, tertiary care facilities in themetropolitan New York area fornearly three decades, Ive beenstruck by the fact that traditionallycaused FUOs are now rarer thanthe FUOs that Im increasinglyasked to evaluate. The new FUOsare often found in patients in theintensive care unit (ICU) who havetraumatic brain injury, other neu-rologic events, or dementia; aremechanically ventilated; have somecombination of urethral, central,and peripheral catheters placed;have recently undergone surgery;and are already receiving multiplebroad-spectrum antibiotics. How-ever, they continue to spike multi-

ple fevers daily for weeks andsometimes months on end, usuallywithout other signs or symptomsof sepsis.

Physical examination often re-veals edema (if not anasarca),early decubital ulcers in thesacral region at minimum, cuta-neous eruptions that do not ap-pear to be drug-related, mild ab-dominal distention, wounds that

Fever of Unknown Origin or Fever of Too Many Origins?Harold W. Horowitz, M.D.

Petersdorf and Beesons classic articles cataloguingthe causes of fever of unknown origin (FUO) haveframed the way generations of physicians think aboutfevers whose source is not readily explainable.1 FUO

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have minimal erythema andsome serous drainage withoutpurulence or obvious infection,no signs suggestive of deep ve-nous thrombosis, and coarsebreath sounds on respiratoryexam. And their lines have beenrecently changed.

Laboratory results include nor-mal or mildly elevated white-cellcounts; intermittent coagulase-negative, staphylococcus-positiveblood cultures; urinalysis withintermittent pyuria and culturesrevealing, sequentially, variousgram-negative organisms withcounts of 10,000 to 20,000 colony-forming units interspersed withnegative cultures; sputum sam-ples with few or moderate num-bers of white cells; and chest im-ages revealing bilateral basilarcongestion with atelectasis, whose

readers say they cannot rule outinfection. Wound cultures revealseveral bacteria but few, if any,white cells, and CT scans showpostsurgical changes or smallfluid collections not particularlysuspicious for infection. Sinusfilms invariably demonstrate thick-ened sinus membranes withoutairfluid levels or other clear-cutfindings of sinusitis. Venous Dop-

pler studies are negative or revealnonocclusive thrombosis. C-reac-tive protein (CRP) levels fluctuatewildly from day to day. Clostridiumdifficileassays performed becauseof chronic loose stools are invari-ably negative. The transthoracicechocardiogram is normal, andthere is a debate about the safetyof and need for a transesopha-geal echocardiographic study.

Generally, before I evaluate thepatient, many diagnostic studieshave been done. Nevertheless, de-termining the cause of a feverand which antibiotics to prescribeis frequently daunting. Althoughthese fevers would be considerednosocomial by Durack and Streetand may be of infectious origin,the differential diagnosis extendswell beyond the usual infectioussuspects. In fact, I wonder

whether these are FUOs or feversof too many origins (FTMOs).Decisions about which other

or repeat diagnostic evaluationsand procedures to undertake,whether to treat empirically forC. difficile (if that isnt already be-ing done), and whether to expandthe antibiotic potpourri or per-haps discontinue antibiotics arenot easy. The nuances and com-

plexity of decisions regarding anti-biotics are also affected by thedissonant messages bombardingphysicians: the mantra that anti-biotics must be used sparingly toavoid creating antibiotic-resistantbacteria versus the urgency to

start antibiotics earlier while en-suring they are the appropriatechoices (translated as broad,given the resistance patterns inmany ICUs). When patients havebeen hospitalized for many monthsand have received numerous anti-biotics but have persistent fevers,it can be unclear whether appro-priate antibiotics exist or arewarranted. Although some phy-sicians sing CRPs praises, the

near-daily variation in this mea-sure and its nonspecificity makeit difficult to use to guide treat-ment decisions. Certainly, neitherCRP levels nor procalcitonin levelshelp determine which culturesshould be addressed with treat-ment. Moreover, if one choosesto use antibiotics, the questionof which of the multiple bacterialisolates need to be covered iscomplex.

As the keeper of the antibiot-ics, should I be a conservative ora cowboy? Should the current anti-biotics be continued, changed, orstopped? If there are no pre-scribed antibiotics, should I rec-ommend some? These are inter-esting questions in the abstract,but there is a real patient suffer-ing, a family with questions, andmedical teams awaiting my opin-

ion. There are no evidence-basedstudies and there is no guidanceon which potential source of fe-ver is the single appropriate oneto treat. Frequently, the treat-ment approach is like playingWhac-A-Mole: positive culturesare treated sequentially pneu-monia, then catheter cultures,then urine cultures. When the feverpersists, the cycle begins again.

Fever of Unknown Origin or Too Many Origins?

0

10

20

30

4050

60

70

80

90

100

DiagnosesinFe

brilePatients(%)

100

40

50

10

60

20

30

0

70

80

90

1961 1982 1992

Publication Year

1994 1997 2002 2007

No diagnosis

Miscellaneous

Noninfectiousinflammatorydisease

Neoplasm

Infection

N=100 N=105 N=133 N=199 N=153 N=167 N=73

36.0 30.5 30.8 28.7 25.8 10.8 16.0

19.031.4 19.6 14.4

12.6

9.77.0

17.012.4

15.0

30.722.7

18.4 22.0

19.0 9.5

12.7

14.4

7.8

8.14.0

9.0

16.221.8

11.8

31.3

53.0 51.0

Distributions of Diagnoses (and Lack of Diagnosis) among Patients with Fever.

Data for studies published in 1961 through 2002 are from Vanderschueren et al.,3

and 2007 data are from Bleeker-Rovers et al.4

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199

The medical team membersmay be frustrated or believetheyve exhausted the workupstudies, and they may prefer notto order any more. They may notbe too keen on continuing thesame antibiotics. The ICU team

hungers for something new andpreferably simple. As I review thedifferential diagnosis, with dis-claimers as to why any given di-agnosis does or does not ade-quately explain the fever, I get afeeling of dj vu. The team hasheard these ruminations from meand my colleagues many times,and I suspect that by now thediscussion is minimally compel-ling or interesting academically.

This is not the multidimen-sional great case that FUOswere once advertised to be thecases presented on chief-of-ser-vice rounds in which an expertdiagnostician pontificates aboutthe differential diagnosis of rare

or subtle disease complexes andtheir presentations. Given the na-ture of the illness in many ofthese patients, the conferencesare more likely to be family con-ferences that include plans forpalliative care. If the old FUOs

were sometimes exhilarating, theFTMOs can be debilitating. Al-though some patients will recoverand be discharged to lead fulland active lives, many will eitherdie or be sent to a long-term carefacility.

We debate whether using anti-biotics in apparently futile situa-tions is ethical. After all, we maycreate some extremely resistantbacteria in one patient that could

be transmitted to others. Alter-natively, antibiotics may be life-saving. There are few directives,ethical guidelines, or clinical path-ways to follow in these cases. AsI mull over the options, I am dis-heartened by the knowledge that

whether I use or withdraw anti-biotics (asking the team to ob-serve the patient closely) or re-quest more testing, I may simplybe deferring the tough decisionsfor another day.

Disclosure forms provided by the author

are available with the full text of this arti-cle at NEJM.org.

From the Division of Infectious Diseasesand Immunology, New York UniversitySchool of Medicine, New York.

1. Petersdorf RG, Beeson PB. Fever of unex-plained origin: report on 100 cases. Medi-cine (Baltimore) 1961;40:1-30.2. Durack DT, Street AC. Fever of unknownorigin reexamined and redefined. CurrClin Top Infect Dis 1991;11:35-51.3. Vanderschueren S, Knockaert D, Adri-aenssens T, et al. From prolonged febrile ill-ness to fever of unknown origin: the chal-

lenge continues. Arch Intern Med 2003;163:1033-41.4. Bleeker-Rovers CP, Vos FJ, de KleijnEMHA, et al. A prospective multicenterstudy on fever of unknown origin: the yield ofa structured diagnostic protocol. Medicine(Baltimore) 2007;86:26-38.

DOI: 10.1056/NEJMp1212725

Copyright 2013 Massachusetts Medical Society.

Fever of Unknown Origin or Too Many Origins?

Should Blood Be an Essential Medicine?Harvey G. Klein, M.D.

According to the World HealthOrganization (WHO), approx-imately 92 million units of bloodare collected worldwide each year.Given that transfusions are gener-ally credited with saving millionsof lives, it may surprise cliniciansto know that blood and bloodcomponents are not included onthe WHO Model List of Essential

Medicines.The Model List, established in1977, originally included about 200active substances. It was meantto guide countries in providingaccess to cost-effective medicinesthat are vital for public health.1The list is revised every 2 yearsby a WHO expert committee.Medicines are designated as es-sential on the basis of their effi-

cacy and safety, availability, easeof use in various settings, compar-ative cost-effectiveness, and pub-lic health need. In many coun-tries, the list forms the basis ofnational drug policies. Govern-ments and health ministries oftenrefer to it when making decisionsregarding resource allocation andhealth care spending. The list

does not include all efficaciousmedicines, the latest medicines,or even all medicines needed in acountry. Rather, it helps to definethe minimum medicine needs fora basic health system.

Although some protein con-centrates (factors VIII and IX andimmunoglobulins) are listed, nolabile blood components are onthe Model List. The reason for

their absence is unclear. Certain-ly, the lengthy, exhaustive processfor applying for a listing can bediscouraging: each component re-quires a separate detailed, complexapplication. Most medicines areproposed by manufacturers witha commercial interest in havingtheir products listed. There hasbeen no similar advocacy for blood

components that are collected andprepared by not-for-profit organi-zations, until now.

There are compelling reasonsto add whole blood and red-cellconcentrates to the list. Bloodtransfusion originated as a medi-cal practice requiring either sur-gical intervention to join donor torecipient or a licensed practitionerto draw and immediately infuse

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