Evaluation of the Febrile Patient

Fevers and Fevers of Unknown Origin

A case-based approach

Richard Serrao MD
Assistant Professor of Medicine, BUSM
Sections of Internal Medicine and Infectious Diseases
The febrile patient

 Fevers: Relatively straightforward approach

 Definitions
 Fever vs hyperthermia vs hyperpyrexia
 Mechanisms
 Initial approach
 Fevers of unknown origin: More complex, more fun
to chase
 Definition
 Spectrum
 Fun Cases and categories
What is a fever?

 Elevation in body temperature above normal

range from increase in temperature
regulatory set point : 99.5–100.9 °F
 Mouth >99.9
 Axilla/otic >99.0
 Anus >99.5-100.9
 Hyperpyrexia: typically not infectious
 104–106.7 °F

Set points vary depending on clinical setting

Fever versus hyperthermia
 Fever: resetting of the thermostatic set-point in the
anterior hypothalamus and the resultant initiation of
heat-conserving mechanisms until the internal
temperature reaches the new level
 If acute (and less commonly chronic), infection unless
proven otherwise
 Hyperthermia: an elevation in body temperature that
occurs in the absence of resetting of the hypothalamic
thermoregulatory center
 Usually not mediated by infectious diseases

The difference between these two is mechanism

Mechanisms of fever (in 3 sentences)

 Pyrogens (endogenous and exogenous) trigger

fevers via release of prostaglandin E2 
hypothalamic stimulation  vasoconstriction,
then shivering  temp rise
 Endogenous: IL1, 6,8, TNF, IFNa,b,g  arachidonic
acid pathway activated
 Can be released in collagen vascular, malignancy
 Exogenous: i.e. LPS  binds to lipopolysaccharide
binding protein  release of IL-1
 Typically infectious
Mechanisms of fever: Examples of
Common Bacterial pyrogens
Lipopolysaccharide (LPS) endotoxin of GNRs
 binds to LPS-binding protein and is transferred to CD14 on macrophages,
which stimulates the release of TNFα.

Staphylococcus aureus enterotoxins

Staphylococcus aureus toxic shock syndrome toxin

(TSST)
 Both Staphylococcus toxins are superantigens and activate T cells leading to
the release of interleukin (IL)-1, IL-2, TNFα and TNFβ, and interferon (IFN)-
gamma in large amounts

Group A and B streptococcal toxins

 Exotoxins induce human mononuclear cells to synthesize not only TNFα but
also IL1 and IL-6
Fever types (by severity): Mechanisms of
hyperthermia/hyperpyrexia

Excessive heat production:

exertional hyperthermia, thyrotoxicosis,
pheochromocytoma, cocaine, delerium tremens,
malignant hyperthermia

Disorders of heat dissipation:

heat stroke, autonomic dysfunction

Disorders of hypothalamic function:

neuroleptic malignant syndrome, CVA, trauma
All non infectious!
General approach to Fevers

 Chase the symptom

 Headache, meningismus, pharyngitis, dysuria, diarrhea,
abdominal pain, etc.
▪ Makes it obvious!
 Start with the basics: ua/urine culture, CXR, blood
cultures
 Follow the pattern
 Look at everything for patients in whom the pattern is
inconsistent
 Most fevers diagnosed early (i.e. not an FUO yet) will
have an infectious cause…
…ergo: The preliminary work-up

 History
 PE
 CBC with diff
 Blood cultures (3 sets drawn from different
sites over at least several hours OFF abx)
 Chem 7 and LFTs
 Hepatitis serologies if LFTs abnormal
 UA, urine culture
 CXR
Most patients will have the answer here
“A patient with a fever that has not had a basic
work up yet does not an FUO make”
Fever of Unknown Origin (FUO)-
Petersdorf and Beeson 1961

“Fever > 38.3 (101) on several occasions,

persisting without diagnosis for at least 3
weeks in spite of at least 1 week’s
investigation in hospital.”
 Categories of FUO/updated criteria
Featurea Nosocomial Neutropenic HIV-associated Classic

Patient’s Hospitalized, Neutrophil count Confirmed HIV- All others with

situation acute care, no either <500/µL or positive fevers for ≥3
infection when expected to reach weeks
admitted that level in 1-2
days
Duration of 3 daysb 3 daysb 3 daysb (or 4 3 daysb or 3+
illness while weeks as outpatient
investigated outpatient) visits

Examples Septic Perianal infection, MAIc infection, Infections,

thrombophlebitis, aspergillosis, TB, non- malignancy,
sinusitis, C. candidemia Hodgkin’s inflammatory
difficile colitis, lymphoma, drug diseases, drug
drug fever fever fever
a
All require temperatures of ≥38.3°C (101°F) on several occasions. Modified from DT Durack, AC Street, in JS Remington, MN Swartz (eds):
b
Includes at least 2 days’ incubation of microbiology cultures. Current Clinical Topics in Infectious Diseases. Cambridge, MA, Blackwell,
cM. avium/M. intracellulare.
1991.
The changing spectrum
 Over decades, the etiology has been shifting

 3 classic categories are consistent:

 Infections
 Malignancies
 Connective tissue diseases

 True FUOs are uncommon

 Excessive use of empiric antibiotics can mask/delay diagnosis of

occult abscesses/infections; drug fevers increasing

 MDR organisms, lengthy ICU and chemo regimens changing the flora
The changing spectrum
 Undiagnosed FUOs has gone from 75% to <10%, but the
fraction of FUOs that are undiagnosed has increased

 More connective tissue diseases are being diagnosed

 Extrapulm TB, solid tumors and intrabdominal abscesses are

less prevalent due to CT scanning
 CT guided IR has replaced ex-laps for diagnosis

 Better blood culturing techniques has reduced IE as an

etiology for FUO
 Culture negative or fastidious organisms (bartonella) remain as FUOs
The longer a patient has a fever, the less likely an ID cause will be found
Case #1

 72 y.o, male with cirrhosis, diabetes and is

on chronic steroids for RA who is s/p partial
colectomy for recurrent diverticular
disease
Case #1: (Occult) abscess
 usually located in the abdomen or pelvis
 cirrhosis, steroid or immunosuppressive medications, recent
surgery, and diabetes are predisposing factors
 arise in locations of disrupted barrier in bowel wall (appy, tics, IBD).
 develop in subphrenic, omental, pouch of Douglas, pelvic, and
retroperitoneal locations.
 Pyogenic liver abscesses in setting of biliary tract disease,
appendicitis or diverticulitis.
 Amebic liver abscesses can look like pyogenic abscesses; check e
histolytica serologies.
 Splenic abscesses occur from hematogenous seeding: look for
concominant endocarditis
 Perinephric abscesses can have normal UA/urine culture
When an infection is the cause of FUO
by disease
 Intraabdominal abscess (liver, splenic, psoas, etc)
 Appendicitis
 Cholecystitis
 tubo-ovarian abscess
 Intracranial abscess
 Sinusitis
 dental abscess
 Chronic pharyngitis
 Tracheobronchitis
Things that are hidden,
 lung abscess may give false negative
 Septic jugular phlebitis blood cultures, or have an
 mycotic aneurysm unrevealing (missed on)
 Endocarditis
exam
 intravenous catheter infection
 vascular graft infection
 Wound infection
 Osteomyelitis
 infected joint prosthesis
 Pyelonephritis We’re getting better at finding these things!
 prostatitis
We’re getting better at finding infections and cancers
thereby reducing the total FUOs seen, but leaving
many undiagnosed cases
True FUOs rare

 2800 hospital beds over 2 year period (2003-

2005); only 73 cases of FUOs found
 Noninfectious inflammatory diseases (vasculitis,
SLE, PMR) — 22%
 Infection — 16%
 Malignancy — 7%
 Miscellaneous — %
No diagnosis — 51%
Bleeker-Rovers et al. Medicine (Baltimore). 2007 Jan;86(1):26-38.
Case #2
 45 y.o G5, P5 woman from subsaharan Africa with HIV
who presents with daily fevers as high as 103.
 She has no cough, SOB, headache. She is on no meds.
 Her LFTs are mildly elevated with mild hepatomegaly
and ascites. HAV/HBV/HCV negative.
 CXR is negative.
 CBC demonstrates microcytic anemia with teardrop
cells.
 She is not on HAART and has a CD4 of 376, VL 28,000
Case #2

 Ascites fluid is lymphocytic predominant.

Blood cultures, ascitic fluid: no growth.
 BM aspirate:

oraclesyndicate.twoday.net
Case #2: Tuberculosis as an FUO
 single most common infection in most FUO series.
 Can be extrapulmonary, miliary, or occur in the lungs of
patients with significant preexisting pulmonary disease,
or immunodeficiency
 pulmonary tuberculosis in AIDS patients is subtle; CXR
normal in up to 20%
 Readily treatable
 PPD positive in <50%
 Sputum + in only 25%
 May require lymph node, BM or liver biopsy
 Isolator blood cultures need incubation for >16 days
Geography and FUOs
 Developing world
 TB
 Typhoid
 Amebic liver abscesses
 AIDS

 Returning traveler
 Malaria
 Brucellosis
 Kala azar
 Filariasis
 Schistosomiasis
 Lassa fever
Worldwide “FUOs”
 Ease of travel can increase risk for non endemic
(autochthonous) infections to be present in the recent
traveler given long incubation period
 malaria, brucellosis, kala azar, filariasis, schistosomiasis, Lassa fever

 the most common infections among series of FUOs have not

changed over the century:
 typhoid fever, TB, amebic abscesses, malaria.

 FUOs are more often caused by an atypical presentation of a

common entity than by a rare disorder
Case: Fever in the states

 56 y.o. male HIV+, CD4 332, VL ND on HAART

presents in Nov with fever 104.0 q day,
shaking chills, myalgias and malaise. Mild
diffuse HA. Evanescent rash noted on left
shoulder
 Recent hiking in NH
 PE: flushed, ill but not toxic. No focality
 Pancytopenia (new), AST 150, ALT 161, TB 0.4
Anaplasmosis (Ehrlichiosis)

 Always look at peripheral smear in

presumptive BM disorders
 Intraleukocytic/intraerythrocytic inclusions
 <60% recall tick exposure
 Search for coexistent lyme and babesiosis
When an infection is the cause of FUO
by pathogen
 Tuberculosis, Mycobacterium avium complex,
syphilis, Q fever, legionellosis
 Salmonellosis (including typhoid fever), listeriosis,
ehrlichiosis,
 Actinomycosis, nocardiosis, Whipple’s disease
 Fungal (candidaemia, cryptococcosis, sporotrichosis,
aspergillosis, mucormycosis, Malassezia furfur)
 Malaria, babesiosis, toxoplasmosis, schistosomiasis,
fascioliasis, toxocariasis, amoebiasis, infected
hydatid cyst, trichinosis, trypanosomiasis
 Cytomegalovirus, HIV, Herpes simplex, Epstein-Barr
virus, parvovirus B19
Subpopulations of FUOs

 HIV/AIDS:
 79% infections
▪ 50% mycobacterial (2/3 atypical mostly MAC)
 8% malignancies: NHL; disseminated KS rare
 9% no diagnosis

 Neutropenia
 Most due to bacteremia
 Fungi as source of FUO increases after 7 days (fungemia, then aspergillus)
 Confounders include: cancer, drugs, blood products
 Fever when neutropenia resolves: hepatosplenic candidiasis

 Age:
 Children: 30% self limited viral syndrome
 Age >65: 30% caused by PMR, vasculitis, GCA, sarcoid; 22% infections; 12% cancers
Case #3: FUO in AIDS

 55 y.o. HCV/HIV+, CD4 5, VL

115,000 noncompliant with
HAART. CC: confusion, fever,
anisocoria
 Head CT: mass lesion with
hemorrhage; CT body: no
lymph node enlargement
 CSF: normal
 Pyrimethamine/sulfadiazine
started empirically for toxo
Case #3: FUO in AIDS
 Within 2 days, >20 SC erythematous tender
nodules on shins and buttocks
Fever with erythema nodosum
(panniculitis)
 Rheumatic fever
 Sarcoidosis
 Drug induced
 Post-streptococcal
 Mycoplasma
 Coccidioidomycosis
 Other fungal
 TB/nontuberculous mycobacteria
 SLE
 Vasculitis
 syphilis
Case #3: FUO in AIDS: Skin Biopsy
Case #3: FUO in AIDS: Culture results:
Mycobacterium avium intracellulare

 Blood and skin grew Mycobacterium avium

intracellulare
 Patient recovered with Clarithromycin,
rifampin and ethambutol

Tandon R, Kim K, Serrao R. Disseminated mycobacterium avium-intracellulare

infection in a person with AIDS with cutaneous and CNS lesions. The AIDS
Reader. 2007; 17(11): 555-560
FUO in AIDS case 2
 36 y.o. male with ? PMH of PCP PNA 1yr PTA and
several suicide attempts with benzos/percocets
 BIB family members who noted patient to be
lethargic, c/o chills and RUQ pain
 Exam notable for T102.6, HR 110, 100/55, O2 sat 90%
RA, lethargic, conjunctival injection, thrush, ? Nuchal
rigidity, dry crackles, mod RUQ tenderness,
hepatomegaly, +/- guarding
 Admitted to ICU with dx of acute hepatic failure
secondary to probable tylenol overdose (sister saw
empty bottles in room)
 Grew up in Chicago
 WBC: 12 (90P), 11/33, Plts 90
 134/3.3/102/9/34/2.3 AG 23
 LFTs: AST 2344, ALT 2688, Alk Phos 113
 PT 15, PTT 42
 DIC screen +
 Acetominophen level, pancultures pending
 CXR: diffuse interstitial infiltrates
 Patient started on ceftriaxone 2g iv q 12,
vanco 1 g q 12, ampicillin 2 q 8 and high dose
Bactrim.
 N-acetylcysteine administered empirically
 STAT RUQ ultrasound read as hepatomegaly
with TNTC punctate lesions throughout
parenchyma of liver; no bil dil; no stones
Disseminated histoplasmosis
Disseminated histoplasmosis
Disseminated histoplasmosis

 Consider in immunocompromised host

(AIDS, solid organ transplant) with
transaminase elevations, unexplained fever,
reticulonodular pulmonary infiltrates from
endemic area
Case #4

 35 y.o. recuperating counts after prolonged

neutropenia for AML who has been on
cefepime and vanco and defervesced early.
 C/o RUQ tenderness, LFT abnormalities,
febrile
 CT abdomen reveals multiple punctate small
echogenic lesions
CT Scan shows multiple hypodense lesions in the
liver and spleen .

Curr Probl Diagn Radiol, November/December 2004

Case #4: Hepatosplenic candidiasis

 Complication of prolonged neutropenia that

required systemic antimicrobials when fever
abates
 Due to duration of systemic antimicrobials
(as compared to aspergillus which is due to
duration of neutropenia)
 Treat with fluconazole/echinocandins if
suspect glabrata
Case #5

 71 y.o. male c/o fevers, night sweats, weight

loss for 3 months. Generalized muscle aches
and difficulty getting up from chair
 PMH: sulfa allergy, noted to be anemic 1 yr
ago, negative blood loss w/u
 PPD neg
 Labs anemic & leukopenic with monocytosis.
ANA, DS DNA, and LFTS nl
 ESR 102, elevated serum ferritin
Temporal artery biopsy in giant cell (temporal) arteritis. Left panel:
Granulomatous and lymphocytic inflammation of the adventitia and medial
wall of the temporal artery. Right panel: Elastic tissue stain showing disruption
of the elastica (arrows) due to immunologically mediated destruction of the
elastica.
Courtesy of Cynthia Magro, MD via uptodate.com
DDx of FUO in elderly
 Temporal arteritis/PMR/vasculitis/sarcoid: 30%

 Infectious: 22%
 Endocarditis
 Cryptogenic intraabdominal abscess
 Extrapulm TB

 Malignancy: 12%
 Lymphoma
 Hepatoma
 Renal cell ca
 Unusual to cause FUO: colon ca, leukemia, MDS
Approach to FUO: Clues

 Clues on exam and labs:

 11 diagnostic clues/patient in history and physical
 3/patient in laboratory tests
 81% of these clues are misleading
 Ask about:
 Travel
 Animal exposure (pets, living on a farm, occupational)
 Immunosuppression
 Drug and toxin history
 Localizing symptoms
Bleeker-Rovers CP et al Medicine. 2007 Jan;86(1):26-38 .
Clues: Fever types (by curves)

 Intermittent: fever for a certain period, cycling back to normal: Malaria, kala-azar, sepsis
 Quotidian fever, with a periodicity of 24 hours, typical of Plasmodium falciparum or Plasmodium
knowlesi
 Tertian fever (48 hour periodicity), typical of Plasmodium vivax or Plasmodium ovale malaria
 Quartan fever (72 hour periodicity), typical of plasmodium malariae

 Continuous: Temperature remains above normal throughout the day and does not
fluctuate more than 1 °C in 24 hours:
 lobar pneumonia, typhoid, UTI, brucella or typhus

 Pel-Ebstein fever: high for one week, low for the next:
 Hodgkins lymphoma

 Remittent fever: Temperature remains above normal throughout the day and fluctuates
more than 1 °C in 24 hours
 Infective endocarditis
Old school curves

A. Malaria
B. Typhoid fever
C. Hodgkins (Pel Ebstein)
D. Borreliosis (relapsing fever)

Specificity of these curves is still generally poor

Hirschmann Clin Infect Dis. 1997 Mar;24(3):291-300; quiz 301-2 www.bioscience.org

Clues: Fever types (by severity)

 Hyperpyrexia >106.7
 Intracranial hemorrhage most common
 Sepsis
 Kawasaki syndrome
 Neuroleptic malignant syndrome
 Drug fever
 Serotonin syndrome
 Thyroid storm
Clues: ID associated relative
bradycardia
 Typhoid fever
 Malaria
 Typhus
 Yellow fever
 Leptospirosis
 Dengue
 RMSF
 Q fever
Clues: Fever after travel

 Malaria
 Typhoid fever
 Acute HIV
 Kala-azar
 Amebic liver abscess
 Tuberculosis
 Brucellosis
 meloidosis
Case #5: interesting clue

27 y.o. female presents

with sore throat, fever
and diffuse
myalgias/arthralgias
-WBC 14.3, ESR 67, CPK
slightly incr. Neg CXR,
blood cxs neg
-CT abd/pelvis:
splenomegaly.
-RF, ANA, ANCA neg
-Unprotected sex 2
months ago

http://www.dailystrength.org/groups//media/611476
Case #5

 HIV 1,2 Ab negative

 HIV-RNA PCR (viral load) returns at 121
copies
Still’s disease (Juvenile Rheumatoid
Arthritis)
 Arthralgias, fevers, elevated ferritin and
salmon colored evanescent rash
 1.5 cases per 100,000-1,000,000 population
 Bimodal distribution: 15–25 and second peak
between ages of 36–46
 Diagnosis of exclusion
Diagnostic criteria: need 5 (at least 2 of
them major)
 Major criteria:
 fever >39C for > 1 week
 Arthralgias or arthritis for at least two weeks,
 Nonpruritic salmon colored rash (usually over trunk or extremities while
febrile),
 Leukocytosis ( 10,000/microL or greater), with granulocyte
predominance
 Minor criteria:
 Sore throat,
 Lymphadenopathy,
 Hepatomegaly or splenomegaly,
 Abnormal liver function tests,
 Negative tests for antinuclear antibody and rheumatoid factor
What infectious disease does this sound like? Mono syndrome: HIV/EBV/CMV
Collagen vascular disease as FUO

 SLE and ANCA+ disorders rare

 Polymyalgia rheumatica
 Temporal arteritis
 Giant cell arteritis
 Adult still’s disease
 Behcets
 Kikuchi’s disease

Again, most of these in older patients

Case #6: interesting clue (?)

 55 y.o. female presents with 4 months of

persistent night sweats, fevers
 Visited a farm with kids and watched a goat
give birth 5 months ago
Q fever (and culture neg endocarditis)

 Caused by coxiella burnetii (serologies): “parturient cats,” sheep,

goats, cattle; aerosolization/contact with body fluids/ingestion of
infected milk; ticks as reservoirs; ILI, painless hepatitis, atypical pna,
prolonged FUO; dx: serologies
 Cultures are negative in 2-5% in all cases of BE especially in partially
treated
 Culture negativity common with Coxiella Burnetii, tropheryma
whippeli, brucella, mycoplasma, chlamydia, histoplasma, legionella,
bartonella
 HACEK: haemophilus spp, actinobacillus, cardiobacterium, eikenella
and kingella: alert lab to incubate cultures for 7-21 days
 Peripheral manifestations are rare
 TEE reveals veg in 90% of SBE presenting as FUO
 Treated with tetracycline
The algorithmic approach to workup/labs/imaging
Mourad, et al. Arch Intern Med. 2003;163:545
Laboratory work up: False positive
rate=rate of a helpful result
 ESR and crp: TB,osteo, CA, CVD >100
 LDH: lymphoma, PJP
 PPD or quantiferon: TB
 HIV ab (consider viral load): HIV
 3 blood culture sets over several hours (prior to
antibiotics): bacteremia
 RF: rheumatoid arthritis
 CPK: PMR, polymyositis
 Heterophile ab (children, young adults): mono (EBV)
 SPEP: MM
 ANA: autoimmune process
 CT of abdomen and chest: r/o lymphadenopathy,
nodules
Utility of ESR: good negative
predictive value
 ESR > 100
 Malignancy (lymphoma, myeloma, metastatic colon or breast): 58%
 Infections: endocarditis, TB, osteo: 25%
 Collagen vascular disease: 25%

 Less serious causes causing ESR > 100

 Drug hypersensitivity
 Thrombophlebitis
 Renal disease (nephrotic syndrome)

 Normal ESR suggests that a significant inflammatory process, of

whatever origin, is absent
 can be seen in GCA, however
Zacharski et al JAMA. 1967 Oct 23;202(4):264-6.
Utility of CT, tagged WBC and PET
Scanning
 Useful to pick up lymphadenopathy,
granulomas
 Lymphomas, tuberculous, fungal
 Gallium-67 and/or indium-111: highly
sensitive for whole body but not specific
 PET scan data is limited in FUO
 Start with CT/ultrasounds, then tagged
wbc/PET later
Additional tests
 Dictated by history
 Subtle nervous system signs: LP
 Travel to midwest or southwest: investigate cocci, histo, blasto
 Trauma: LENI
 Biopsies:
 Liver biopsy generally low yield for miliary tb, granulomatous
hepatitis or sarcoid
 Lymph nodes: better for lymphoma, cat scratch
 Temporal artery: low yield in minimal clinical signs
 BM: generally high yield in thrombocytopenic/anemic, otherwise
low in immunocompetent
 Therapeutic antibiotic trials: do not do
Bleeker-Rovers CP et al. Medicine (Baltimore). 2007;86(1):26
Outcomes

 Treatment of fever alone is generally not

necessary except in hyperpyrexia (>106.7)
 Outcome depends on underlying diagnosis
 Children: 88% with infections have no
sequelae
 Adults: most who remain undiagnosed after
extensive evaluation have a good prognosis
Pattern recognition: a couple more
classic and interesting cases
Fever in patient with “spider bites” and
back pain
 21 y.o. male presents for the 3rd time to local
ER for back pain. H/o narcotic abuse. Sent out
after toradol injections and ibuprofen. Each
visit noted to have temps of 99.8. Multiple
“spider bites” near buttocks
Vertebral discitis

 Strongly consider in IVDU

 Plain films notoriously negative
 Blood cultures can have high yield if
concominant endocarditis
 Detailed neurologic exam necessary
 Urgent imaging if focal neuro deficits
 Need to rule out osteomyelitis, epidural
abscess
Sterile pyuria

 46 y.o. male with poorly controlled DM,

chronic active HCV, and active IVDU presents
with 1 month of dysuria and eventual fevers
 Several outpatient cultures negative
 Admitted with acute B obstructive uropathy,
pyelo, and ureteral “clots”
Bilateral renal aspergillus obstructive
uropathy
 Suspect TB in patient at risk for tuberculous
pyelo as top cause for ID diff for sterile pyuria
 In non-endemic area, IVDU/HCV/DM suspect
aspergillus
Fever and bullous eruption

 78 y.o. female with COPD/CHF intubated x 1

week in ICU. She is on vancomycin, cefepime.
She has mild eosinophilia. Her hands look like
this:
http://www.jaoa.org/content/104/4/157/F4.expansion
Drug allergies

 Vancomycin mediated linear IgA: appears like

bullous pemphigoid
 Responds to drug cessation/steroids
 Generally requires biopsy
 Drug fevers
 30% of hospitalized patients suffer from adverse drug reactions; outpatients can develop
drug fever years later after starting a drug
 Eosinophilia and rash are only seen in 25% of drug fevers
 Most common drugs:
 Antimicrobials: sulfonamides, penicillins, nitrofurantoin, vancomycin, antimalarials
 H1 and H2 blocking agents
 Antiepileptics: barbiturates, phenytoin
 Iodide contrast media
 NSAIDS
 Antihypertensive drugs: hydralazine, methyldopa
 Antiarrythmics: quinidine, procainamide
 Antithyroid
 Contaminants such as quinine (in heroin or cocaine)
 Rarely cause:digoxin, aminoglycosides
 25% of AIDS patients develop drug fever usually manifest as nausea and vomiting
 Diagnosis: therapeutic trial off drug: wait at least a week before ruling in/out
The “at-risk” patient

 82 y.o. male s/p urgent partial colectomy for

diverticular abscess. NPO, NGT, on vanco and
zosyn, TPN, vented, triple lumen left IJ. Yeast
in sputum, febrile daily with negative cxr, UA,
abdominal CT
Fungemia

 Strongly consider empiric or pre-emptive

treatment in patients on broad spectrum
antibiotics, TPN, intrabdominal surgery,
central lines, critically ill
 If fungemic, check ophtho and TTE to rule out
endophthalmitis/endocarditis.
 Consider line/mucosa/bowel as source
 Discontinue antimicrobials asap to minimize
pressure for fungemia
The culture negative “impetigo”

 25 y.o. female presents with intermittent

fevers for past week and painful facial lesions
 Temp 103
 HgB 9.2, WBC 2 (50% pmns), platelets 60
 BM Bx: myelodysplastic syndrome
 Patient remains febrile despite broad
spectrum abx and systemic antifungals for 1
week
Biopsy reveals PMNs, neg gram stain, neg culture
Dermis.net
Neutrophilic dermatosis: Sweet’s
syndrome
 Acute onset of fever, leukocytosis,
erythematous plaques infiltrated by
neutrophils with no evidence of vasculitis or
infection
 Responds to steroids
Final word on esoteric causes
 Factitious fevers: psych patients, munchausens
 Disordered heat homeostasis: follows hypothalamic dysfunction
(CVA, anoxic brain injury) or abnormal heat dissipation (skin
conditions such as ichthyiosis); hyperthyroidism
 Dental abscess: 20 case reports in literature: defervesced after
removal of decayed teeth; consider concominant brain abscess,
meningitis, mediastinal abscess, endocarditis
 Other infections (previously described): with pulm manifestations:
Q fever, leptospirosis, psittacosis, tularemia, meliodosis; without
pulm manifestations: secondary syphilis, disseminated
gonococcal infections, chronic meningococcemia, whipple’s
disease, yersiniosis
 Alcoholic hepatitis: fever, hepatomegaly, jaundice, anorexia
Final word on esoteric causes

 PE: 14%
 Hematoma
 Hyperthyroidism and subacute thyroiditis
 Pheochromocytoma
 Heriditary: FMF, tumor necrosis factor
receptor-1-associated periodic syndrome
(TRAPS), hyper-IgD syndrome, Muckle-Wells
syndrome, and familial cold
autoinflammatory
Thank you and, please, don’t get
burned