Transcript Fever Cases - Case Western Reserve University

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Definition of pyrexia, hyperpyrexia hyperthermia
Pathophysiology of fever
Evaluate best methods to measure
temperature
Diagnostic and therapeutic approach for fever
in select patient populations
Review of IDSA guidelines for important select
clinical conditions that cause fevers
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Normal temperature 36.5ºC - 37.5ºC
› Lowest temperature at 6 AM
› Highest at 4 - 6 PM
› Diurnals variations are maintained during illness
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Hypothalamus control
› Heat producers: muscle and liver
› Heat dissipators: skin and lungs
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Fever
› A.M. temperature > 37.2 C
› P.M. temperature > 37.7 C
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Hyperpyrexia
› Temp > 40.0ºC -41.5ºC
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Each 1○C increase = 13% increase O2 consumption
(without shivering)
Journal of Infection and Public Health (2011) 4, 108—124
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Hyperpyrexia
› Temp > 40.0ºC -41.5ºC
 Severe infections
 CNS hemorrhage
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Hyperthermia (Heat stroke)
› Does not involve intrinsic body pyrogens
› Exertional vs non-exertional
› Skin: "hot and dry"
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Drug induced hyperthermia
Malignant hyperthermia
Neuroleptic malignant syndrome
Serotonin syndrome
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Where to measure
Oral
N/A
Rectal
+0.5 ºC
TM
+0.5 ºC
Axillary
-0.5 ºC
Women and ovulation
› Lower temp 2 weeks
before ovulation
› Raises by 0.6 during
 Higher temperatures after
eating
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Steroids
Exogenous
Pyrogens
Antipyretics
Related to phases of fever
 Initiation phase
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› Elevation of set point  chills/shivering/rigors
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Plateau phase
› Tc = Set point
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Defervescence
› Tc > set point
› Patient feels warm  sweating
Tc = Core Temp
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Non-infectious causes of fevers
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Connective tissue disease
Malignancy
Medications
Myocardial infarction
Pulmonary embolism
Fever curve/height does not correlate with
etiology
› Fever > 39.4 F = Greater concern  infection
› Fever > 40.8 = Tissue damage
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Fever within 48 hours of admission is often
caused by organisms found in the
community
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Therapies may interfere with the generation of fevers
› NSAIDS, steroids, etc.
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Continuous fever
› Drugs, RMSF, gram negative pneumonia
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Remittent fever
› Malaria, Legionella
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Intermittent fevers
› Endocarditis, peritonitis, sepsis, TSS
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Do not use fever patterns alone to make a diagnosis
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Likelihood that fever is due to bacterial
infection:
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Advanced age
Indwelling catheter
Nursing home residency
Leukocytosis
Elevated ESR
Diabetes
Identification of source complicated if
difficult history and physical examination
› Understand potential causes of fever
› Studied approach
All Hosts
Elderly/debilitated
Viral Influenza
Pneumonia
Acute HIV
Genitourinary infection
Malaria
Cholecystitis/cholangitis
Primary bacteremia
(meningococcemia, S. aureus,
typhoid fever)
AMI, PE
Occult abscess
Apathetic hyperthyroidism
Hypoadrenalism
Drug fever (β-lactams,
sulfonamides, procainamide,
hydralazine)
CVA
Host Factors
EPIDEMIOLOGY
Age
Sex
Local Defenses
Phagocytes
Complement
Antibodies
Cellular Immunity
Recent
Remote
Social Risks
Clinical
Manifestations
Physical Exam
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Blood cultures
› Mandatory if new fever*
› Clinical findings cannot exclude bacteremia
› 2 sets from two different sites
› 30-60 mins apart
› Peripheral always preferred
› Contamination vs bacteremia
› Volume matters
› 3% ↑ Sensitivity per mL
› Contamination:
› Staph epidermidis, Staph hominis, Bacillus spp,
Corynecbacterium
› Gram negative, fungi, and anaerobes are
always pathogenic
› Document clearance of bacteremia!
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Sputum – Gram stain and culture
› Sputum vs saliva
› New sputum, change in color, amount, thickness, new or
progressive pulmonary infiltrate, increased RR, increased in
VE, decreased oxygenation.
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Urine culture
› Catheter, obstruction, renal calculi, GU surgery, trauma,
neutropenia
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Stool culture
Nasal culture
Throat culture
Spinal fluid culture
Wound abscess culture
GU culture
55-year-old man with a history of mitral
regurgitation seeks care after an episode of
transient weakness in his right arm and speech
difficulties. He underwent dental scaling 1 month
earlier. He notes recent intermittent fevers and
weight loss. On cardiac examination, his
regurgitation murmur appears to be unchanged.
A TTE shows a mobile, 12-mm mitral-valve
vegetation and grade 2 (mild) regurgitation.
Magnetic resonance imaging of the brain reveals
recent ischemic lesions. How should the patient
be further evaluated and treated?
N Engl J Med. 2013 Jun 27;368(26):2536.
N Engl J Med 2013; 368:1425-1433
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3 sets (aerobic & anaerobic bottles) from
different sites
› One hour apart
Repeat blood cultures every 24 hours
 CBC, ESR, RFP, U/A, Urine culture
 ECG
 Imaging
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Circulation 2005;111;e394-e434
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Native valve acute bacterial endocarditis
› Vancomycin +/- gentamycin
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Prosthetic valve endocarditis
› Vancomycin + cefepime + gentamycin
› **Staphylococcal prosthetic-valve infective
endocarditis, the regimen should include rifampin
whenever the strain is susceptible + gentamicin
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Repeat blood cultures until defervescence
and blood culture negative
› Fever may last a week
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Duration of abx : 4-6 weeks
Heart failure
 Uncontrolled infection
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› Abscess, aneurysm, dehiscence
Persistent fevers or positive blood cultures
for 5-7 days
 Prevention of embolism from large
vegetations (10-15 mm)
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57-year-old man presents with fever, chills,
and new lumbar back pain 2 weeks after
undergoing a prostate biopsy because of
an increased PSA level. His temperature is
39.7°C; he has an enlarged, tender
prostate and lumbar spine tenderness. His
white-cell count is 9.1, and the CRP level is
3.43 mg/L.
Urine and blood cultures reveal multidrugresistant, extended-spectrum β-lactamase–
producing Escherichia coli susceptible to
imipenem. How should he be evaluated
and treated?
N Engl J Med 2010;362:1022-9.
N Engl J Med 2010;362:1022-9.
ESR, CRP >95% sensitivity
 Blood cultures are crucial (30 - 78%)
 MRI : high signal on T2 weighted image
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› CT or MRI are not 100% specific
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Biopsy: If blood cultures are negative or if
polymicrobial is suspected
› Open or CT guided
› Biopsy prior to antibiotics is preferred
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Drain periosteal abscess
58 year old man is hospitalized because of fever and chills for
the last 2 days. He denies productive cough, shortness of breath,
headaches, nausea, vomiting, abdominal pain, diarrhea, dysuria,
or rash. According to his wife, he has been "acting differently" for
the past 24 hours. He was recently diagnosed with AML. His
leukemia is currently in remission, and he is receiving
maintenance chemotherapy.
He has no known drug allergies. Works at a local grocery and
denies use of tobacco, alcohol or illicit drug. His temperature is
39.4 ºC, blood pressure 81/45 mm Hg, pulse is 122/min, and
respirations 22/min. SaO2 96% on RA.
A Hickman catheter is present in the left IJ and it shows
erythema and induration over the insertion site. Two sets of blood
cultures are obtained, one from a peripheral vein and second
from the catheter port. 3 liters of normal saline are given IV, this
improves patient's hemodynamics. CXR shows infiltrates. UA
without evidence of infection.
Risk factors: Catheters, skin breakdown, GI mucositis,
immune defects associated with malignancy
 Seeding of bloodstream by GI flora*
 Evaluation: Physical Exam
› Teeth, eyes, skin, lungs, abdomen, rectum
› Catheter sites
› Avoid digital rectal examination
 Work up : CBC with diff, RFP, CXR, LFTs, UA, at least two
sets of blood cultures, CXR, ?C. difficile
 Low threshold for ordering a CT scan
 Other:
› LP if confused, fungal markers*, bronchoscopy
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Type of underlying malignancy
› Abnormal antibody production
 High risk for encapsulated organism infection
› T cell defects (e.g., Hodgkins Lymphoma)
 High risk of Intracellular infections
Breeches in host defenses related to the
underlying malignancy
 The direct effects of chemotherapy on
mucosal barriers and the immune system
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Bacteria are the most frequent infectious
causes of neutropenic fever
 Shift from gram-negative bacteria to grampositive bacteria
 Gram-negative bacteria (eg, P.
aeruginosa) are generally associated with
No. of
39
38
411
62
161
2142
75
428
patients the most serious infections
Grampositive
18epidermidis
(41.9) 4 (80)
41 (44.1)
7 (43.7)
70common
(72.9) 353 (63.5) gram6 (46.1) 81 (64.8)
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S.
is
the
most
organisms
Grampositive
pathogen
negative
25 (58.1) 1 (20)
52 (55.9) 9 (56.3)
26 (27.1) 203 (36.5) 7 (53.9) 44 (35.2)
organisms
 An
infectious
source
identified
in 20 to
30 - %
Other
2 (4.6)
4 (4.3)
1 (6.3)
1 (1)
31 (5.6)
1 (7.7)
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Carratala et
al.Arch Intern
Med 1998
De La Rubia et
Regazzoni et
Harter et al.
Klastersky et al. Metallidis et al. Biol Blood
Gruson et al.
Feld et al. J Clin al.Intensive Care BoneMarrow
Int J Antimicrob al. Eur J Intern Marrow
Euro Respir 1999 Oncol 2000
Med 2003
Transplant 2006 Agents 2007
Med 2008
Transplant 2009
Ann Intensive Care. 2011;1:22-22.
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Vancomycin or Linezolid*
Fever not resolved after 3-5 days
Hemodynamically instability / Sepsis
CXR with pneumonia
Blood culture with gram positive bacteria
Suspicion for serious catheter-related infection
› Chills/rigors with infusion through catheter
› Cellulitis around catheter
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Severe mucositis if fluroquinolone as
prophylaxis and ceftazidime as empiric
therapy
MRSA colonization
Remember Leuconostoc, Lactobacilus, and
Pediococcus not covered with vancomycin
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Fungal colonizers
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Candida yeast and aspergillus
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Caspofungin *
Amphoterecin B
Voriconozale
Micafungin
Antifungal therapy after day 5-7
Do not use fluconazole in this setting
Fungal coverage resolves fever in 50% of patients
Cryptococus, Fusarium, Mucor, histo, blasto, cocci
?Duration
› 14 days if source if known
› Source not known: Until afebrile + ANC > 500 c/µL
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Role of G-CSF, $$
Anaerobic infections are not commonly seen
Tumor and Malignancy
Lymphoma, especially non-Hodgkin's*
 Leukemia
 Renal cell carcinoma (20% of cases)
 Hepatocellular carcinoma or other
tumors metastatic to the liver
 Atrial myxomas (30% of cases)
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"“There are no shortcuts to any place
worth going.”
Beverly Sills
20-year-old man who had a history of IV drug use
and multiple sexual partners initially presented to the
ED with a chief complaint of blood per rectum when
he passed stool, and chills for the prior few days. His
work-up was normal, including a rapid HIV screen,
and he was discharged.
He returned 2 weeks later with constipation, fatigue,
myalgias, decreased urination, chills, and a
productive cough. His physical examination was most
remarkable for temp 39.2, HIV antibody test was
negative, but his laboratory tests showed an
elevation of CK, amylase, and lipase. His blood count
showed a normal hematocrit and white blood cell
count. HIV viral load was reported as > 1,000,000
copies/mL.
J Emerg Med. 2013 May;44(5):e341-4
Fever almost always accompanies the
acute retroviral syndrome
 Drug adverse effect (Bactrim)
 Lymphoma
 Opportunistic disease
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Opportunistic infections uncommon if
CD4 > 200
› TB exception
› M. avium rare if CD4 > 50
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Neutropenia can develop in patients
with HIV
› Primary infection
› Secondary infection
› Bone marrow suppression of therapy
 Zidovudine
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HIV + Neutropenia + Fever = Infection*
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Bacteria:
› More common in children > adults, Strep.
Pneumonia, salmonella, enteric bacteria,
pseudomonas, salmonella, enteric bacteria
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Viruses
› HSV, CMV, VZV, EPV, Adenovirus,
parainfluenza, measles
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Fungi
› Candida, cryptococcus, histoplasma,
coccidioides, pneumocystis carinii,
toxoplasma, cryptosporidia, microsporida
Site
Diagnosis / Organism
Blood
Streptococcus pneumonia
Gastrointestinal tract
Mucositis, esophagitis, colitis from
candida, HSV, CMV, Clostridium
difficile, microsporidia
Liver
Hepatitis A, B, C
Nervous system
Toxoplasma, cryptococcal
meningitis, neurosyphilis, CVM
Cutaneous
HSV, CMV, varicella-zoster
Other
Pyomyositis
N Engl J Med. 1999 Sep 16;341(12):893-900
Fever > 40.8
 Immunosuppresion
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› Neutropenia
› Asplenia
› Hypogammaglobulinemia
› Cirrhosis
Elderly
 Unstable vitals signs
 Presence of prosthetic device/foreign body
 Recent bite, travel
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Fever coinciding with administration
Disappearing after the discontinuation
› Diagnosis of exclusion
› 6.7% of patients admitted
› Timing not always helpful: Median 8 days
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HIV infection increased susceptibility to drug
reactions, including fever
↑ Serum/Urine eosinophil (<20% of patients)
Causes: Pyrogenic contaminants,
hypersensitivity reactions, genetic determinants
Stop most probable offending drug first
Fever and Connective Tissue
Diseases
Vasculitis
 Giant cell arteritis
 Adult still’s disease
 Polyarteritis nodosa
 Granulomatosis polyangitis
 Mixed cryoglobulinemia
 SLE
 Sarcoidosis
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Yes
› Temperature > 40.8 ºC (Tissue damage)
› Metabolic stress of fever (e.g., ACS)
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No
› Stimulates immune function
› Decreases iron necessary for pathogen
survival
› Artificially lowering temperature does not
allow for monitoring
“The future belongs to those who believe in
the beauty of their dreams.”
–Eleanor Roosevelt
47 year old man with HTN, HLP, asthma, admitted to the MICU
5 days ago from ED with acute asthma attack which required
intubation in the ED. Initial vitals Temp: 38.7, HR 110, BP
90/42, 95% on the vent with 50% FiO2, RR 20 (above vent).
Patient has right radial arterial line, right IJ central line, sites
which do not appear erythematous or indurated. Pt also has
OG. Chest x-ray with new small left lower lobe infiltrate, ETT 3
cm above carina, Right central line with tip in SVC, no
pneumothorax. Labs with CBC 15/12/36/253, 79% neutrophils,
2% eosinophils. RFP within normal limits. Patient is on
steroids, but no antibiotics.
How would you work up and manage fever in this patient?
50% of patients admitted to the ICU
 Fever associated with mortality in ICU
 Classifications
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› Hyperthermia syndromes
 Heat stroke, malignant hyperthermia
› Infectious
 Bacterial, protozoa, fungal, viral, parasitic
› Non-infectious
 Transfusion reactions, drugs, VTE, hematomas,
MI, pancreatitis, neurogenic fever
J Intensive Care Med. 2012 Sep-Oct;27(5):290-7.
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Compromised natural host defenses
› Invasive monitoring
 Violation of skin barrier
 Microbial colonization
› Endotracheal intubation
 Retards mucociliary clearance
› Nasogastric tubes
 Splints open GE junction  aspiration of gastric
contents
› TPN
› Already on antibiotics  resistant infections
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Non-infectious causes
More so if temp > 41
Without Shock
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Transfusion reactions
Drug fever
Acalculous cholecystitis
Mesenteric ischemia
Pancreatitis
Thromboembolic disease
Without Shock
› Adrenal crisis
› Thyroid storm
› Acute hemolytic transfusion reaction
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Empiric antibiotics
› Deteriorating
› Shock
› Neutropenic
› LVAD
› Fever > 38.9 C(102 F)
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Removal of lines
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Definition:
› Temp: > 38.3ºC
› Lasting >3 weeks
› 1 week of intensive studying*
 History, PE, CBC with diff, LFTs, blood cultures (3
sets from different sites without abx), hepatitis
serology, UA, CXR
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Same major categories:
› Infectious, malignancies, connective tissue dz
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True FUO are uncommon
Typical distribution:
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Non-infectious 22%
Infection 16%
Malignancy 7%
Miscellaneous 4%
No diagnosis 51%
Contributing factors: Age, AIDS,
Neutropenia
 No diagnosis in 10-50% of cases
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› Good prognosis, mortality ~1%
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ESR or CRP
Serum lactate dehydrogenase
Tuberculin skin test or interferon-gamma release assay
HIV antibody assay and HIV viral load for patients at
high risk
Three routine blood cultures drawn from different sites
over a period of at least several hours without
Administering antibiotics, if not already performed*
Rheumatoid factor
Creatine phosphokinase
Heterophile antibody test in children and young adults
Antinuclear antibodies
Serum protein electrophoresis
CT scan of chest, abdomen, pelvis
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Controversial and nonspecific
Highly sensitive: Gallium-67 and indium-111 Leukocyte
scan
 Compared to CT / US covers a larger body area
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In series of 145 cases of FUO:
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Useful in 29% of cases
Fall positives 11-20% of cases
Reserve nuclear evaluation if initial eval remains
negative and a screening “look” at whole body is
desired
Be aware of false and true positive rates
Temperature should be measured with
precision and consistency
 Approach to patient with fever requires
evaluation of clinical manifestation, host
factors and epidemiology
 Neutropenic fever is a medical emergency
 In all cancer patients presenting with
neutropenic fever, empiric antibacterial
therapy should be initiated immediately
 Have a low threshold for antibiotics in the
critically ill patient

Love fever
 Barrel fever
 Buck fever
 Staff fever
 Cabin fever
 Disco fever (boogie fever)
 Gate fever
 Bieber fever
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Muriel Ghosn, MD
 Salim Thabet, MD

"I do not actually remember which one of
my parents taught me this, but one of them
told me: 'Son, in this world there are stupid
people and there are smart people; there
are mean people and there are nice
people. If you are smart and nice, you will
do well in your work and have a lot of
friends. If you are smart and mean, you will
be successful but not happy. If you are
stupid and nice, you will not be successful
but at least you will be happy. But if you
are stupid and mean, you will not get
anywhere in life.' knowing my limitations, I
have always aspired to be the nicest
person I can ever be."
--Chin-to Fong , MD
University of Rochester
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Porat R, Weller PF, Thomer AR. Pathophysiology and treatment of fever in adults. UpToDate UptoDate 2013. Last accessed 2013.
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Wingard JR, Marr KA, Thorner AR. Diagnostic Approach to the adult presenting with Neutropenic Fever. UpToDate 2013. Last accessed 2013.
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Barbour AG, Sexton DJ, Mitty J. Clinical features, diagnosis, and management of relapsing fever. UptoDate 2013. Last accessed 2013.

Henker R, Kramer D. Fever. AACN Clinical Issues 1997. 8(3): 351-367.
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http://en.wikipedia.org/wiki/File:Biological_clock_human.svg
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Pizzo PA. Fever in Immunocompromised Patietns. NEJM (1999) 341(12): 893-900.
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Ogoina DO. Fever, fever pattern and diseases called "fever" - A review. Journal of Infection and Public Health (2011) 4, 108—124.
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Arnold BM, Casal G, Higgins. Apathetic thyrotoxicosis. Can Med Assoc J. (1974), 111(9): 957–958.

Clinician's Pocket Medicine. Chapter 7: Clinical Microbiology.
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Levinson W. Chapter 9. Laboratory Diagnosis.
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Review of Medical Microbiology & Immunology, 12th ed. New York: McGraw-Hill;2012.
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Legrand M, Max A, Schlemmer B, Azoulay E, Gachot B.The strategy of antibiotic use in critically ill neutropenic patients. Ann Intensive Care. 2011 Jun 15;1(1):22.
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Naurois J, NOvitzky, Gill MJ, Marti M, Cullen MH, Roila. Management of febrile neutropenia: ESMO Practice Guidelines. Clinical Practice Guidelines. Annals of Oncology 21 (Supplement 5): v252-v256, 2010.
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Flowers CR, Seidenfeld J, Bow EJ, Karten C, Hawley DK, Langston AA, Marr, K. Antimicrobial Prophylaxis and Outpatient Management of Fever and Neutropenia in Adults Treated for Malignancy: American Society of
Clinical Oncology Clinical Practice Guideline. J Oncol Pract. Pages: 1-35.
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Syrjala M, Valtonen V, Liewendahl, Myllyla G. Diagnostic Significance of Indium-111 Granulocyte Scintigraphy in Febrile Patients. J Nuc Med 28: 155-160, 1987

Baddour et al. Infective Endocarditis: Diagnosis, Antimicrobial Therapy, and Management of Complications: A Statement of Healthcare Professionals From the Committee on Rheumatic Fever, Endocarditis, Kawasaki
Disease, Council on Cardiovascular Disease in the Young, and the Councils on Clinical Cardiology, Stroke, and Cardiovascular Surgery and Anesthesia, American Heart Association. Circulation 2005; 111; e394-e434.
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Niven DJ, Léger C, Stelfox HT, Laupland KB.Fever in the critically ill: a review of epidemiology, immunology, and management. J Intensive Care Med. 2012 Sep-Oct;27(5):290-7.
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O'Grady NP, Barie PS, Bartlett JG, Bleck T, Carroll K, Kalil AC, Linden P, Maki DG, Nierman D, Pasculle W, Masur H; American College of Critical Care Medicine; Infectious Diseases Society of America. Guidelines for
evaluation of new fever in critically ill adult patients: 2008 update from the American College of Critical Care Medicine and the Infectious Diseases Society of America. Crit Care Med. 2008 Apr;36(4):1330-49.
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Lyman GH, Rolston KV. How we treat febrile neutropenia in patients receiving cancer chemotherapy. J Oncol Pract. 2010 May;6(3):149-52.
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Hoen B, Duval X. Clinical practice. Infective endocarditis. N Engl J Med. 2013 Apr 11;368(15):1425-33.