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Approach to Fever Work Up Fever Cases. Pedro M. Calderon PGY-3. Learning Objectives. Definition of pyrexia, hyperpyrexia hyperthermia Pathophysiology of fever Evaluate best methods to measure temperature Diagnostic and therapeutic approach for fever in select patient populations

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Approach to fever work up fever cases

Approach to Fever Work Up Fever Cases

Pedro M. Calderon


Learning objectives
Learning Objectives

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


  • Normal temperature 36.5ºC - 37.5ºC

    • Lowest temperature at 6 AM

    • Highest at 4 - 6 PM

    • Diurnals variations are maintained during illness

  • Hypothalamus control

    • Heat producers: muscle and liver

    • Heat dissipators: skin and lungs

  • Fever

    • A.M. temperature > 37.2 C

    • P.M. temperature > 37.7 C

  • Hyperpyrexia

    • Temp > 40.0ºC -41.5ºC

  • Each 1○C increase = 13% increase O2 consumption (without shivering)

Journal of Infection and Public Health (2011) 4, 108—124

Fever variations
Fever Variations

  • Hyperpyrexia

    • Temp > 40.0ºC -41.5ºC

      • Severe infections

      • CNS hemorrhage

  • Hyperthermia (Heat stroke)

    • Does not involve intrinsic body pyrogens

    • Exertional vs non-exertional

    • Skin: "hot and dry"

  • Drug induced hyperthermia

  • Malignant hyperthermia

  • Neuroleptic malignant syndrome

  • Serotonin syndrome

Where and when to measure
Where and When to Measure

  • Where to measure

  • Women and ovulation

    • Lower temp 2 weeks before ovulation

    • Raises by 0.6 during

  • Higher temperatures after eating

Approach to fever work up fever cases





Fever symptomatology
Fever symptomatology*

  • Related to phases of fever

  • Initiation phase

    • Elevation of set point  chills/shivering/rigors

  • Plateau phase

    • Tc = Set point

  • Defervescence

    • Tc > set point

    • Patient feels warm  sweating

Tc = Core Temp


  • Non-infectious causes of fevers

    • 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

  • Fever within 48 hours of admission is often caused by organisms found in the community

Use of fever patterns is controversial
Use of Fever Patterns is Controversial

  • Therapies may interfere with the generation of fevers

    • NSAIDS, steroids, etc.

  • Continuous fever

    • Drugs, RMSF, gram negative pneumonia

  • Remittent fever

    • Malaria, Legionella

  • Intermittent fevers

    • Endocarditis, peritonitis, sepsis, TSS

  • Do not use fever patterns alone to make a diagnosis

Etiology cont d
Etiology – Cont’d

  • Likelihood that fever is due to bacterial infection:

    • 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

General approach to the patient
General Approach to the Patient


Host Factors



Local Defenses




Cellular Immunity



Social Risks

Clinical Manifestations

Physical Exam

Fever general diagnostic approach clinical microbiology general principles
Fever: General Diagnostic ApproachClinical Microbiology General Principles

  • 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!

Fever general diagnostic approach clinical microbiology general principles1
Fever: General Diagnostic ApproachClinical Microbiology General Principles

  • 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.

  • Urine culture

    • Catheter, obstruction, renal calculi, GU surgery, trauma, neutropenia

  • Stool culture

  • Nasal culture

  • Throat culture

  • Spinal fluid culture

  • Wound abscess culture

  • GU culture

Case 1
Case 1

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.

Fever caused by endocarditis diagnostic studies
Fever Caused by Endocarditis: Diagnostic Studies

  • 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

Fever caused by endocarditis empiric therapy
Fever Caused by Endocarditis:Empiric Therapy

  • Native valve acute bacterial endocarditis

    • Vancomycin +/- gentamycin

  • Prosthetic valve endocarditis

    • Vancomycin + cefepime + gentamycin

    • **Staphylococcal prosthetic-valve infective endocarditis, the regimen should include rifampin whenever the strain is susceptible + gentamicin

  • Repeat blood cultures until defervescence and blood culture negative

    • Fever may last a week

  • Duration of abx : 4-6 weeks

Fever caused by endocarditis surgical therapy
Fever Caused by Endocarditis:Surgical Therapy

  • Heart failure

  • Uncontrolled infection

    • Abscess, aneurysm, dehiscence

  • Persistent fevers or positive blood cultures for 5-7 days

  • Prevention of embolism from large vegetations (10-15 mm)

Case 2
Case 2

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 multidrug-resistant, 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.

Fever caused by osteomyelitis diagnostic work up
Fever Caused by Osteomyelitis:Diagnostic Work Up

  • ESR, CRP >95% sensitivity

  • Blood cultures are crucial (30 - 78%)

  • MRI : high signal on T2 weighted image

    • CT or MRI are not 100% specific

  • Biopsy: If blood cultures are negative or if polymicrobial is suspected

    • Open or CT guided

    • Biopsy prior to antibiotics is preferred

  • Drain periosteal abscess

Case 3
Case 3

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.

Fever and neutropenia
Fever and Neutropenia

  • 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

Important cofactors in febrile neutropenia
Important Cofactors in Febrile Neutropenia

  • 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

Key points about bacterial infections in febrile neutropenic patients
Key Points About Bacterial Infections in Febrile Neutropenic Patients

  • Bacteria are the most frequent infectious causes of neutropenic fever

  • Shift from gram-negative bacteria to gram-positive bacteria

  • Gram-negative bacteria (eg, P. aeruginosa) are generally associated with the most serious infections

  • S. epidermidis is the most common gram-positive pathogen

  • An infectious source identified in 20 to 30 %

Ann Intensive Care. 2011;1:22-22.

When to add gram positive coverage to the empirical regimen for neutropenic fever
When to Add Gram Positive Coverage to the Empirical Regimen for Neutropenic Fever

  • 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

  • Severe mucositis if fluroquinolone as prophylaxis and ceftazidime as empiric therapy

  • MRSA colonization

  • Remember Leuconostoc, Lactobacilus, and Pediococcus not covered with vancomycin

When to add fungal coverage to the empirical regimen for neutropenic fever
When to Add Fungal Coverage to the Empirical Regimen for Neutropenic Fever

  • Fungal colonizers

    • Candida yeast and aspergillus

  • Antifungal therapy after day 5-7

    • Caspofungin *

    • Amphoterecin B

    • Voriconozale

    • Micafungin

  • 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

  • Role of G-CSF, $$

  • Anaerobic infections are not commonly seen

Tumor and malignancy
Tumor and Malignancy Neutropenic Fever

Lymphoma, especially non-Hodgkin's*


Renal cell carcinoma (20% of cases)

Hepatocellular carcinoma or other tumors metastatic to the liver

Atrial myxomas (30% of cases)

Approach to fever work up fever cases

" Neutropenic Fever“There are no shortcuts to any place worth going.”

Beverly Sills

Case 4
Case 4 Neutropenic Fever

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 in patients with hiv aids
Fever in Patients with HIV/AIDS Neutropenic Fever

  • Fever almost always accompanies the acute retroviral syndrome

  • Drug adverse effect (Bactrim)

  • Lymphoma

  • Opportunistic disease

Fever in hiv aids patients
Fever in HIV / AIDS Patients Neutropenic Fever

  • Opportunistic infections uncommon if CD4 > 200

    • TB exception

    • M. avium rare if CD4 > 50

  • Neutropenia can develop in patients with HIV

    • Primary infection

    • Secondary infection

    • Bone marrow suppression of therapy

      • Zidovudine

  • HIV + Neutropenia + Fever = Infection*

Predominant causes of fever in hiv aids patients
Predominant Causes of Fever in HIV / AIDS Patients Neutropenic Fever

  • Bacteria:

    • More common in children > adults, Strep. Pneumonia, salmonella, enteric bacteria, pseudomonas, salmonella, enteric bacteria

  • Viruses

    • HSV, CMV, VZV, EPV, Adenovirus, parainfluenza, measles

  • Fungi

    • Candida, cryptococcus, histoplasma, coccidioides, pneumocystis carinii, toxoplasma, cryptosporidia, microsporida

Acute febrile conditions often warranting empiric antimicrobials
Acute Febrile Conditions Often Warranting Empiric Antimicrobials

  • Fever > 40.8

  • Immunosuppresion

    • Neutropenia

    • Asplenia

    • Hypogammaglobulinemia

    • Cirrhosis

  • Elderly

  • Unstable vitals signs

  • Presence of prosthetic device/foreign body

  • Recent bite, travel

Drug fever
DRUG FEVER Antimicrobials

  • Fever coinciding with administration Disappearing after the discontinuation

    • Diagnosis of exclusion

    • 6.7% of patients admitted

    • Timing not always helpful: Median 8 days

  • 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
Fever and Connective Tissue Diseases Antimicrobials


Giant cell arteritis

Adult still’s disease

Polyarteritis nodosa

Granulomatosis polyangitis

Mixed cryoglobulinemia



Fever to lower or not to lower
Fever: To Lower or Not to Lower Antimicrobials

  • Yes

    • Temperature > 40.8 ºC (Tissue damage)

    • Metabolic stress of fever (e.g., ACS)

  • No

    • Stimulates immune function

    • Decreases iron necessary for pathogen survival

    • Artificially lowering temperature does not allow for monitoring

Approach to fever work up fever cases

AntimicrobialsThe future belongs to those who believe in the beauty of their dreams.”

–Eleanor Roosevelt

Case 6
Case 6 Antimicrobials

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?

Fever in the critically ill patient
Fever in the Critically Ill Patient Antimicrobials

  • 50% of patients admitted to the ICU

  • Fever associated with mortality in ICU

  • Classifications

    • 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.

Fever in the critically ill patient1
Fever in the Critically Ill Patient Antimicrobials

  • 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

Fever in the icu non infectious causes
Fever in the ICU: Non-Infectious Causes Antimicrobials

  • Non-infectious causes

    • More so if temp > 41

  • Without Shock

    • Transfusion reactions

    • Drug fever

    • Acalculous cholecystitis

    • Mesenteric ischemia

    • Pancreatitis

    • Thromboembolic disease

  • Without Shock

    • Adrenal crisis

    • Thyroid storm

    • Acute hemolytic transfusion reaction

Major decision making in the febrile critically ill patient
Major Decision Making in the Febrile Critically Ill Patient Antimicrobials

  • Empiric antibiotics

    • Deteriorating

    • Shock

    • Neutropenic

    • LVAD

    • Fever > 38.9 C(102 F)

  • Removal of lines

Fever of unknown origen
Fever of Unknown Origen Antimicrobials

  • 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

  • Same major categories:

    • Infectious, malignancies, connective tissue dz

Fever of unknown of origin
Fever of Unknown of Origin Antimicrobials

  • True FUO are uncommon

  • Typical distribution:

    • Non-infectious 22%

    • Infection 16%

    • Malignancy 7%

    • Miscellaneous 4%

    • No diagnosis 51%

  • Contributing factors: Age, AIDS, Neutropenia

  • No diagnosis in 10-50% of cases

    • Good prognosis, mortality ~1%

Additional diagnostic testing
Additional Diagnostic Testing Antimicrobials

  • 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

Nuclear medicine testing in fever of unknown origin
Nuclear Medicine Testing in Fever of Unknown Origin Antimicrobials

  • Controversial and nonspecific

  • Highly sensitive: Gallium-67 and indium-111 Leukocyte scan

    • Compared to CT / US covers a larger body area

  • In series of 145 cases of FUO:

    • 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

Conclusion Antimicrobials

  • 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

Which fevers you should not treat
Which fevers you should not treat… Antimicrobials

Love fever

Barrel fever

Buck fever

Staff fever

Cabin fever

Disco fever (boogie fever)

Gate fever

Bieber fever

Acknowledgments Antimicrobials

  • Muriel Ghosn, MD

  • Salim Thabet, MD

Approach to fever work up fever cases

"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

References 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."

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