Approach to the patients with

fever

BEHESHTI
UNIVERSITY OF MEDICAL
SCIENCES

Yadegarynia, D. MD. MPH

January 11, 2006
 Overview
• Clinical approach to the patients with fever
• Differential diagnosis
• Fever with underlying diseases
• Fever with nonspecific laboratory findings
• Fever in the neutropenic cancer patients
• Current epidemiology/ spectrum
• Empirical antibiotic therapy
 Case report 1
• A 65 years old Afghanian male presented to the
hospital with history of fever and lower
abdominal pain. He was admitted to the hospital
and appendectomy was performed. Three days
after the operation, he complained of fever,
shaking chills, and headache.
• After blood culture, treatment with Ceftriaxone
was initiated. On the fourth day, he developed a
change in his mental status. ID consultation was
requested.
• Laboratory findings:
• WBC 12000 mm3 (Neutrophil 60%, Lymphocyte
25%, Band 15%)
• Chest X- Ray normal
• Urine analysis: 2+ blood, 2+ albumin, 60 RBC, 5
WBC
• Elevated AST, ALT
• Blood culture negative
• Diagnostic clues:
 Traveler from Afghanistan
 Fever and shaking chills
 Abdominal surgery
 Confusion
 Bandemia
How to approach this patient?
1. Fever with focal signs and symptoms
(confusion and fever) ?
2. Fever and shaking chills?
3. Post operative fever ?
4. Fever in returning traveler ?
5. Fever with CNS sign in returning traveler ?
 What is the DDx?
1. Emergency treatable diseases
2. Non-emergency treatable diseases
3. Non-emergency non-treatable diseases
 Laboratory diagnosis
• Lumbar puncture and CT of the brain were
negative
• Peripheral blood smear shows:

• Treatment with Quinine was initiated.

• Repeated peripheral blood smear shows:

• Pathological report doesn’t show appendicitis.

 FEVER in the ER
• Fever is part of the presenting complaint in
6% of all adult (ages 18-65) visits. 10% to
15% of all elderly (>65 years old) visits and
20% to 40% of all pediatric visits to the ER.
Approach to the patients with fever
Key factors are:
• Age
• Height of temperature
• Severity of illness
• Presence of a focus of infection
• White cell count
 Age
(neonates and young infants)
• May not have the characteristic signs of
serious infection
• Localizing features may be absent
• Can deteriorate rapidly
• May be infected with organisms from the birth
canal
 Height of Fever( > o
40 )
• The sensitivity of hyperpyrexia to detect
serious bacterial infection in young infants is
only 21% and the specificity is 97% (Neto
2000) [Level III-2].
 Clinical Assessment
Severity of illness (toxicity)
• The sensitivity of a “toxic appearance” in
detecting serious bacterial infection varied
from 11% to 100% in different studies (Neto
2000) [Level I].
 Toxic appearance
Clinical presentation
• High grade fever
• Lethargy
• Evidence of poor perfusion
• Cyanosis
• Hypoventilation or hyperventilation
• Tachycardia
 While blood cell count
• A total white cell count >15×109/L has only
31- 52% sensitivity in predicting serious
bacterial infection [level III- 2 evidence, Neto
2000]
 Identifying Lukocytosis
(elderly)
• There is a high probability of underlying
bacterial infection in and older person whose
WBC count is elevated if they have a high
percentage of Neutrophils or they show an
elevated total band count.
• Only 60% of elderly patients with
bacteraemia present with leukocytosis
(Evidence- based Steven Levenson 2004)
• An elevated WBC, therefore is reasonably
specific but not sensitive for infection.
Approach to the patient with
fever
• Fever and age
• Fever pattern
• Duration of fever
• Fever in returning travelers
• Pattern syndrome
• Fever with underlying diseases
• Fever with nonspecific signs
• Fever with focal signs & symptoms
• Fever of unknown origin
• Fever with nonspecific laboratory finding
 Fever Pattern
A. Degree
• High grade fever
• Low grade fever
B. Fever chart
• Remittent
• Intermittent
• Relapsing
• Sustained
• Double Quotidian
• Reversed Diurnal Gradient
 High grade fever
• Flu
• Meningitis & Encephalitis
• Sepsis
• Malaria
• Infective endocarditis
• MDR typhoid fever
• Pneumonia
• Viral hemorrhagic fever
• TSS
• Leptospirosis
• Juvenile Rheumatoid arthritis
• Neuroleptic Malignant Syndrome
 Relapsing fever
• Malaria
• Rat bite fever (3- 5 days)
• Charcot’s intermittent fever
• Relapsing fever (Borrelia 2-3 weeks)
• FMF
• Cyclic Neutropenia (21 days)
• Pel Ebstein Fever (Hodgkins, Brucellosis 7-
10 days)
 Sustained fever
• Lobar pneumonia (pneumococcal)
• Rickettsial diseases
• Drug fever
• Typhoid fever
• CNS damage
 Fever pattern
• In general, correlation between fever pattern
and specific disease is weak, notable
exceptions are relapsing fever and sustained
fever.
 Fever and shaking chills
• Pneumonia
• Sepsis
• Malaria
• Absceses
• Legionaires disease
• Pylonephritis
• Bacterial endocarditis
• Filariasis
 Fever and age
Age Category Infection pattern
0-7 days Newborn Early onset- sepsis, torch
8- 30 days Newborn Late onset- sepsis, nursery infection
1- 3 months Young infant Late onset- sepsis
3- 24 months Infant Primary bacteremia, meningitis, UTI, virus
2- 5 years Preschool Meningitis, Pneumococcal infection,
systemic haemophilus infection, viral
infection
6- 12 years Primary Mycoplasma, strep- pharingitis, viral
school hepatitis, UTI, viral infection
13- 20 years Teen age Infectious mononucleosis, Mycoplasma,
viral infection, STD, UTI
>65 years Elderly UTI, Pneumonia, viral infection ,sepsis
 Fever & Age
Clinical approach
• Depends on age of child.
• First month of life: greatest risk of invasive
bacterial disease.
• Clinical examination notoriously unreliable
under 3 month of age.
• Full sepsis evaluation for febrile infants less
than 3 month.
• Admit all febrile infants <1 month.
 Duration of fever
• Fever lasting for more than 4- 7 days is rarely
due to self limiting viral illness and needs
investigation.
 Duration of fever
• Fever lasting for more than 2 weeks indicated
serious underlying problem and needs
thorough investigation.
 Fever

Fever <4- 7 days

Viral signs & Focal signs No Focal, No

symptoms & symptoms viral signs &
symptoms

Symptomatic Management
management General No general
Danger signs danger signs
•CBC- FBS
Refer to •Urine analysis
Hospital Symptomatic
•Chest X-Ray management
•Blood culture
 Fever

Fever >4- 7 days

Focal signs No Focal, No viral

& symptoms signs & symptoms

Diagnosis CBC+ FBS+ Urine analysis+ Blood culture

Chest X- Ray+ Serological test+ ESR
Management
No diagnosis Diagnosis
Management Diagnosis
CT+ Echo Management
Refer No diagnosis
 Fever in returning travelers
• The number of travelers at risk for febrile
illness is significant. More than 500 million
people cross international borders each year,
more than 45 million of these travelers are
U.S. citizens half of whom visit tropical or
developing countries, it is reported that up to
5- 10 % of all international will consult a
physician upon their return.
Typical incubation periods for infectious
diseases in the returned travelers
< 21 days >21 days
Trypanosomiasis HIV
Dehgue fever Schistosomiasis
Japanease encephalitis Amoebic liver abscess
Leptospirosis Borreliosis
Malaria Brucellosis
Meningococcemia Leishmaniasis
Nontyphoidal salmonellosis Malaria
Plague Rabies
Typhoid fever TB
Typhus Viral hepatitis
Viral hemorrhagic fever Trypanosomiasis
Yellow fever
Fever with underlying diseases
• Fever in the Neutropenic cancer patients
• Fever in the Diabetic patients
• Fever in the Alcoholic patients
• Fever in intravenous drug users
• Fever in the HIV infected patients
• Fever in the patients with splenectomy
 Fever with underlying diseases

Fever in the alcoholic patients

• Alcohol withdrawal
• Delirium tremens
• Hepatitis
• Pancreatitis
• Subarachnoid hemorrhage
• Pneumonia (aspiration)
• TB
• Spontaneous bacterial peritonitis (cirrhosis)
• Vibrio vulnificus sepsis
• Spontaneous bacteraemia
 Fever with underlying diseases
life threatening infectious associated
with diabetes
•Rhinocerebral mucoromycosis
•Malignant otitis externa
•Emphysematous cholecystitis
•Emphysematous pyelonephritis
•Necrotizing fasciitis
•Sepsis
 Fever with underlying disease

Fever in the intravenous drug

• HIV
users
• Viral hepatitis
• Infective endocarditis
• Pneumonia
• Cellulites at injection sites
• Tetanus
• Septic pulmonary emboli
• TB
• Pyrogenic reaction
 Fever Of Unknown Origin
• Physicians should repeatedly interview and
examine the patients and review laboratory
test results and imaging studies
• In two pediatric series, abnormal physical
findings where reported to have contributed
to the diagnosis in 60% of causes of FUO, in
the half of these the abnormalities where
detected only after repeated examination
 Evaluation Of FUO In adults
• Thorough history (travel, exposure, drug, sexual
contact)
• Screen as usual (CBC/diff, ESR, LFT, BCs, PPD,
consider TSH, ANA, ANCA, HIV)
• Site directed
• No clear site (Abd/pelvic CT scan)
• ESR elevation and anemia or age>65 TABx
• LFTs elevation or hepatomegalia liver Bx
• Pancytopenia, high Ca++ BM Bx
 Fever With Nonspecific Laboratory Finding
Leukocytosis ,Neutrophilia &
Bandemia
• Sever sepsis
• Sever pneumonia
• Meningitis
• Infective endocardaitis
• Some time complicated sever viral infection
• Hemorrhagic fever viruses
• Toxic shock syndrome
• Sever abdominal infection
 Fever with Nonspecific laboratory finding

WBC>50-100000mm3
•Leukemia
•Myeloproliferative disorders
 Fever with Nonspecific laboratory finding
Fever with lymphocytosis (lymphosite count greater
than 4000/mcl)
• Pertusis
• Mononucleosis
• Cytomegalovirus infection
• RSV
• Viral hepatitis
• Chronic lymphocytic leukemia
• HIV
• TB
 Fever with Nonspecific laboratory finding

Fever and monocytosis ( > 950mcl)

• Infective endocarditis
• TB
• Brucellosis
• Solid tumor
• Hodgkin’s diseases
• I.B.D
• Rockymountain spotted fever
• Monocytic leukemia
• Syphilis
• Sarcoidosis
• Malaria
 Fever with Nonspecific laboratory finding
Bandemia With Normal WBC
• Sever typhoid fever
• Malaria
• Sever Viral Infection
• Hemorrhagic Fever Viruses
 Fever with Nonspecific laboratory finding

Fever with Leukopenia

• Malaria
• TB
• Brucellusis
• Typhoid Fever
• Kala-azar
• Sever sepsis
• Viral infection
 Fever with Nonspecific laboratory Finding

ESR
• Erythrocyte sedimentation rate determination
is a commonly performed laboratory test with
a time-honored role, however the usefulness
of this test has decreased as a new method
of evaluating diseases have been developed.
• The test remains helpful in the specific
diagnosis of a few conditions including
temporal arteritis, polymyalgia rheumatica
and possibly rheumatoid arthritis and multiple
myeloma
 Fever With Nonspecific Laboratory Finding

Fever and ESR > 100 mm/hr

• Sepsis
• Abscess
• TB
• Osteomyelitis
• Infective endocarditis
• Kala azar
• Lymphoma
• Leukemia
• Collagen vascular diseases
• Multiple myeloma
• Subacute thyroiditis
Fever With Nonspecific Signs
• Fever and splenomegaly
• Fever and anemia
• Fever and abdominal mass
• Fever and hepatomegalia
 Fever With Focal Signs and
Symptoms
• Fever with gastrointestinal signs and symptoms
 Fever with diarrhea

 Fever with constipation

 Fever with abdominal pain

 Fever with abdominal mass

• Fever with CNS signs and symptoms

• Fever with lower respiratory signs and symptoms
• Fever and rash
Fever Without Focal
signs
• Documented fever
• Duration 2-3 weeks
• No localizing signs
• Normal urine analysis
 Case Report 2
• A 24-year-old man with newly diagnosed AML
presented to the ER with fever (>40oC) and
neutropenia. He had received therapy with
idarubicin and a high dose of cytarabine 7
days previously and was discharged with
ciprofloxacin prophylaxis. A central venous
catheter had recently been implanted.
 Case Report 2
• At examination, the patient had moderate
mucositis and appeared to be fatigued. The
central venous catheter site was not inflamed.

• The patient was admitted to the hospital and

was given a β-lactam plus an amino glycoside
antibiotic. He appeared to be stable.
 Case Report 2
• 36 hr later, he developed a high fever and
hypotension.
• He was then transferred to the intensive care
unit (ICU) and died within 48 hr.
 Diagnostic Clues :
• Underlying malignancy (AML)
• High grade fever
• Idarubicin+ cytarabine
• Moderate mucositis
• Ciprofloxacin prophylaxis
• Neutropenia
 Case Report 2
• Potential choices for initial therapy for the
case patient would include broad-spectrum iv
therapy with agents such as piperacillin-
tazobactam, ticarcillin-clavulanate, cefepime,
or imipenem, given either as monotherapy or
in combination with vancomycin, amikacin, or
both.
• Outpatient therapy would not be advised for
this patient because of his underlying cancer
and unwell appearance.
 Cause :
• Vancomycin-resistant enterococci (rarely)
• P. aeruginosa (less likely)
• Acinetobacter and Stenotrophomonas
species (rarely)
• Viridans streptococcus (toxic shock-like
syndrome)
• Diagnosis: The diagnosis was sepsis and
toxic shock due to viridans streptococcus.
Approach to Patients with Febrile
Neutropenia
• Infection is the most common complication of
chemo therapy- induced neutropenia.
Bacterial infections predominate during the
early stages of a neutropenic episode
whereas invasive fungal infections tend to
occur later.
 Approach to Patients with febrile Neutropenia

Definition
• Fever: fever has been defined as an oral
temperature of ≥ 38.3oC or a temperature of
≥ 38.0oC for ≥1 hr.
• Neutropenia: Neutropenia is defined as an
absolute neutrophil count of either <500
cells/mm3 or <1000 cells/mm3 with a
predictable decline to <500 cells/mm3 in 24-
48 hr.
 Duration of Neutropenia is important
determination of the risk of infection
Current Spectrum of Bacterial Infections in
patients with Neutropenia
• The pattern of bacterial infections and antimicrobial
susceptibility has changed significantly during the
past 20- 30 yrs.
 The prevalence of gram- negative organisms
decresed.1
 prevalence of gram- positive organisms
increased.1
 Despite a decline in the frequency of gram-
negative infection, there has been an increase in
the proportion of such infections caused by non-
fermentative gram- negative bacilli.2
1Yadegarynia, D. et al. CID, 2003:37, 1145.
2Yadegarynia,
D. et al. Diagnostic Microbiology and Infectious Disease, 51 (2005) 215-
218
 Polymicrobial infection in
Neutropenic Patients
• Approximately 80% have gram- negative
component
• 30- 35%- multiple gram- negative
species
• P aeruginosa- most common GNR
isolated from polymicrobial infections
(45- 55%)

Elting et al. Medicine. 1986; 65; 218-225; Adachi et al. Presented at: American
Society of Microbiology; Oct. 19- 23; 2003, Lake Tahoe, Nev. Abstract 4.
Bacterial infections in patients with solid tumors and
hematologic malignancies.
Percentage of infections in patients
Type of bacterial
infection With hematologic
With solid tumors
malignancies
Single organism
(monomicrobial)
Gram positive 42 47
Gram negative 27 30
Polymicrobial 31 23

Data are from Yadegarynia et al. [15].CID 2005:40 (suppl 4)

S247.
 Gram-Positive Pathogens in
Neutropenic Patients
Organism (n= 487) % Frequency Comment
Coagulase- negative 52 77% methicillin
staphylococci resistance
Staphylococcus 20 29% methicillin-
aureus resistant
Staphylococcus
aureus (MRSA)
Enterococcus spp 10 56% of E faecium
were VRE
Viridans group 5 MIC ≥0.12 in 27%
stretoccoci

Wisplinghoff et al. Clin Infect Dis. 2003; 36: 1103- 1110.

 Common sites of infection in
patients with cancer
No. (%) of infections
Type of infection In patients with In patients with solid
hematological malignancy tumor
Pneumonia 93 (38) 99 (26)
Bloodstream 88 (35) 74 (20)
Urinary Tract 27 (11) 85 (22)
Skin and soft
17 (6) 65 (17)
tissue
Gastrointestinal 16 (6) 38 (10)
Other 12 (4) 17 (5)
Total 253 (100) 378 (100)

Data are from Yadegarynia, D. et al. CID 2003:37 1144.

Scoring system for determining the risk of serious
medical complication with the febrile neutropenia.
Clinical Characteristics Weight
No symptoms (or mild) 5
Moderate symptoms 3
No hypotension 5
No COPD 4
Solid tumor/ no fungal infection 4
No dehydration 3
Outpatient at fever onset 3
Age <60 years 2

Note. Score of ≥21 predicts a <5% risk for sever complication

Klostersky. CID 2004: 39.
 Management of the Febrile
Neutropenic Patient
• Prompt administration of empiric, broad-
spectrum antibiotics therapy based on local
epidemiology and susceptibility/ resistance
patterns is essential
• Conduct risk assessment (identify low-risk
patients)
• Consider pervious infection/ therapy/ prophylaxis
• Combination regimens/ monotherapy
• Treatment setting (hospital/ outpatient)
• Route of administration (parenteral, oral)
 Clinical Assessment
• Symptoms and signs of inflammation may be
minimal or absent in the severely neutropenic
patients.
• History and examination
• Look for inflammation/ infection at the
following sites and sample as appropriate:
mouth-gums ,pharynx, sinuses, upper
gastrointestinal, lung, perineum, skin lesion
genito-urinary ,vascular sites, bone marrow
aspiration sites, diarrhea.
 Fever + Neutropenia

Low risk High risk

Oral Iv Vancomycin Vancomycin

not needed needed

Monotherapy Two Drugs Vancomycin +

Ciprofloxacin Cefepime, Aminoglycoside Vancomycin

+ Ceftazindime, or + +
Amoxicillin- Carbapenem Antipseudomonal Cefepime, ceftazidime,
clavulanate penicillin, or carbapenem
Cefepime,
Ceftazidime, or ± aminoglycoside
Carbapenem

Reassess after 3- 5 days

 Afebrile within first 3-5 days of treatment

No etiology identified Etiology identified

Low High
risk risk

Change to: Continue Adjust to most

ciprofloxacin + same appropriate
amoxicillin-clavulanate antibiotics treatment
(adult) or cefixime
(child)

Discharge
 Fever and Neutropenia:
Duration of Therapy
• The single most important determinate of
successful discontinuation of antibiotics is the
neutrophil count.
• Therapy can be stopped if
 No infection identified

 Neutrophil count ≥500 for 2 days

 Patients afebrile for ≥48 hr

• If patient afebrile but still neutropenic

 Continue therapy until ANC >500

 Stop therapy and monitor closely

 Persistent fever during first 3- 5 days of
treatment: no etiology

Reassess patient on days 3- 5

Continue initial Change Antifungal drug,

antibiotics antibiotics with or without
antibiotic
change

If no change in If progressive disease, If febrile through days

patient’s condition If criteria for 5-7 and resolution of
(consider stopping vancomycin are met neutropenia is not
vancomycin) imminent
 BEHESHTI
UNIVERSITY OF MEDICAL
SCIENCES