Download Approach to the patient with fever

Approach to the patients with
fever
BEHESHTI
UNIVERSITY OF MEDICAL
SCIENCES
Yadegarynia, D. MD. MPH
January 11, 2006
Overview
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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:
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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
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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
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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
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Flu
Meningitis & Encephalitis
Sepsis
Malaria
Infective endocarditis
MDR typhoid fever
Pneumonia
Viral hemorrhagic fever
TSS
Leptospirosis
Juvenile Rheumatoid arthritis
Neuroleptic Malignant Syndrome
Relapsing fever
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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 710 days)
Sustained fever
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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
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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
school
Mycoplasma, strep- pharingitis, viral
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 &
symptoms
Focal signs
& symptoms
Symptomatic
management
Management
No Focal, No
viral signs &
symptoms
General
Danger signs
No general
danger signs
•CBC- FBS
Refer to
Hospital
•Urine analysis
•Chest X-Ray
•Blood culture
Symptomatic
management
Fever
Fever >4- 7 days
Focal signs
& symptoms
No Focal, No viral
signs & symptoms
Diagnosis
CBC+ FBS+ Urine analysis+ Blood culture
Chest X- Ray+ Serological test+ ESR
Management
Management
Refer
No diagnosis
Diagnosis
CT+ Echo
Management
Diagnosis
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
Dehgue fever
Japanease encephalitis
Leptospirosis
Malaria
Meningococcemia
Nontyphoidal salmonellosis
Plague
Typhoid fever
Typhus
Viral hemorrhagic fever
Yellow fever
HIV
Schistosomiasis
Amoebic liver abscess
Borreliosis
Brucellosis
Leishmaniasis
Malaria
Rabies
TB
Viral hepatitis
Trypanosomiasis
Fever with underlying diseases
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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
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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
users
• HIV
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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
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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
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than 4000/mcl)
Pertusis
Mononucleosis
Cytomegalovirus infection
RSV
Viral hepatitis
Chronic lymphocytic leukemia
HIV
TB
Fever with Nonspecific laboratory finding
Fever and monocytosis ( > 950mcl)
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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
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Sever typhoid fever
Malaria
Sever Viral Infection
Hemorrhagic Fever Viruses
Fever with Nonspecific laboratory finding
Fever with Leukopenia
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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
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Sepsis
Abscess
TB
Osteomyelitis
Infective endocarditis
Kala azar
Lymphoma
Leukemia
Collagen vascular diseases
Multiple myeloma
Subacute thyroiditis
Fever With Nonspecific Signs
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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
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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 :
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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 piperacillintazobactam, 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 2448 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 gramnegative infection, there has been an increase in
the proportion of such infections caused by nonfermentative gram- negative bacilli.2
1Yadegarynia,
2Yadegarynia,
D. et al. CID, 2003:37, 1145.
D. et al. Diagnostic Microbiology and Infectious Disease, 51 (2005) 215218
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.
Type of bacterial
infection
Percentage of infections in patients
With solid tumors
With hematologic
malignancies
Gram positive
42
47
Gram negative
27
30
31
23
Single organism
(monomicrobial)
Polymicrobial
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
staphylococci
52
77% methicillin
resistance
Staphylococcus
aureus
20
29% methicillinresistant
Staphylococcus
aureus (MRSA)
Enterococcus spp
10
56% of E faecium
were VRE
Viridans group
stretoccoci
5
MIC ≥0.12 in 27%
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
hematological malignancy
In patients with solid
tumor
Pneumonia
93 (38)
99 (26)
Bloodstream
88 (35)
74 (20)
Urinary Tract
27 (11)
85 (22)
Skin and soft
tissue
17 (6)
65 (17)
Gastrointestinal
16 (6)
38 (10)
Other
12 (4)
17 (5)
253 (100)
378 (100)
Total
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, broadspectrum 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
Oral
High risk
Iv
Vancomycin
not needed
Monotherapy
Ciprofloxacin
+
Amoxicillinclavulanate
Cefepime,
Ceftazindime, or
Carbapenem
Two Drugs
Aminoglycoside
+
Antipseudomonal
penicillin,
Cefepime,
Ceftazidime, or
Carbapenem
Reassess after 3- 5 days
Vancomycin
needed
Vancomycin +
Vancomycin
+
Cefepime, ceftazidime,
or carbapenem
± aminoglycoside
Afebrile within first 3-5 days of treatment
No etiology identified
Low
risk
Change to:
ciprofloxacin +
amoxicillin-clavulanate
(adult) or cefixime
(child)
Discharge
Etiology identified
High
risk
Continue
same
antibiotics
Adjust to most
appropriate
treatment
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
antibiotics
If no change in
patient’s condition
(consider stopping
vancomycin)
Change
antibiotics
If progressive disease,
If criteria for
vancomycin are met
Antifungal drug,
with or without
antibiotic
change
If febrile through days
5-7 and resolution of
neutropenia is not
imminent
BEHESHTI
UNIVERSITY OF MEDICAL
SCIENCES