1. Approach to the patients with fever
BEHESHTI
UNIVERSITY OF MEDICAL SCIENCES
Yadegarynia, D. MD. MPH

2. 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

3. 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.

4. Laboratory findings:
WBC 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

5. How to approach this patient?
Fever with focal signs and symptoms (confusion and fever) ?
Fever and shaking chills?
Post operative fever ?
Fever in returning traveler ?
Fever with CNS sign in returning traveler ?

6. What is the DDx? Emergency treatable diseases
Non-emergency treatable diseases
Non-emergency non-treatable diseases

7. Laboratory diagnosis Lumbar puncture and CT of the brain were negative
Peripheral blood smear shows:
Treatment with Quinine was initiated.

9. Repeated peripheral blood smear shows:
Pathological report doesn’t show appendicitis.

10. 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.

11. 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

12. 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

13. Height of Fever( > 40o)
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].

14. 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].

15. Toxic appearance Clinical presentation
High grade fever
Lethargy
Evidence of poor perfusion
Cyanosis
Hypoventilation or hyperventilation
Tachycardia

16. While blood cell count
A total white cell count >15×109/L has only % sensitivity in predicting serious bacterial infection [level III- 2 evidence, Neto 2000]

17. 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.

18. 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

19. Fever Pattern Degree High grade fever Low grade fever Fever chart
Remittent
Intermittent
Relapsing
Sustained
Double Quotidian
Reversed Diurnal Gradient

20. 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

21. 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 days)

22. Sustained fever Lobar pneumonia (pneumococcal) Rickettsial diseases
Drug fever
Typhoid fever
CNS damage

23. Fever pattern
In general, correlation between fever pattern and specific disease is weak, notable exceptions are relapsing fever and sustained fever.

24. Fever and shaking chills
Pneumonia
Sepsis
Malaria
Absceses
Legionaires disease
Pylonephritis
Bacterial endocarditis
Filariasis

25. Fever and age Age Category Infection pattern 0-7 days Newborn
Early onset- sepsis, torch
8- 30 days
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
years
Teen age
Infectious mononucleosis, Mycoplasma, viral infection, STD, UTI
>65 years
Elderly
UTI, Pneumonia, viral infection ,sepsis

26. 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.

27. Duration of fever
Fever lasting for more than 4- 7 days is rarely due to self limiting viral illness and needs investigation.

28. Duration of fever
Fever lasting for more than 2 weeks indicated serious underlying problem and needs thorough investigation.

29. Fever Fever <4- 7 days Viral signs & symptoms
Focal signs & symptoms
No Focal, No viral signs & symptoms
Management
Symptomatic management
General Danger signs
No general danger signs
CBC- FBS
Urine analysis
Chest X-Ray
Blood culture
Refer to Hospital
Symptomatic management

30. No Focal, No viral signs & symptoms
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
No diagnosis
Diagnosis
Management
Diagnosis
CT+ Echo
Management
Refer
No diagnosis

31. 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 % of all international will consult a physician upon their return.

32. 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
Rabies TB
Viral hepatitis

33. 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

34. 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

35. Rhinocerebral mucoromycosis Malignant otitis externa
Fever with underlying diseases life threatening infectious associated with diabetes
Rhinocerebral mucoromycosis
Malignant otitis externa
Emphysematous cholecystitis
Emphysematous pyelonephritis
Necrotizing fasciitis
Sepsis

36. Fever with underlying disease Fever in the intravenous drug users
HIV
Viral hepatitis
Infective endocarditis
Pneumonia
Cellulites at injection sites
Tetanus
Septic pulmonary emboli TB
Pyrogenic reaction

37. 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

38. 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> TABx
LFTs elevation or hepatomegalia liver Bx
Pancytopenia, high Ca BM Bx

40. Infective endocardaitis Some time complicated sever viral infection
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

41. Fever with Nonspecific laboratory finding WBC>50-100000mm3
Leukemia
Myeloproliferative disorders

42. Cytomegalovirus infection RSV Viral hepatitis
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

43. 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

44. Fever with Nonspecific laboratory finding Bandemia With Normal WBC
Sever typhoid fever
Malaria
Sever Viral Infection
Hemorrhagic Fever Viruses

45. Fever with Nonspecific laboratory finding Fever with Leukopenia
Malaria TB
Brucellusis
Typhoid Fever
Kala-azar
Sever sepsis
Viral infection

46. 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

47. 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

48. Fever With Nonspecific Signs
Fever and splenomegaly
Fever and anemia
Fever and abdominal mass
Fever and hepatomegalia

49. 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

50. Fever Without Focal signs
Documented fever
Duration 2-3 weeks
No localizing signs
Normal urine analysis

51. 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.

52. 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.

53. 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.

54. Diagnostic Clues : Underlying malignancy (AML) High grade fever
Idarubicin+ cytarabine
Moderate mucositis
Ciprofloxacin prophylaxis
Neutropenia

55. 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.

56. 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.

57. 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.

58. 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 hr.
Duration of Neutropenia is important determination of the risk of infection

59. Current Spectrum of Bacterial Infections in patients with Neutropenia
The pattern of bacterial infections and antimicrobial susceptibility has changed significantly during the past 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)

61. 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; ; Adachi et al. Presented at: American Society of Microbiology; Oct ; 2003, Lake Tahoe, Nev. Abstract 4.

62. Percentage of infections in patients With hematologic malignancies
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
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.

63. Gram-Positive Pathogens in Neutropenic Patients
Organism (n= 487)
% Frequency
Comment
Coagulase- negative staphylococci 52
77% methicillin resistance
Staphylococcus aureus 20
29% methicillin- resistant 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:

64. Common sites of infection in patients with cancer
Type of infection
No. (%) of infections
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)
Total
253 (100)
378 (100)
Data are from Yadegarynia, D. et al. CID 2003:

65. 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
No COPD 4
Solid tumor/ no fungal infection
No dehydration
Outpatient at fever onset
Age <60 years 2
Note. Score of ≥21 predicts a <5% risk for sever complication
Klostersky. CID 2004: 39.

66. 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)

67. 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.

68. Cefepime, ceftazidime, or carbapenem Amoxicillin-clavulanate
Fever + Neutropenia
Low risk
High risk
Oral Iv
Two Drugs
Aminoglycoside +
Antipseudomonal penicillin,
Cefepime,
Ceftazidime, or
Carbapenem
Vancomycin +
Vancomycin
Cefepime, ceftazidime, or carbapenem
± aminoglycoside
Vancomycin needed
Vancomycin not needed
Monotherapy
Ceftazindime, or
Ciprofloxacin +
Amoxicillin-clavulanate
Reassess after 3- 5 days

69. Afebrile within first 3-5 days of treatment
No etiology identified
Etiology identified
Low
risk
High risk
Change to: ciprofloxacin + amoxicillin-clavulanate (adult) or cefixime (child)
Continue same antibiotics
Discharge
Adjust to most appropriate treatment

70. 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

71. Persistent fever during first 3- 5 days of treatment: no etiology
Reassess patient on days 3- 5
Continue initial antibiotics
Change antibiotics
Antifungal drug, with or without antibiotic change
If no change in patient’s condition (consider stopping vancomycin)
If progressive disease,
If criteria for vancomycin are met
If febrile through days 5-7 and resolution of neutropenia is not imminent

72. UNIVERSITY OF MEDICAL SCIENCES
BEHESHTI
UNIVERSITY OF MEDICAL SCIENCES