The document discusses the approach to febrile neutropenia. It defines neutropenia and febrile neutropenia. It classifies neutropenia as mild, moderate or severe based on absolute neutrophil count. It describes the types of febrile neutropenia such as microbiologically documented, clinically documented and unexplained fever. It discusses the epidemiology, risk factors, pathophysiology, diagnostic evaluation and risk stratification of patients with febrile neutropenia.

1. APPROACH TO FEBRILEAPPROACH TO FEBRILE
NEUTROPENIANEUTROPENIA
DR VIKAS LAKHANPALDR VIKAS LAKHANPAL

2. Febrile neutropeniaFebrile neutropenia
Neutropenia is usually defined as an absolute neutrophil count (ANC)Neutropenia is usually defined as an absolute neutrophil count (ANC)
below 1500 cells/microL (<1.5 x 10below 1500 cells/microL (<1.5 x 1099
/L) in an adult (the World Health/L) in an adult (the World Health
Organization uses ≤1800 cells/microL)Organization uses ≤1800 cells/microL)
ANC = white blood cells/microL x percent (PMNs+bands) ÷ 100ANC = white blood cells/microL x percent (PMNs+bands) ÷ 100
Fever in neutropenic patients is defined as a single oral temperature ofFever in neutropenic patients is defined as a single oral temperature of
>38.3 °C (101°F) or a temperature of >38.0°C (100.4°F) sustained for>38.3 °C (101°F) or a temperature of >38.0°C (100.4°F) sustained for
>1 hour.>1 hour.
Freifeld AG, Bow EJ, Sepkowitz KA, et al. Clinical practice guideline for the use of antimicrobial agents in neutropeniFreifeld AG, Bow EJ, Sepkowitz KA, et al. Clinical practice guideline for the use of antimicrobial agents in neutropeni
2010 update by the infectious diseases society of america. Clin Infect Dis 2011; 52:e56.2010 update by the infectious diseases society of america. Clin Infect Dis 2011; 52:e56...
Valent P. Low blood counts: immune mediated, idiopathic, or myelodysplasia. Hematology Am Soc Hematol Educ PrValent P. Low blood counts: immune mediated, idiopathic, or myelodysplasia. Hematology Am Soc Hematol Educ Pro

4. Classification & SeverityClassification & Severity
Constitutional neutropenia is neutropenia of longstanding duration,Constitutional neutropenia is neutropenia of longstanding duration,
typically since childhood.typically since childhood.
Chronic neutropenia is neutropenia that lasts more than three monthsChronic neutropenia is neutropenia that lasts more than three months
Neutropenia can be further categorized as mild, moderate, or severeNeutropenia can be further categorized as mild, moderate, or severe
••Mild neutropenia – Absolute neutrophil count >1000 and <1500Mild neutropenia – Absolute neutrophil count >1000 and <1500
cells/microLcells/microL
••Moderate neutropenia – Absolute neutrophil count >500 and <1000Moderate neutropenia – Absolute neutrophil count >500 and <1000
cells/microLcells/microL
••Severe neutropenia – Absolute neutrophil count<500 cells/microLSevere neutropenia – Absolute neutrophil count<500 cells/microL
Boxer LA. How to approach neutropenia. Hematology Am Soc Hematol Educ Program 2012; 2012:174.Boxer LA. How to approach neutropenia. Hematology Am Soc Hematol Educ Program 2012; 2012:174.

6. Febrile neutropeniaFebrile neutropenia
●●Microbiologically documented infectionMicrobiologically documented infection ––
Neutropenic fever with a clinical focus of infectionNeutropenic fever with a clinical focus of infection
and an associated pathogenand an associated pathogen
●●Clinically documented infectionClinically documented infection – Neutropenic– Neutropenic
fever with a clinical focus (eg, cellulitis, pneumonia),fever with a clinical focus (eg, cellulitis, pneumonia),
but without the isolation of an associated pathogen.but without the isolation of an associated pathogen.
●●Unexplained feverUnexplained fever – Neutropenic fever with– Neutropenic fever with
neither a clinical focus of infection nor an identifiedneither a clinical focus of infection nor an identified
pathogenpathogen
From the Immunocompromised Host Society. The design, analysis, and reporting of clinical trials on the empirical anFrom the Immunocompromised Host Society. The design, analysis, and reporting of clinical trials on the empirical an

7. AA persistent neutropenic feverpersistent neutropenic fever syndrome is a febrile episodesyndrome is a febrile episode
without defervescence after at least five days of initial empiric broad-without defervescence after at least five days of initial empiric broad-
spectrum antibacterial therapy in high-risk neutropenic patients orspectrum antibacterial therapy in high-risk neutropenic patients or
after at least two days in low-risk neutropenic patients.after at least two days in low-risk neutropenic patients.
AA recrudescent neutropenic fever syndromerecrudescent neutropenic fever syndrome is a febrile episodeis a febrile episode
that recurs following initial defervescence during a course of broad-that recurs following initial defervescence during a course of broad-
spectrum antibacterial therapyspectrum antibacterial therapy
From the Immunocompromised Host Society. The design, analysis, and reporting of clinical trials on the empirical anFrom the Immunocompromised Host Society. The design, analysis, and reporting of clinical trials on the empirical an

8. EpidemiologyEpidemiology
Fever occurs frequently during chemotherapy-Fever occurs frequently during chemotherapy-
induced neutropenia,10%–50% of patients withinduced neutropenia,10%–50% of patients with
solid tumors and 80% of those with hematologicsolid tumors and 80% of those with hematologic
malignancies will develop fever during >1malignancies will develop fever during >1
chemotherapy cycle associated with neutropenia.chemotherapy cycle associated with neutropenia.
Klastersky J. Management of fever in neutropenic patients with different risks of complications. Clin InfectKlastersky J. Management of fever in neutropenic patients with different risks of complications. Clin Infect
Dis 2004; 39(Suppl 1):S32–7.Dis 2004; 39(Suppl 1):S32–7.

9. EpidemiologyEpidemiology
Most patients will have no infectious etiology documented. ClinicallyMost patients will have no infectious etiology documented. Clinically
documented infections occur in 20%–30% of febrile episodes;commondocumented infections occur in 20%–30% of febrile episodes;common
sites of tissue-based infection include the intestinal tract, lung, and skin.sites of tissue-based infection include the intestinal tract, lung, and skin.
Bacteremia occurs in 10%–25% of all patients,with most episodesBacteremia occurs in 10%–25% of all patients,with most episodes
occurring in the setting of prolonged or profound neutropenia (ANC, ,occurring in the setting of prolonged or profound neutropenia (ANC, ,
100 neutrophils/mm3)100 neutrophils/mm3)
Ramphal R. Changes in the etiology of bacteremia in febrile neutropenic patients and the susceptibilities of theRamphal R. Changes in the etiology of bacteremia in febrile neutropenic patients and the susceptibilities of the
currently isolated pathogens. Clin Infect Dis 2004; 39(Suppl 1):S25–31.currently isolated pathogens. Clin Infect Dis 2004; 39(Suppl 1):S25–31.
Bodey GP, Buckley M, Sathe YS, et al. Quantitative relationships between circulating leukocytes and infection inBodey GP, Buckley M, Sathe YS, et al. Quantitative relationships between circulating leukocytes and infection in
patients with acutepatients with acute leukemia. Ann Intern Med 1966; 64:328–40.leukemia. Ann Intern Med 1966; 64:328–40.

10. EpidemiologyEpidemiology
Changing etiology of bacteremiaChanging etiology of bacteremia
IATG-EORTC 1973-2000 trials of febrile neutropeniaIATG-EORTC 1973-2000 trials of febrile neutropenia
Gram positiveGram positive
dominant sincedominant since
mid 1980smid 1980s
1) More intensive chemoTx1) More intensive chemoTx
•MucositisMucositis
2) In-dwelling catheters2) In-dwelling catheters
• Cutaneous-IV portalCutaneous-IV portal
4) Antacids4) Antacids
•Promote oro-Promote oro-
oesophagealoesophageal
colonisation with GPCcolonisation with GPC
Viscoli et al, Clin Inf Dis;40:S240-5Viscoli et al, Clin Inf Dis;40:S240-5
Gram negativeGram negative

11. Risk of Infection as Absolute Neutrophil Count DeclinesRisk of Infection as Absolute Neutrophil Count Declines

12. PATHOPHYSIOLOGYPATHOPHYSIOLOGY
Decreased production of neutrophils from the bone marrow.Decreased production of neutrophils from the bone marrow.
Shift of circulating neutrophils to the vascular endothelium or tissuesShift of circulating neutrophils to the vascular endothelium or tissues
such as the spleen, termed "margination", which can occur withsuch as the spleen, termed "margination", which can occur with
splenomegaly and/or hypersplenism.splenomegaly and/or hypersplenism.
In addition to neutropenia, disruption of mucociliary barriers,In addition to neutropenia, disruption of mucociliary barriers,
extensive use of invasive devices and shifts in inherent microbial floraextensive use of invasive devices and shifts in inherent microbial flora
due to prolonged antimicrobial usage predispose these patients todue to prolonged antimicrobial usage predispose these patients to
infection. Besides these, qualitative defects in neutrophil functioninfection. Besides these, qualitative defects in neutrophil function
described in hematological malignancies also contribute to FN.described in hematological malignancies also contribute to FN.
Kar M, Biswas S. Oncological emergencies. JIACM. 2008;9(2):120-6.Kar M, Biswas S. Oncological emergencies. JIACM. 2008;9(2):120-6.

13. Immune-mediated destruction----The current hypothesis ofImmune-mediated destruction----The current hypothesis of
immune-mediated drug-induced agranulocytosis suggests that theimmune-mediated drug-induced agranulocytosis suggests that the
drug, or more commonly a reactive metabolite of the drug,drug, or more commonly a reactive metabolite of the drug,
irreversibly binds to the neutrophil membrane. In some cases, theirreversibly binds to the neutrophil membrane. In some cases, the
reactive metabolite results in the production of antibodies or T cellsreactive metabolite results in the production of antibodies or T cells
directed against the altered membrane structure; in others, truedirected against the altered membrane structure; in others, true
antineutrophil autoantibodies are produced that do not require theantineutrophil autoantibodies are produced that do not require the
presence of the drug .presence of the drug .
Christie DJ. Specificity of drug-induced immune cytopenias. Transfus Med Rev 1993; 7:230.Christie DJ. Specificity of drug-induced immune cytopenias. Transfus Med Rev 1993; 7:230.
Direct toxic effects upon marrow granulocytic precursors----SomeDirect toxic effects upon marrow granulocytic precursors----Some
drugs can directly damage myeloid precursors. As an example,drugs can directly damage myeloid precursors. As an example,
detoxification of many nonpolar compounds requires conversion todetoxification of many nonpolar compounds requires conversion to
a chemically reactive intermediate that may bind to nucleara chemically reactive intermediate that may bind to nuclear
material or cytoplasmic proteins, causing direct toxicitymaterial or cytoplasmic proteins, causing direct toxicity
Tesfa D, Keisu M, Palmblad J. Idiosyncratic drug-induced agranulocytosis: possible mechanisms andTesfa D, Keisu M, Palmblad J. Idiosyncratic drug-induced agranulocytosis: possible mechanisms and
management. Am J Hematol 2009; 84:428.management. Am J Hematol 2009; 84:428.

15. Patients with neutropenic fever who are at highPatients with neutropenic fever who are at high
risk for serious complicationsrisk for serious complications
Neutropenia (absolute neutrophil count <500 cells/microL) anticipated to last >7Neutropenia (absolute neutrophil count <500 cells/microL) anticipated to last >7
days* Presence of any comorbid medical problemsdays* Presence of any comorbid medical problems
Oral or gastrointestinal mucositis that interferes with swallowing or causesOral or gastrointestinal mucositis that interferes with swallowing or causes
severe diarrheasevere diarrhea
Neurologic or mental status changes of new onsetNeurologic or mental status changes of new onset
Intravascular catheter infection.Intravascular catheter infection.
New pulmonary infiltrate or hypoxemiaNew pulmonary infiltrate or hypoxemia
Underlying chronic lung diseaseUnderlying chronic lung disease
Complex infection at the time of presentationComplex infection at the time of presentation
Evidence of hepatic insufficiency (defined as aminotransferase levels >5 timesEvidence of hepatic insufficiency (defined as aminotransferase levels >5 times
normal values) or renal insufficiency (defined as a creatinine clearance of <30normal values) or renal insufficiency (defined as a creatinine clearance of <30
mL/min) Multinational Association for Supportive Care in Cancer (MASCC) riskmL/min) Multinational Association for Supportive Care in Cancer (MASCC) risk
index score <21index score <21
2010 update by the Infectious Diseases Society of America. Clin Infect Dis 2011; 52:e56.2010 update by the Infectious Diseases Society of America. Clin Infect Dis 2011; 52:e56.

16. MASCC risk-index scoreMASCC risk-index score [for adults][for adults]
The Multinational Association for Supportive Care (MASCC) index allows the clinician to rapidly assess risk beforeThe Multinational Association for Supportive Care (MASCC) index allows the clinician to rapidly assess risk before
access to neutrophil count and without knowledge of the burden of underlying cancer, and has been prospectivelyaccess to neutrophil count and without knowledge of the burden of underlying cancer, and has been prospectively
validated*.validated*.
Scores 21 or more are at low risk of complications.Scores 21 or more are at low risk of complications.
Clinical Index of Stable Febrile Neutropenia [cisne]Clinical Index of Stable Febrile Neutropenia [cisne]
Criteria Score
Burden of illness(no/mild) 5
Burden of illness(moderate) 3
Burden of illness (sever) 0
No Hypotension 5
No COPD 4
Solid Tumor/ Lymphoma, no previous
Fungal infection
4
No Dehydration 3
Outpatient Status (onset of
fever)
3
Age < 60 years 2

17. Diagnostic evaluation of patients with feverDiagnostic evaluation of patients with fever
and neutropeniaand neutropenia
Targeted historyTargeted history
Seek sites suspicious for infectionSeek sites suspicious for infection
Allows detection of symptoms of infectionAllows detection of symptoms of infection
 Physical exam with emphasis on skin, oral cavity, oropharynx, lungs, abdomen,Physical exam with emphasis on skin, oral cavity, oropharynx, lungs, abdomen,
perianal areaperianal area
Pain and/or erythema may point to infection, chest examination may be unremarkablePain and/or erythema may point to infection, chest examination may be unremarkable
even with pneumonia; abdominal tenderness may suggest neutropenic enterocolitis;even with pneumonia; abdominal tenderness may suggest neutropenic enterocolitis;
perianal tenderness may point to gram-negative or anaerobic infection.perianal tenderness may point to gram-negative or anaerobic infection.
Complete blood count with differential countComplete blood count with differential count
Defines the depth of neutropeniaDefines the depth of neutropenia
The lower the initial neutrophil count, the greater the likelihood of serious infection orThe lower the initial neutrophil count, the greater the likelihood of serious infection or
bacteremia; daily counts allow prognosticationbacteremia; daily counts allow prognostication

18. Creatinine, liver function tests, electrolytesCreatinine, liver function tests, electrolytes
Allows optimal selection and dose of antimicrobial agent(s) and serialAllows optimal selection and dose of antimicrobial agent(s) and serial
monitoring of toxicities.monitoring of toxicities.
 Blood cultures (2 sets, one peripheral and one from central venousBlood cultures (2 sets, one peripheral and one from central venous
catheter).catheter).
MicrobiologyMicrobiology
-Blood cultures (peripheral and all central line lumens)-Blood cultures (peripheral and all central line lumens)
-Oral ulcers or sores –send swabs-Oral ulcers or sores –send swabs
-Exit site swabs-Exit site swabs
-Wound swabs-Wound swabs
-Urine Cultures-Urine Cultures
-Stool Cultures and CDiff Toxin/PCR-Stool Cultures and CDiff Toxin/PCR

19.  CXR if Symptomatic or if out pt Rx consideredCXR if Symptomatic or if out pt Rx considered
 High resolution CT Chest Indicated ONLY if persistent fevers withHigh resolution CT Chest Indicated ONLY if persistent fevers with
pulmonary symptoms after initiation of empiric Antibioticspulmonary symptoms after initiation of empiric Antibiotics
 CT abdomen for Necrotizing Enterocolitis or TyphilitisCT abdomen for Necrotizing Enterocolitis or Typhilitis
 CT brain R/o ICH / MRI of the spine or brain - more for evaluation ofCT brain R/o ICH / MRI of the spine or brain - more for evaluation of
metastatic disease than FNmetastatic disease than FN
Examination of CSF specimens isExamination of CSF specimens is not recommendednot recommended
as a routine procedureas a routine procedure but should be considered if abut should be considered if a
CNS infection is suspected and thrombocytopenia isCNS infection is suspected and thrombocytopenia is
absent or manageable.absent or manageable.

20. Point to rememberPoint to remember
Do not order CT scan in a neutropenic patientDo not order CT scan in a neutropenic patient
with a normal CXR initially.with a normal CXR initially.
In clinical practice if patient remains febrile for 3In clinical practice if patient remains febrile for 3
to 5 days then the next step is HRCT. ( 50 % ofto 5 days then the next step is HRCT. ( 50 % of
patients with + imaging have a normal CXR)patients with + imaging have a normal CXR)

21. Range of pathogens encountered in febrileRange of pathogens encountered in febrile
neutropenic patients [ IDSA 2012 ]neutropenic patients [ IDSA 2012 ]
Commonly cultured organismsCommonly cultured organisms
Gram-negative bacteria ---Gram-negative bacteria ---Escherichia coli,Escherichia coli, KlebsiellaKlebsiella spp ,spp ,EnterobacterEnterobacter
sppspp Pseudomonas aeruginosaPseudomonas aeruginosa
Gram-positive bacteria ---Coagulase-negative staphylococciGram-positive bacteria ---Coagulase-negative staphylococci
,,Staphylococcus aureusStaphylococcus aureus EnterococcusEnterococcus spp ,spp ,ViridansViridans group streptococci,group streptococci,
Streptococcus pneumoniaeStreptococcus pneumoniae Streptococcus pyogenesStreptococcus pyogenes ..
Other bacteria ----Other bacteria ----Clostridium difficile,Clostridium difficile, AnaerobesAnaerobes
Fungi--------Fungi-------- AspergillusAspergillus spp ,spp ,CandidaCandida sppspp

22. TreatmentTreatment
Timing of antibiotics---- Antimicrobial therapy should beTiming of antibiotics---- Antimicrobial therapy should be
administered withinadministered within 60 minutes60 minutes of presentation.of presentation.
Initiation of monotherapy with an antipseudomonal beta-Initiation of monotherapy with an antipseudomonal beta-
lactam agent, such as cefepime, meropenem, imipenem-lactam agent, such as cefepime, meropenem, imipenem-
cilastatin, or piperacillin-tazobactam.cilastatin, or piperacillin-tazobactam.
Other antibiotics (eg, aminoglycosides, fluoroquinolones,Other antibiotics (eg, aminoglycosides, fluoroquinolones,
and/or vancomycin) may be added to the initial regimen inand/or vancomycin) may be added to the initial regimen in
patients with complicated presentations (eg, hypotensionpatients with complicated presentations (eg, hypotension
and/or mental status changes), focal findings (eg, pneumoniaand/or mental status changes), focal findings (eg, pneumonia
or cellulitis), or if antimicrobial resistance is suspected oror cellulitis), or if antimicrobial resistance is suspected or
provenproven

23. THREE approaches for IVTHREE approaches for IV
EMPIRIC therapyEMPIRIC therapy
IV MONO THERAPYIV MONO THERAPY
IV DUAL THERAPYIV DUAL THERAPY
COMBINATION THERAPYCOMBINATION THERAPY
Mono or dual therapy + VANCOMYCINMono or dual therapy + VANCOMYCIN

24. Indications for VancomycinIndications for Vancomycin
1.1. Clinically suspected serious catheter-related infectionsClinically suspected serious catheter-related infections
2.2. Known colonization with penicillin- andKnown colonization with penicillin- and
cephalosporin-resistant pneumococci orcephalosporin-resistant pneumococci or MRSA,MRSA,
3.3. Positive results of blood culture for gram-positivePositive results of blood culture for gram-positive
4. Hypotension or other evidence of cardiovascular impairment4. Hypotension or other evidence of cardiovascular impairment

27. Other consideration in antibiotics selection :Other consideration in antibiotics selection :
- Local patterns of infection: Type, frequency,- Local patterns of infection: Type, frequency,
antibiotic susceptibilitiesantibiotic susceptibilities
- Drug allergies- Drug allergies
- Drug interactions- Drug interactions
- Organ dysfunction (renal and liver)- Organ dysfunction (renal and liver)
– Cisplatin, amphotericin B, cyclosporine, vancomycin,Cisplatin, amphotericin B, cyclosporine, vancomycin,
and aminoglycosides should be avoided in combinationand aminoglycosides should be avoided in combination
- Suspected catheter-related infection- Suspected catheter-related infection
- Colonized with MRSA or VRE- Colonized with MRSA or VRE

28. IDSA guidelinesIDSA guidelines
MAINTAIN BROADMAINTAIN BROAD
SPECTRUMSPECTRUM
ACTIVITY FOR AACTIVITY FOR A
MINIMUM OF 7MINIMUM OF 7
DAYS OR UNTILDAYS OR UNTIL
ANC >500ANC >500

29. PERSISTANT FEVER (PERSISTANT FEVER (WhenWhen
temperatures do not go away)temperatures do not go away)
Evaluate for source of persistent feverEvaluate for source of persistent fever
Resistant pathogen or slow response to therapyResistant pathogen or slow response to therapy
Emergence of second infection (overgrowth, superinfection,Emergence of second infection (overgrowth, superinfection,
nosocomial infection)nosocomial infection)
Inadequate serum or tissue level of antibiotic(s)Inadequate serum or tissue level of antibiotic(s)
Drug feverDrug fever
Abscess, obstruction, foreign body infectionAbscess, obstruction, foreign body infection
2010 update by the Infectious Diseases Society of America. Clin Infect Dis 2011; 52:e562010 update by the Infectious Diseases Society of America. Clin Infect Dis 2011; 52:e56

30. IDSA GUIDELINESIDSA GUIDELINES

31. Role of Empirical or Pre-emptiveRole of Empirical or Pre-emptive
Antifungal therapyAntifungal therapy
Candida species are the most common fungal pathogens duringCandida species are the most common fungal pathogens during
neutropenia, typically occurring during neutropenic episodes lasting >neutropenia, typically occurring during neutropenic episodes lasting >
1 week, and Aspergillus species are less common, usually occurring1 week, and Aspergillus species are less common, usually occurring
with prolonged neutropenia lasting > 2–3 weekswith prolonged neutropenia lasting > 2–3 weeks
Past studies have shown that use of empiric antifungal therapy inPast studies have shown that use of empiric antifungal therapy in
neutropenic patients with persistent fever reduced mortality comparedneutropenic patients with persistent fever reduced mortality compared
with patients who did not receive empiric antifungal therapywith patients who did not receive empiric antifungal therapy
**Pizzo PA, Robichaud KJ, Gill FA, Witebsky FG. Empiric antibiotic and antifungal therapy for cancer patientsPizzo PA, Robichaud KJ, Gill FA, Witebsky FG. Empiric antibiotic and antifungal therapy for cancer patients
with prolonged fever and granulocytopenia. Am J Med 1982;72:101–111.with prolonged fever and granulocytopenia. Am J Med 1982;72:101–111.

32. Empiric antifungal therapyEmpiric antifungal therapy
Until recently,Until recently, amphotericin Bamphotericin B was the drug of choice for febrilewas the drug of choice for febrile
neutropenia not responding to broad-spectrum antibiotics .neutropenia not responding to broad-spectrum antibiotics .
A small study comparingA small study comparing itraconazoleitraconazole and AmB demonstrated higherand AmB demonstrated higher
rates of clinical success (composite of defervescence, absence ofrates of clinical success (composite of defervescence, absence of
breakthrough fungal infections, and absence of adverse drug events)breakthrough fungal infections, and absence of adverse drug events)
with itraconazole.with itraconazole.
VoriconazoleVoriconazole , a second-generation triazole with an extended spectrum, a second-generation triazole with an extended spectrum
that includes molds.that includes molds.
Boogaerts M, Winston DJ, Bow EJ, et al. Intravenous and oral itraconazole versusBoogaerts M, Winston DJ, Bow EJ, et al. Intravenous and oral itraconazole versus
intravenous amphotericin B as empirical antifungal therapy for persistent fever inintravenous amphotericin B as empirical antifungal therapy for persistent fever in
neutropenic patients with cancer who are receiving broad-spectrum antibacterial therapy:neutropenic patients with cancer who are receiving broad-spectrum antibacterial therapy:
a randomized, controlled trial. Ann Intern Med 2001;135:412–422a randomized, controlled trial. Ann Intern Med 2001;135:412–422..

33. OTHER THERAPIESOTHER THERAPIES
Antiviral drugsAntiviral drugs
– No indication for empirical use of antiviral agentsNo indication for empirical use of antiviral agents
– Treat HSV or VZV lesionsTreat HSV or VZV lesions
– Consider acyclovir (famiciclovir or valacyclovir) forConsider acyclovir (famiciclovir or valacyclovir) for
suppression of HSV.suppression of HSV.

34. OTHER THERAPIESOTHER THERAPIES
Granulocyte transfusionsGranulocyte transfusions
– Not routineNot routine
– Consider with profound neutropenia and failure toConsider with profound neutropenia and failure to
control bacterial infection despite optimal antibiotics andcontrol bacterial infection despite optimal antibiotics and
G-CSF, and for severe uncontrollable fungal infectionsG-CSF, and for severe uncontrollable fungal infections

35. Use of CSF’s [ASCO GUIDELINES]Use of CSF’s [ASCO GUIDELINES]
INDICATIONS----Expected prolonged (>10 day) or profoundINDICATIONS----Expected prolonged (>10 day) or profound
(<100 cells/microL) neutropenia, age >65, uncontrolled(<100 cells/microL) neutropenia, age >65, uncontrolled
primary disease, pneumonia, hypotension, and multiorganprimary disease, pneumonia, hypotension, and multiorgan
dysfunction (sepsis syndrome), invasive fungal infection, ordysfunction (sepsis syndrome), invasive fungal infection, or
being hospitalized at the time of the development of fever.being hospitalized at the time of the development of fever.
Many placebo-controlled trials have shown that both G-CSFMany placebo-controlled trials have shown that both G-CSF
and GM-CSF (sargramostim) are effective at reducing theand GM-CSF (sargramostim) are effective at reducing the
incidence of neutropenic fever and infectious complications inincidence of neutropenic fever and infectious complications in
cancer patients receiving chemotherapycancer patients receiving chemotherapy

36. MYELOID RECONSTITUTIONMYELOID RECONSTITUTION
SYNDROMESYNDROME
Clinicians should be aware of the myeloid reconstitutionClinicians should be aware of the myeloid reconstitution
syndrome, which there may be onset or progression of ansyndrome, which there may be onset or progression of an
inflammatory focus defined clinically or radiologically thatinflammatory focus defined clinically or radiologically that
manifests at the time of neutrophil recovery. Because suchmanifests at the time of neutrophil recovery. Because such
processes appear in the context of a persistent neutropenicprocesses appear in the context of a persistent neutropenic
fever syndrome, the likelihood of superinfection must befever syndrome, the likelihood of superinfection must be
considered with respect to the antimicrobial spectrum of theconsidered with respect to the antimicrobial spectrum of the
patient’s current empiric antibacterial therapy.patient’s current empiric antibacterial therapy.
Bow EJ. Neutropenic fever syndromes in patients undergoing cytotoxic therapy for acute leukemia andBow EJ. Neutropenic fever syndromes in patients undergoing cytotoxic therapy for acute leukemia and
myelodysplastic syndromes. Semin Hematol 2009; 46:259.myelodysplastic syndromes. Semin Hematol 2009; 46:259.

37. Scenario in IndiaScenario in India
The cost of antibiotics in India is becoming quickly the most expensiveThe cost of antibiotics in India is becoming quickly the most expensive
component of the treatment—even higher than the cost of chemotherapycomponent of the treatment—even higher than the cost of chemotherapy
and growthand growth factors .factors .
Unique to our country, due to challenging logistics, e.g. difficult terrain,Unique to our country, due to challenging logistics, e.g. difficult terrain,
inaccessible medical facilities and inability to reach hospital within 24inaccessible medical facilities and inability to reach hospital within 24
hours of onset of fever many International guidelines are flouted andhours of onset of fever many International guidelines are flouted and
India centric innovative measures are needed . This clearly shows thatIndia centric innovative measures are needed . This clearly shows that
prophylactic use of G-CSF was, is and shall remain “standard” of care inprophylactic use of G-CSF was, is and shall remain “standard” of care in
India (and many developing countries) for majority of patients receivingIndia (and many developing countries) for majority of patients receiving
aggressive chemotherapy, beyond the scope of the revised Internationalaggressive chemotherapy, beyond the scope of the revised International
guidelines like ASCO or ESMO (European Society of Medical Oncology) .guidelines like ASCO or ESMO (European Society of Medical Oncology) .
Indian Guidelines for Febrile Neutropenia Madhuchanda Kar, ,Roy RakeshIndian Guidelines for Febrile Neutropenia Madhuchanda Kar, ,Roy Rakesh
National Comprehensive Cancer Network. Practice Guidelines in Oncology – v.2.2009. Prevention and Treatment ofNational Comprehensive Cancer Network. Practice Guidelines in Oncology – v.2.2009. Prevention and Treatment of
Cancer Related Infections.Cancer Related Infections.

38. Initial management of febrile neutropenia.Initial management of febrile neutropenia.
F. Marti Marti et al. Ann Oncol 2009;20:iv166-iv169F. Marti Marti et al. Ann Oncol 2009;20:iv166-iv169
ESMO ClinicalESMO Clinical
RecommendationsRecommendations

40. Antibiotic stopping guideAntibiotic stopping guide
IDSA, Clin Infect Disease, 2002IDSA, Clin Infect Disease, 2002
Minimum 1 week of therapy ifMinimum 1 week of therapy if
 Afebrile by day 3Afebrile by day 3
 Neutrophils >500/mmNeutrophils >500/mm33
(2 consecutive days)(2 consecutive days)
 Cultures negativeCultures negative
 Low risk patient, uncomplicated courseLow risk patient, uncomplicated course
> 1 week of therapy based if> 1 week of therapy based if
 Temps slow to settle (>3 days)Temps slow to settle (>3 days)
 Continue for 4-5 days after neutrophil recovery (>500/mmContinue for 4-5 days after neutrophil recovery (>500/mm33
))
Minimum 2 weeksMinimum 2 weeks
 Bacteraemia, deep tissue infectionBacteraemia, deep tissue infection
 After 2 weeks if remains neutropenic (< 500/mmAfter 2 weeks if remains neutropenic (< 500/mm33
), BUT), BUT afebrileafebrile, no disease focus,, no disease focus,
mucous membranes, skin intact, no catheter site infection, no invasive proceduresmucous membranes, skin intact, no catheter site infection, no invasive procedures
or ablative therapy planned…cease antibiotics and observeor ablative therapy planned…cease antibiotics and observe

41. Antibiotic Prophylaxis forAntibiotic Prophylaxis for
Afebrile Neutropenic PatientsAfebrile Neutropenic Patients
Use of antibiotic prophylaxis is not routine because of emergingUse of antibiotic prophylaxis is not routine because of emerging
antibiotic resistance except forantibiotic resistance except for
Trimethoprim-sulfamethoxazole to preventTrimethoprim-sulfamethoxazole to prevent Pneumocystis cariniiPneumocystis carinii
pneumonitis.pneumonitis.
Antifungal prophylaxis with fluconazoleAntifungal prophylaxis with fluconazole
Antiviral prophylaxis with acyclovir or ganciclovir are warranted forAntiviral prophylaxis with acyclovir or ganciclovir are warranted for
patientspatients undergoing allogenic hematopoietic stem cellundergoing allogenic hematopoietic stem cell
transplantationtransplantation..
2010 update by the Infectious Diseases Society of America. Clin Infect Dis 2011; 52:e562010 update by the Infectious Diseases Society of America. Clin Infect Dis 2011; 52:e56

42. Duration Of Neutropenia andDuration Of Neutropenia and
response rates to therapyresponse rates to therapy
1988,Rubin and colleagues1988,Rubin and colleagues
< 7 days of neutropenia ~ response rates to initial< 7 days of neutropenia ~ response rates to initial
antimicrobial therapy was 95%, compared to onlyantimicrobial therapy was 95%, compared to only
32% in patients with more than 14 days of32% in patients with more than 14 days of
neutropenianeutropenia
Patients with intermediate durations of neutropeniaPatients with intermediate durations of neutropenia
between 7 and 14 days had response rates of 79%between 7 and 14 days had response rates of 79%

43. OUTCOMESOUTCOMES
The efficacy of the treatment of patients with neutropenicThe efficacy of the treatment of patients with neutropenic
fever syndromes has improved greatly as demonstrated by afever syndromes has improved greatly as demonstrated by a
progressive decline in mortality rates since the promptprogressive decline in mortality rates since the prompt
initiation of empiric coverage was implemented in the 1970s.initiation of empiric coverage was implemented in the 1970s.
Studies from the 1960s, before the routine use of empiricStudies from the 1960s, before the routine use of empiric
therapy, documented mortality rates of 90 percent intherapy, documented mortality rates of 90 percent in
neutropenic patients with bacteremia caused by gram-neutropenic patients with bacteremia caused by gram-
negative bacilli. Sepsis due to P. aeruginosa or Escherichianegative bacilli. Sepsis due to P. aeruginosa or Escherichia
coli resulted in death within 48 hours after the first bloodcoli resulted in death within 48 hours after the first blood
culture had been drawn in approximately one-half of patientsculture had been drawn in approximately one-half of patients

44. Neutropenic Enterocolitis orNeutropenic Enterocolitis or
TyphilitisTyphilitis
Inflammatory process involvingInflammatory process involving coloncolon and/orand/or smallsmall
bowelbowel
ischemia, necrosis, bacteremiaischemia, necrosis, bacteremia
Hemorrhage, and perforation.Hemorrhage, and perforation.
Fever and abdominal pain ( typically RLQ).Fever and abdominal pain ( typically RLQ).
Bowel wall thickening on ultrasonography or CTBowel wall thickening on ultrasonography or CT
imaging.imaging.

45. TreatmentTreatment
( 50-70% mortality)( 50-70% mortality)
Initial conservative managementInitial conservative management
• bowel rest,bowel rest,
• intravenous fluids,intravenous fluids,
• TPN,TPN,
• broad-spectrum antibioticsbroad-spectrum antibiotics
• and normalization of neutrophil counts.and normalization of neutrophil counts.
Surgical interventionSurgical intervention
• obstruction, perforation, persistent gastrointestinal bleedingobstruction, perforation, persistent gastrointestinal bleeding
despite correction of thrombocytopenia and coagulopathy,despite correction of thrombocytopenia and coagulopathy,
and clinical deterioration.and clinical deterioration.

46. ThanksThanks