Management of Neutropenic fever
Dr. G/yesus E.
Moderator : Dr. G/Hiwot (Pediatrician)
1-Apr-23 1
Febrile neutropenia

Presentation Out lines
• Introduction
• Definition
• Etiology of fever
• Clinical manifestations
• Approach Neutropenic fever
• Investigations
• Risk stratification
• Management
• Modified Guideline for ACSH
1-Apr-23 Febrile neutropenia 2

Questions
• What clinical features and laboratory markers can be used to classify FN ?
• What clinical, laboratory, and imaging studies are useful at the initial
presentation of FN?
• What empirical antibiotics are appropriate for children with high-risk FN?
• When and how should the initial empirical antibiotic therapy be modified ?
• When can empirical antibiotics be discontinued in low- and high-risk FN?
1-Apr-23 Febrile neutropenia 3

Introduction
• Infection is a major cause of morbidity and mortality in cancer patients.
• Fever may be the first manifestation of a life-threatening infection, particularly
during periods of neutropenia.
• Febrile episodes occur in approximately one-third of Neutropenic episodes in
children with chemotherapy-induced neutropenia or after hematopoietic cell
transplantation .
Up-to-date,2018
1-Apr-23 Febrile neutropenia 4

Introduction …
• Fever occurs frequently during chemotherapy-induced neutropenia:
• 10%–50% of patients with solid tumors
• >80% hematologic malignancies with >/=1chemotherapy cycle associated with
neutropenia
• Most patients will have not documented infectious etiology.
• Clinically documented infections ~ 20%–30%.
• Bacteremia occurs in 10%–25% of all patients.
• Most episodes occur in prolonged or profound neutropenia (ANC<100 ne/mm)
• common sites of tissue-based infection include the intestinal tract, lung, and skin.
• Clinical Practice Guideline for the Use of Antimicrobial Agents in Neutropenic Patients with
Cancer , IDSA, 2010
1-Apr-23 Febrile neutropenia 5

Introduction …..
• In a 2yr retrospective study of 226 cancer patients in ACSH 2018-20
• 55 episodes of FN among 40 oncologic patients were analyzed
• Hematologic malignancy 96.3% of episodes
• Febrile neutropenia was common in descending order
• Lymphocytic leukemia, AML, NHL, brain tumor ,HL and retinoblastoma
respectively
• Common during induction and consolidation
Kiros T. Treatment outcome and associated factors of febrile neutropenia among pediatric
patients with cancer in ACSH, Northern Ethiopia,sep,2020.
1-Apr-23 Febrile neutropenia 6

Definitions
• Fever is defined as a single oral temperature >/= 38.3°C or oral temperature >/=
38°C for 1 hour or more.
• Oral temperatures are preferred.
• However, when axillary temperatures are the only option, fever is defined as a
single axillary temperature of >/= 37.8°C or axillary temperature >/= 37.5°C for 1
hour or more.
1-Apr-23 Febrile neutropenia 7

Definition …
• Neutropenia
• Neutropenia is defined as an absolute neutrophil count (ANC) <1500 cells/mm3
• Neutropenia
• ANC of <500 cells/mm3 or an
• ANC that is expected to decrease to <500 cells/mm 3 in the next 48 h
• Profound neutropenia: ANC is <100 cells/mm 3
• The ANC is calculated using the following formula:
ANC = total WBC count (cells/ cells/mm3 ) x (percent neutrophils + % bands) ÷ 100
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Introduction …
• First Neutropenic fever: first febrile episode occurring during a given period of
chemotherapy-induced neutropenia
• Persistent Neutropenic fever:
• a febrile episode without defervescence after at least 5 days of initial empiric
broad-spectrum antibacterial therapy in high-risk Neutropenic patients
• Recrudescent fever: febrile episode that recurs following initial defervescence
during a course of broad-spectrum antibacterial therapy
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Introduction …
• Neutropenic fever syndromes
• The International Immunocompromised Host Society has classified initial Neutropenic fever
syndromes into three categories .
• Microbiologically documented infection ( 10-20%)
• Neutropenic fever with a clinical focus of infection and an associated pathogen
• Clinically documented infection ( 20-30%)
• Neutropenic fever with a clinical focus (cellulites)
• No isolated pathogen
• Unexplained fever (50-60%)
• Neutropenic fever without clinical focus or identified pathogen
Up-to-date ,2018
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Etiology of fever
• The etiology of initial fever may be non-infectious, bacterial, viral or less
commonly due to other pathogens.
• Viral pathogens are common and evaluation should be directed at specific
signs and symptoms.
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1950s &early
1960s
• Common pathogens were gram-positive organisms,
Late 1960s
&1970s • Common pathogens were gram-negative organisms- E.coli, Klebsiella, Pseudomonas sp.
1980s • TMP/SMZ started being used for prophylaxis in neutropenic patient
1990
• IDSA Guidelines recommended TMP/SMZ for patients with profound neutropenia for > 1 weeks
• Common pathogens -gram-positives (e.g .s. aureus, & gram- negatives (E. coli, Pseudomonas sp.)
• early 1990s, the increased use of fluoroquinolones for prophylaxis in neutropenic patients began.
1997&
2002
• IDSA Guidelines did not recommend the routine use of TMP/SMZ or quinolones for prophylaxis.
2010
• Increase in drug-resistant pathogens ~ MRSA, VRE, ESBL-producing Enterbacteriaciae
• IDSA Guidelines recommended the use of fluoroquinolones in high-risk patients with prolonged and profound neutropenia
1-Apr-23 12
Febrile neutropenia

Etiology of fever…
• ETIOLOGY OF FEVER
• The rate of documented infection, when a child presents with fever and
therapy-induced neutropenia, ranges between 10 and 40 percent.
• No clinical or microbiologic evidence of infection will be established in the
remainder.
• Bacteremia is the most common form of documented infection (20 to 50 %)
• Other sites of infection
• GIT oral or intestinal mucositis or diarrhea caused by Clostridium
difficile and Salmonella spp
• Upper and lower respiratory tract
• Urinary tract
• Skin and soft tissues
1-Apr-23 Febrile neutropenia 13

Etiology of fever…
• In a 2yr retrospective study of 226 cancer patients in ACSH 2018-20
• 55 episodes of FN among 40 oncologic patients were analyzed
• 17 pathogen was isolated
• Most of isolated bacteria were gram negatives ~ 88.2 %
• ESBL positive ~ 40%
• Klebsiella pneumonia
• Escherichia coli
• Enterobacter cloacae
• Acinobacter species
• Microbiological confirmed FN -27.2 %
• Gram negatives are sensitive to meropenem and amikacin but highly resistant to
cephalosporins
• Mortality rate of febrile neutropenia was 21.8%.
.
1-Apr-23 Febrile neutropenia 14
Kiros T. Treatment outcome and factors of febrile neutropenia among pediatric
patients with cancer in ACSH, sep,2020

Etiology of fever …
• Fungi
• Typically Candida spp, are more likely to be recovered after prolonged
courses of broad-spectrum antibiotics but occasionally may be the primary
pathogen
• Aspergillus spp, Zygomycetes, and Cryptococcus spp
• Antifungal prophylaxis shift the distribution from Candida spp and toward
mold infections.
• Viral etiologies
• Most significant are HSV and VZV
• Respiratory viruses are also frequently detected in nasopharyngeal aspirates
1-Apr-23 Febrile neutropenia 15

Clinical manifestations FN
• Fever often is the sole sign of occult infection in the neutropenic host
• This sign may be absent in some infected patients may present with
hypothermic, hypotensive, listless, or confused
• Infected children who are receiving glucocorticoids
• May present with a lower and/or intermittent temperature elevation or may
be afebrile
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Clinical manifestations FN
 Signs and symptoms of inflammation are often attenuated or absent in
neutropenic patients
• Bacterial infections of skin and soft-tissue
• Lack induration, erythema, warmth, or pustulation
• Pulmonary infection
• No discernible infiltrateon a radiograph
• Meningitis
• CSF pleocytosis might be modest or absent
• Urinary tract infection may demonstrate little or no pyuria
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Patient approach
• Detailed HX and P/E with special attention to clues
• Suggesting etiology or focus of infection
• Try to identify any features that may help to risk stratify the patient
1-Apr-23 Febrile neutropenia 18

Patient approach …
• Detail History
• Important aspects of HX include :
• New site-specific symptoms
• Antimicrobial prophylaxis
• Infection exposures
• History of documented infections or colonization
• Concomitant noninfectious cause of fever (eg, receipt of blood products)
• Underlying co morbid conditions (eg, diabetes, recent surgery)
• Previous chemotherapy, agents used, and the stage of therapy (to anticipate
the length of the Neutropenic episode)
• Intravascular catheters or other devices
1-Apr-23 Febrile neutropenia 19

Patient approach …
• Physical examination
• A careful P/E particular attention paid to most commonly infected sites :
• Abnormal vital signs, particularly tachycardia (even without hypotension)
• HEENT
• Sinus tenderness or nasal ulcerative lesions
• Oral mucosa and periodontium
• Pharynx
• Lower esophagus
1-Apr-23 Febrile neutropenia 20

Patient approach …
• Lungs
• Tachypnea & saturation
• Abdomen
• Retrosternal burning pain
• Decreased bowel sounds
• Typhilitis/colitis
• Acute abdomen (RLQ pain)
• Hypotension
• Bloody diarrhea
1-Apr-23 Febrile neutropenia 21

Patient approach …
• Perineum, particularly the perianal and labial regions
• Perirectal abscess
• Erythema
• Induration
• Anorectal pain, tenderness and painful bowel movements.
• In the neutropenic patient, pus will be absent and the patient will present with
a brawny edema and dense cellulitis.
1-Apr-23 Febrile neutropenia 22

Patient approach …
• Skin
• Skin folds
• Areas surrounding nail beds,
• Central venous line exit sites and subcutaneous tunnel
• Sites of bone marrow aspiration and lumbar puncture
• Mild Erythema or tenderness should not be ignored
• Visual signs of inflammation may become evident only when neutrophil
counts are recovering.
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Investigations of FN
• CBC
• Liver and renal function
• Obtain peripheral blood cultures
• Consider urinalysis and urine culture in patients where clean catch midstream
specimen is readily available.
• Obtain chest X-ray only in symptomatic patients
1-Apr-23 Febrile neutropenia 24

Investigations of FN…
• Blood culture
• Obtaining a blood culture of an adequate volume from all lumens of the CVC
is important.
• Utility of peripheral blood cultures in addition to CVC cultures is
controversial.
• Seven studies evaluated concurrent peripheral and CVC cultures in adults and
children with cancer and/or undergoing HSCT
• The proportion of Bacteremia detected by peripheral blood cultures alone
(CVC cultures were negative) was 13% (95% CI 8-18%).
1-Apr-23 Febrile neutropenia 25
IDSA 2010

Investigations of FN…
• Variables influence blood culture yield
• Blood culture volume
• Choice of media type
• Number of culture bottles inoculated
• 2 retrospective studies found that
• 2 blood culture sets detect 80%–90% of bloodstream pathogens
• whereas >3 sets are required to achieve >96% detection
• Accordingly, at least 2 sets of blood culture specimens should be obtained
1-Apr-23 Febrile neutropenia 26
CPG guideline for use of antimicrobial agent in neutropenic
cancer patients , 2010

Investigations of FN…
Urinalysis and Urine Culture
• Pyuria was found in only 4% of UTI
• Nitrite testing in younger children to be less effective
• Urine culture if symptoms or abnormal urinalysis present
• Avoid invasive methods
• Clean-catch or midstream urine collection is recommended.
• Urine should be obtained prior to commencing antibiotics
• Urine collection should not delay treatment.
1-Apr-23 Febrile neutropenia 27

Investigations of FN…
• CXR:
• Routine CXRs are not recommended in asymptomatic children
• Had been advocated as part of the routine, initial assessment of pediatric FN
• Four studies that included 540 episodes of FN examined the value of routine CXR
• Frequency of pneumonia in an asymptomatic child was 5% or less each of
them
• Asymptomatic children who do not receive a CXR had no significant adverse
clinical consequences
• Findings
• New focal lesion in patient recovering from neutropenia
• New focal lesion in patient with continuing neutropenia
• New interstitial pneumonitis
• induced sputum or Bronchoalveolar lavage
1-Apr-23 Febrile neutropenia 28
Guideline for mgt of PNF ,IDSA 2010

Investigations of FN…
• Fungal
• Serial serum tests for fungal antigens or DNA
• D glucan test sensitivity (63%–90%) and specificity (>95%)
• Candida species
• Aspergillus species
• Pneumocystis species
• Fusarium species
• Galactomannan test ( 58-65 vs 65-95%)
• Aspergillus species
• BAL fungal culture
• PCR of blood and BAL fluid
• High-resolution chest CT
• Macronodules with or without a halo sign  Aspergillosis
• Halo sign represents edema or blood surrounding the nodule
• nodular, wedge-shaped, peripheral, multiple, or cavitary lesions.
1-Apr-23 Febrile neutropenia 29

Risk stratification
• Risk stratification at the time of a child’s presentation with FN
• May allow for intensification of therapy
• Monitoring for those at higher risk for serious infections and/or
complications
• De-escalation of therapy for those at lower risk for severe FN outcomes.
• Patients with fever and neutropenia can be divided into high- and low-risk categories
based upon
• Presenting signs and symptoms
• ANC
• Underlying cancer
• Type of therapy and the anticipated length of neutropenia
• Medical comorbidities.
1-Apr-23 Febrile neutropenia 30

Risk stratification…
• Use of a risk stratification strategy is important, and individual institutional
standards of care for risk assignment should be based on one of the six validated
schemas.
• Each institution should maintain records of which specific strategy was used and
evaluate the performance of the chosen rule to ensure accuracy and safety within
the specific clinical setting
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Risk stratification…
1-Apr-23 Febrile neutropenia 32
ICON 2016 , guideline for mgt of FN

Risk stratification…
High-risk
• Patients with FN with the following criteria , but not limited to:
• Hemodynamic instability
• Oral or GI mucositis that interferes with swallowing or causes diarrhea
• GI symptoms (abdominal pain, nausea, vomiting, or diarrhea)
• New-onset neurologic or mental status changes
• Intravascular catheter infection
• New pulmonary infiltrate or hypoxemia or underlying chronic lung disease
• Hepatic/renal insufficiency
• Patients with ALL, AML, or within 30 days of HCT
• NB
• High-risk patients should be admitted to the hospital for empiric antimicrobial
therapy.
1-Apr-23 Febrile neutropenia 33

Risk stratification…
• Low-risk FN
Low-risk patients are those with :
• Neutropenia expected to resolve within seven days
• Stable and adequate hepatic and renal function
• No active comorbidities
• Nontoxic appearance
• No identifiable source of fever
• Normal chest radiograph
• Malignancy in remission status.
1-Apr-23 Febrile neutropenia 34

Management of FN
• Factors to be considered in Initial management of pediatric FN
• Patient characteristics
• Clinical presentation
• Local infrastructure to support different models of care
• Drug availability and costs
• Local epidemiology of resistance patterns
1-Apr-23 Febrile neutropenia 35

Management of FN…
• Goal of empiric therapy
• To provide coverage for virulent organisms and prevent serious morbidity and
mortality
• Minimizing exposure to unnecessary antibiotics and prevent antibiotic
resistance rates
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Cont…
• The cornerstone of therapy for the febrile, neutropenic patient is prompt initiation
of empiric broad-spectrum antibiotics with antipseudomonal activity to reduced
the mortality rate for Gram-negative infections significantly.
• Administration of antibiotic therapy more than 60 minutes after presentation has
been associated with increased adverse outcomes and length of stay .
• In an observational study in pediatric cancer patients, receipt of antibiotics within 60
minutes of presentation was associated with decreased rates of ICU consultation or
admission among.
1-Apr-23 Febrile neutropenia 37

Empirical Treatment options
• Monotherapy
• Ticarcillin/clavulanate
• Piperacillin/tazobactam
• cefepime
• Imipenem or meropenem
• Two-drug regimen:
• cefepime, or ceftazidime AND gentamicin (or tobramycin or amikacin).
• Ticarcillin/clavulanate or Piperacillin/tazobactam and gentamicin (or tobramycin
or amikacin).
• NB
• Imipenem or meropenem should not be prescribed routinely as empiric therapy.
1-Apr-23 Febrile neutropenia 38

Cont…
• Recommendations on empirical antibiotics use in pediatric HR FN
• Monotherapy with an anti-pseudomonal ß-lactam or a carbapenem
( strong recommendation, high-quality evidence)
• Result from 2 meta-analyses compared monotherapy versus an aminoglycoside-
containing regimen in FN and in immunocompromised patients with sepsis in
adults
• Non-inferiority of monotherapy regimens
• Higher toxicity with combination regimens
1-Apr-23 Febrile neutropenia 39
Guideline for mgt of PNF, IDSA 2010

Cont…
• In review of 68 randomized trials, which includes 30 more trials than the 38
randomized trials.
• Found that monotherapy is similar in efficacy and safety in comparison with
aminoglycoside-containing combination regimens
• Reduce costs , toxicity, and the need for therapeutic drug monitoring
• Fourth-generation cephalosporin monotherapy is an appropriate option for
empirical pediatric high-risk FN management if institutional factors support its
use.
1-Apr-23 Febrile neutropenia 40
Paula D. robinson etal , Strategies for Empiric Management of Pediatric FN in Patients With
Cancer and HSCT Recipients,, journal of clinical oncology ,2016

Cont…
• A pediatric meta-analysis found included only 4 trials with patients younger than
14 years of age show
• Fewer treatment failures with monotherapy (OR 0.88, 95% CI 0.78-0.99)
• Aminoglycoside-containing combination treatment did not improve clinical
outcomes in comparison to monotherapy.
• Limitation – limited trials
1-Apr-23 Febrile neutropenia 41
Guideline for mgt of PNF, IDSA 2010

Cont…
1-Apr-23 Febrile neutropenia 42
ICON 2016 , guideline for mgt of FN

Modification of treatment: after 24-72 hr empirical RX
If responding to empiric therapy
• Do not modify based solely on
persistence of fever if clinically
stable
• Discontinue double gram-negative,
or empiric glycopeptides coverage
(if initiated) after 24-72 hours
UNLESS combination is justified
by specific microbiologic
indication
If NOT responding to empiric therapy
• If persistent fever and clinically
unstable
• Escalate initial empiric antibacterial
regimen to include coverage for
• Resistant gram negative
• Gram-positive
• Anaerobic bacteria
1-Apr-23 43
Febrile neutropenia

Cont…
• MRSA: addition of Vancomycin, linezolid, or daptomycin
• VRE: Consider early addition of linezolid or daptomycin
• ESBLs: Consider early use of a carbapenem
• penicillin-allergic patients can be treated with ciprofloxacin plus clindamycin
or aztreonam plus vancomycin
1-Apr-23 Febrile neutropenia 44

Treatment Cessation :After 24-72 hr empirical RX
For all patients
• Discontinue empiric antibiotics
if:
• blood culture negative at 48 hrs
• Afebrile for at least 24 hours, and
• There is evidence of bone marrow
recovery
For low-risk FN
• Consider discontinuation of empiric
antibiotics in low-risk patients at 72
hours irrespective of marrow recovery
status, if:
• Blood culture negative,
• Afebrile for at least 24 hours, as
long as careful follow-up is ensured
1-Apr-23 45
Febrile neutropenia

Treatment Cessation :After 24-72 hr empirical RX
For all patients
• Discontinue empiric antibiotics
if:
• blood culture negative at 48 hrs
• Afebrile for at least 24 hours, and
• There is evidence of bone marrow
recovery
For low-risk FN
• Consider discontinuation of empiric
antibiotics in low-risk patients at 72
hours irrespective of marrow recovery
status, if:
• Blood culture negative,
• Afebrile for at least 24 hours, as
long as careful follow-up is ensured
1-Apr-23 46
Febrile neutropenia

Cont…
1-Apr-23 Febrile neutropenia 47
ICON 2016 , guideline for mgt of FN

Indication for vancomycin consideration
• Suspected central venous catheter-related infection
• Patients with AML because of the increased risk of infection with alpha hemolytic
streptococcus such as Streptococcus mitis
• Prior history of alpha hemolytic streptococcus Bacteremia
• Patients colonized with resistant organisms only treatable with vancomycin
• Recent history of Bacteremia or venous catheter-related infection requiring
vancomycin
• Intensive chemotherapy causing mucositis (such as high-dose cytosine
arabinoside)
• Hypotension
• Patients who have developed fever despite quinolone prophylaxis.
1-Apr-23 Febrile neutropenia 48

Management of fungal infection
• The risk of fungal infections is related to the cytotoxicity of the chemotherapeutic
regimen and the duration of neutropenia.
• The major cause IFIs
• Aspergillus and Candida with a mortality approaching 30–60% with.
• Higher among post-hematopoietic stem cell transplantation patients.
• Prompt diagnosis and treatment is paramount to improving outcomes in these
patients.
• Difficulty in diagnosing fungal infections is caused by
• Absence of localizing signs and symptoms
• High likelihood of negative blood cultures.
1-Apr-23 Febrile neutropenia 49

Risk stratification of IFIs
• High risks invasive fungal infection
• Acute myeloid leukemia
• Relapsed acute leukemia
• Highly myelosuppressive chemotherapy
• Allogeneic hematopoietic cell transplant recipients
• Children with prolonged neutropenia
• Children receiving high-dose corticosteroid
• Low-risk of IFIs - if do not fulfill the above three criteria
1-Apr-23 Febrile neutropenia 50

Empiric Treatment IFD
High risk IFIs
• Start empiric antifungal therapy if
persistent or recurrent fever of unclear
etiology at or beyond 96 hours of
broad-spectrum antibacterial
treatment.
Low risk IFIs
• consider empiric antifungal therapy if
persistent or recurrent fever of unclear
etiology at or beyond 96 hours of
broad-spectrum antibacterial treatment.
1-Apr-23 51
Febrile neutropenia

Management …
• Choice of antifungal:
• Caspofungin, or liposomal Amphotericin B
• Amphotericin-B in places with limited resources
• Prophylactic antifungal therapy in children with IFD high risk
• No studies evaluating the safety of this approach in pediatric patients found
• Research needed to evaluate its safety and effectiveness in children.
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Management …
• Cessation of antifungal therapy:
• No data exists to guide this decision
• International pediatric FN guideline panel agrees that empiric therapy should
be continued until absolute neutrophil count rises to100-500/µL, and no
documented or suspected IFD.
1-Apr-23 Febrile neutropenia 53

Management …
• Antiviral therapy
• Antiviral treatment for HSV or VZV is only indicated if there is clinical or
laboratory evidence of active viral disease .
• Respiratory virus testing ( influenza, parainfluenza, adenovirus) and CXR are
indicated for patients with URT symptoms ( coryza, cough).
1-Apr-23 Febrile neutropenia 54

Typhilitis/Neutropenic Enterocolitis
• Necrotizing colitis localized in the cecum, occurs in the setting of severe
neutropenia, particularly in patients with leukemia and in stem cell transplant
recipients.
• Should be strongly suspected in patients with right lower quadrant pain or the
development of a partially obstructive right lower quadrant mass.
• Result of bacterial or fungal invasion of the mucosa and can quickly progress
from inflammation to full-thickness infarction to perforation, peritonitis
and septic shock.
1-Apr-23 Febrile neutropenia 55

Typhilitis …
• Responsible pathogens include
• Pseudomonas species, Escherichia coli, other Gram negative bacteria
• Staphylococcus aureus, a-hemolytic Streptococcus, Clostridium,
• Aspergillus, and Candida.
• Typhilitis in patients receiving chemotherapy is linked to mucosal injury caused
by cytotoxicity chemotherapeutic agents.
• The cecum is usually affected ...> its distensibility and its diminished
vascularization relative to the rest of the colon.
• Extends into the ascending colon and terminal ileum
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Clinical manifestations of typhilitis
• Neutropenic enterocolitis must be considered in any severely neutropenic
patient (ANC <500 cells/microL) who presents with fever and abdominal
pain.
• The location of abdominal pain right lower quadrant.
• fever, frequently appear during the 3rd week (median 17 days) after
receiving cytotoxicity chemotherapy
• At a time when neutropenia is most profound.
• Abdominal distension, cramping, tenderness, nausea, vomiting, watery or
bloody diarrhea, and frank hematochezia.
• Paralytic ileus may occur but is uncommon.
• Peritoneal signs and shock suggest the possibility of bowel wall
perforation.
• Stomatitis and pharyngitis, suggesting the presence of widespread
mucositis, may be present.
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Cont…
• Diagnosis
• Typhilitis is usually diagnosed clinically when a neutropenic patient presents
with right lower quadrant pain.
• Physical examination may reveal an
• Absence of bowel sounds
• Bowel distention
• Tenderness on palpation maximal in right lower quadrant
• A palpable mass in right lower quadrant.
• Serial abdominal examinations are required
• Blood and stool cultures and C. difficile toxin assays
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Cont…
• Imaging studies may aid in the diagnosis of typhlitis:
• Radiograph of the abdomen
• Reveal pneumatosis intestinalis
• free air in the peritoneum
• Wall thickening
• US
• Thickening of the bowel wall in the region of the
• cecum and is becoming a
• More commonly used non-radiation modality to image for typhlitis
• CT scan
• definitive imaging study and may
• demonstrate diffuse thickening of the cecal wall
• Barium enema
• show severe mucosal irregularity, rigidity, loss of haustral markings and
occasional fistula formation
1-Apr-23 Febrile neutropenia 59

Cont…
• Medical management is the initial treatment:
• Discontinuation of oral intake
• Nasogastric tube suctioning
• Broad-spectrum antibiotics (anaerobic , Gram-negative and anaerobic)
• Piperacillin-tazobactam /Cefepime/Meropenem with/out metrodazole
• Vancomycin with indication
• Intravenous fluid and electrolytes
• Packed red cell and platelet transfusions, as indicated
• Vasopressors, as needed (hypotension is associated with a poor outcome).
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Cont…
• Indications for surgical intervention:
• Persistent GI bleeding despite resolution of neutropenia and thrombocytopenia
• Evidence of free air in the abdomen on abdominal radiograph
• Uncontrolled sepsis from bowel infarction requiring fluid and pressor support
• Mortality is related to bowel perforation, bowel necrosis and sepsis.
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Cont…
• Fungemia and fungal invasion of the bowel can occur
• Candida spp are the most common cause of fungal bloodstream infection in
patients with neutropenic colitis.
• Protracted fever (>72 hours) despite broad-spectrum antibiotics.
• Voriconazole and amphotericin B formulations.
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Management …
• Myeloid CSFs
• Are not recommended as adjuncts to antibiotics
• Minimally (but statistically significantly) decreased
• Days of neutropenia
• Duration of fever
• Length of hospital stay
• The actual clinical benefit of these reductions is not convincing.
• None of the studies demonstrated a survival benefit associated with
therapeutic CSFs.
• Given the cost of and adverse effects and lack of consistent clinical data
associated with the CSFs routine use is not advocated
1-Apr-23 Febrile neutropenia 63
Guideline FN IDSA 2010

Management …
• Prevention of febrile neutropenia
• Hand hygiene
• Standard barrier precautions and infection specific isolations.
• HSCT recipients should place in private room
• Allogeneic HSCT recipients should placed in private room with >12air exchange
/hr and high efficacy particulate filter room
• Plants and dried or fresh flowers should not allowed in the room of hospitalized
neutropenic patients
• Hospital work exclusion policies should be designed to encourage health workers
to report their illness or exposure.
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Summery
• Fever is frequently the only clinical manifestation of serious infection in a
neutropenic cancer patient,
• Infection is the major cause of treatment related mortality for children with cancer
• Prompt initiation of empiric, broad-spectrum, intravenous antibiotic therapy is the
single most important life-saving intervention in these patients and should Treated
as an emergency.
• Vital sign Q1hr until stable then Q4hror as indicated
• Acetaminophen is the preferred antipyretic agent.
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Guidelines for the management of febrile neutropenia in ACSH,
2021
ACSH Hemato-oncology unit
1-Apr-23 Febrile neutropenia 66

Definition
• The neutropenic patient
• ANC < 500 x 109 /L or ≤1 x 109 /L with predicted fall to < 0.5 x 109 /L)
must be admitted and given intravenous antibiotics in the event of a single
temperature spike of >37.8°C axillary or a temperature of ≥37.5°C axillary
taken on two occasions at least one hour apart
1-Apr-23 Febrile neutropenia 67

Cont…
Please do
• CBC and Differential immediately
• Liver and renal function
• Obtain 2 blood culture sets from separate peripheral vein puncture
• IV antibiotics should be started within 1 hour
• Provide blood transfusion if indicated
• Consult pediatric hemato-oncologist
1-Apr-23 Febrile neutropenia 68

Risk stratification
Low risk features
• Vitally stable
• No evident focus of infection
• ANC>100 and anticipated to rise
within 7days
• Solid tumors and ALL during
maintenance
• No abdominal pain
High risk features
• AML, MDS, ALL(during induction,
consolidation , re-induction), NHL
• ANC<100, and/or anticipated to extend >
7 days
• Presence of any co-morbid medical
problem including: vital instability, GIT
manifestation, pneumonia, altered mental
status
• Vital instability: Hypotension, tachypnea,
Hypoxia (O2 sats < 94% in room air)
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Management of FN
Low risk features
• Start with ceftriaxone and
gentamicin
• 2nd line: Ceftazidime &Vancomycin
• Outpatient management
• who refused inpatient management
• Do blood culture
• first dose of ceftriaxone and
gentamicin IV at PEOPD
• Ciprofloxacin and Augmentin PO
• Phone number
High risk features
• Start ceftazidime and gentamicin
• 2ndline: cefepime
• Ciprofloxacin if microbiological
documented
• Vancomycin can be used as first line
based on indications
• Metronidazole for abdominal
symptoms or suspected C. difficile
infection
•
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Treatment Cessation :after 24-72 hr empirical RX
For all patients
• Discontinue empiric antibiotics
if:
• blood culture negative at 48 hrs
• Afebrile for at least 24 hours, and
• There is evidence of bone marrow
recovery
For low-risk FN
• Consider discontinuation of empiric
antibiotics in low-risk patients at 72
hours irrespective of marrow recovery
status, if:
• Blood culture negative,
• Afebrile for at least 24 hours, as
long as careful follow-up is ensured
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Treatment Cessation :after 24-72 hr empirical RX
For all patients
• Discontinue empiric antibiotics
if:
• blood culture negative at 48 hrs
• Afebrile for at least 24 hours, and
• There is evidence of bone marrow
recovery
For low-risk FN
• Consider discontinuation of empiric
antibiotics in low-risk patients at 72
hours irrespective of marrow recovery
status, if:
• Blood culture negative,
• Afebrile for at least 24 hours, as
long as careful follow-up is ensured
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Empiric Treatment IFD
High risk IFIs
• start empiric antifungal therapy if
persistent or recurrent fever of unclear
etiology at or beyond 96 hours of
broad-spectrum antibacterial
treatment.
• Liposomal Amphotericin B
Low risk IFIs
• consider empiric antifungal therapy if
persistent or recurrent fever of unclear
etiology at or beyond 96 hours of broad-
spectrum antibacterial treatment.
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Reference
• Up to date 2018
• Clinical practice Guidelines for the use of antimicrobial Agents in neutropenic
patients with cancer :2010 update by Infectious Disease Society of America
• Manual of Pediatric Hematology &Oncology,5th edition
• Guideline for the management of fever and neutroprnia in children with cancer
and HSCT recepient ,2017
• Nelson text book of pediatrics ,21st edition
• Febrile neutropenia current guidelines for children, ICON 2016
• CPG guideline for use of antimicrobial agent in neutropenic cancer patients ,
2010
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Thank you!
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