Topic presentation by: Dr. Saurav Kumar Upadhyay
1st Year, Junior resident
Dept. of Pediatrics
S.V.P. P.G.I.P. Cuttack
Definition- decrease in the absolute number of circulating
segmented neutrophils and band cells in peripheral blood
Absolute neutrophil count (ANC) = Total white blood
cells/microL x percent (PMNs+band cells) ÷ 100
Neutrophil count must be stratified for age & race.
At birth- predominant but rapid decrease begins at 12 hour
through the 1st wk of life.
Infancy- 20- 30% of TLC
At 5 years- equal number of neutrophils & lymphocytes count
In adults – characteristic 70% predominance of neutrophils is
usually attained during puberty
Constitutional neutropenia is neutropenia of
longstanding duration, typically since childhood
For white children lower limit of normal for ANC is
For black children , it’s 1200/cu mm.
The relative lower limit of normal in blacks likely reflects the
prevalence of the Duffy negative ( Fy-/-) blood group, which is
selectively enriched in populations in Malaria belt of Africa
and is associated with ANCs 200 – 600/ cu mm less than those
who are Duffy positive.
Chronic neutropenia is neutropenia that lasts more than three
Mild neutropenia – ANC 1000 – 1500/cu mm
Moderate neutropenia – ANC 500 – 1000/cu mm
Severe neutropenia – ANC less than 500/cu mm
Agranulocytosis- ANC less than 200/cu mm
Profound neutropenia – ANC less than 100/cu mm
Prolonged neutropenia – lasting more than 7 days
Cyclic neutropenia – Patients with chronic neutropenia since
infancy and a history of recurrent fevers and chronic
gingivitis should have WBC counts & DLC determined 3/wk
for 6-8 wks to evaluate the periodicity suggestive of cyclic
neutropenia. (oscillations ranging from Normal ANCs to
The term ‘‘Functional neutropenia’’ refers to patients whose
hematologic malignancy results in qualitative defects
(impaired phagocytosis and killing of pathogens) of
circulating neutrophils. These patients should also be
considered to be at increased risk for infection, despite a
‘‘normal’’ neutrophil count.
Patients with neutropenia caused by increased destruction
(e.g. autoimmune) may tolerate very low ANCs without
increased frequency of infection.
Severe congenital neutropenia :
Incidence 1-2 cases per 1 million population
Characterised by an arrest in maturation at the promyelocyte stage in
the bone marrow, resulting in ANCs consistently < 200/cu mm
Autosomal Dominant form : mutations in the ELANE gene (60- 80%
Autosomal Recessive form : mutations in HAX1 ( also known as
Kostmann disease) or G6PC3 ( encoding a myeloid specific isoform of
Febrile neutropenia - Introduction
Development of fever in a neutropenic patient.
Defined as single oral/axillary temperature
> 38.3 °C (101 °F) OR two consecutive temperature > 38 °C
in a 12 hr period for at least 1 hr WITH ANC < 500/cu mm
or < 1000/cu mm with expected decline to < 500/cu mm
during the next 48 hours.
Microbiologically documented infection –
Neutropenic fever with a clinical focus of infection and an
Clinically documented infection – Neutropenic fever
with a clinical focus (eg, cellulitis, pneumonia), but
without the isolation of an associated pathogen.
Unexplained fever – Neutropenic fever with neither a
clinical focus of infection nor an identified pathogen
A persistent neutropenic fever is a febrile episode without
defervescence after at least five days of initial empiric broad-
spectrum antibacterial therapy in high-risk neutropenic
patients or after at least two days in low-risk neutropenic
A recrudescent neutropenic fever is a febrile episode that
recurs following initial defervescence during a course of
broad-spectrum antibacterial therapy
Common in children who are on chemotherapy and the
most common oncologic emergency.
Occurs in children diagnosed to have acute
leukemia,lymphoma,solid tumor or aplastic anemia
It may result from underlying malignancy per se or typically
due to effect of chemotherapy
The risk of infection is clearly increased when ANC drops
below 1000/cu mm , with a marked increase when the ANC
is below 500/cu mm.
Neutropenic patient can have serious life threatening
infections even in the absence of fever and may not present
with any localizing symptoms and signs of infection such
as exudate, fluctuance, and regional lymphadenopathy.
Sometimes only fever remain the only consistent early sign.
Fever occurs frequently during chemotherapy-induced neutropenia.
10%–50% of patients with solid tumors and 80% of those with
hematologic malignancies will develop fever during >1 chemotherapy
cycle associated with neutropenia.
Most patients will have no infectious etiology documented. Clinically
documented infections occur in 20%–30% of febrile episodes. Common
sites of tissue-based infection include the intestinal tract, lung, and
skin. Bacteremia occurs in 10%–25% of all patients, with most episodes
occurring in the setting of prolonged or profound neutropenia
(ANC<100 neutrophils/cu mm)
Risk of Infection as Absolute Neutrophil
Decreased production of neutrophils from the bone marrow.
Shift of circulating neutrophils to the vascular endothelium or tissues
such as the spleen, termed "margination", which can occur with
splenomegaly and/or hypersplenism.
In addition to neutropenia, disruption of mucociliary barriers,
extensive use of invasive devices and shifts in inherent microbial flora
due to prolonged antimicrobial usage predispose these patients to
infection. Besides these, qualitative defects in neutrophil function
described in hematological malignancies also contribute to FN.
Immune-mediated destruction :
The current hypothesis of immune-mediated drug-induced
agranulocytosis suggests that the drug, or more commonly a
reactive metabolite of the drug, irreversibly binds to the neutrophil
membrane. In some cases, the reactive metabolite results in the
production of antibodies or T cells directed against the altered
membrane structure; in others, true antineutrophil autoantibodies
are produced that do not require the presence of the drug .
Direct toxic effects upon marrow granulocytic precursors :
Some drugs can directly damage myeloid precursors. As an
example, detoxification of many nonpolar compounds requires
conversion to a chemically reactive intermediate that may bind to
nuclear material or cytoplasmic proteins, causing direct toxicity
Common pathogens in febrile neutropenic
Gram Positive Bacteria-
Staphylococcus species ( e.g. S. epidermidis & S. aureus)
Streptococcus species ( alpha hemolytic, e.g. S . mitis)
Enterococcus species ( e.g. E. faecium, E. faecalis)
Clostridium species ( C. difficile, C. septicum, C. tertium)
Gram Negative Bacteria-
Enterobacteriaceae ( E. coli, Klebsiella spp. , Enterobacter spp.)
Anaerobes (e.g. Bacteroides spp & Prevotella spp. )
Candida spp. ( e.g. C. albicans, C. glabrata, C. tropicalis, C. krusei)
Aspergillus spp. ( e.g. A. fumigatus, A. flavus, A.terreus)
Fusarium spp. ( e.g. F. solani & F. oxysporum)
Pneumocystis jiroveci ( formerly known as P. carinii)
System specific infections
Skin specific :
While cellulitis caused by Streptococcus or Staphylococci is common,
neutropenic patients ,i.e. with ANC < 500/cu mm may develop
infections with unusual organisms.
Innocent looking macules may be the first sign of bacterial or fungal
sepsis. Signs of infection , e.g. purulence are often lacking.
It may progress rapidly to ecthyma gangrenosum which is localised in
non pressure areas. It is often associated with Pseudomonas
aeuroginosa bacteremia but may be caused by other bacteria.
Debridement to prevent spread sometimes necessary early in the
course of disease but can be performed after chemotherapy when the
Candidemia is also associated with a variety of skin conditions and
commonly presents as a maculopapular rash. Punch biopsy of the skin
may be the best method for diagnosis.
Cytokines , used adjuvants or primary treatments for cancer , can
themselves cause rashes, complicating the differential diagnosis
GI tract specific:
Upper GIT : Mouth ulcerations afflict most patients receiving
chemotherapy and often associated with viridans streptococcal
Use of Keratinocyte growth factor ( Palifermin ) in a dose of 60 mcg/kg
for 3 days before chemotherapy and total body irradiation is of proven
value in preventing mucosal ulcerations after stem cell transplantation.
Fluconazole is effective in the treatment of both local infections
(thrush) and systemic infections ( esophagitis ) due to candida
Newer azoles are similarly effective.
Viruses, particularly HSV are a prominent cause of morbidity in
immunocompromised patients, in whom they cause severe
mucositis. Use of Acyclovir , either prophylacticaly or therapeuticaly,
is of value.
Hepatic candidiasis results from seeding of the liver ( usually from
a GI source ) in neutropenic patients. Most common in patients
treated for acute leukemia and usually presents around the time
the neutropenia resolves.
Characteristic picture : persistent fever unresponsive to antibiotics,
abdominal pain and tenderness or nausea and elevated levels of
serum alkaline phosphatase in a patient with hematologic
malignancy who has recently recovered from neutropenia.
Hepatic USG or CT may reveal bull’s eye lesions. In some cases ,
MRI reveals small lesions not visible by other imaging modalities.
Neutropenic Enterocolitis or Typhilitis
Also known as necrotising colitis, necrotising enteropathy, ileocecal
syndrome & cecitis.
Inflammatory process involving colon and/or small bowel
Ischemia, necrosis, bacteremia
Hemorrhage, and perforation.
Fever and abdominal pain ( typically RLQ).
Diarrhea (often bloody)
Bowel wall thickening on ultrasonography or CT imaging, MRI
Common among patients with AML or ALL than among those with
other types of cancer
Initial conservative management
and normalization of neutrophil counts.
obstruction, perforation, persistent gastrointestinal bleeding
despite correction of thrombocytopenia and coagulopathy,
and clinical deterioration.
Pneumonia in immunocompromised patients may be difficult to
diagnose because conventional methods of diagnosis depend on the
presence of neutrophils.
Bacterial pneumonia in neutropenic patients may present without
purulent sputum or, in fact, without any sputum at all- and may not
produce physical findings suggestive of chest consolidation (rales or
Aspergillus spp. can colonise the skin and respiratory tract or cause
fatal systemic illness. In neutropenic patients, A. flavus or A.
fumigatus can invade the blood vessels. Likely to present as a
thrombotic or embolic event.
Aspergillus infection often present with pleuritic chest pain & fever.
Hemoptysis may be an omnious sign. Chest X-ray may reveal new
focal infiltrates or nodules. Chest CT may reveal a characteristic halo
consisting of a mass-like infiltrate surrounded by an area of low
attenuation. Presence of “ crescent sign” on a chest X-ray or CT scan
suggest invasive Aspergillus infection.
Candida infection of the thyroid may be difficult to diagnose during
the neutropenic period. Can be defined by indium-labelled WBC scans
or gallium scans after neutrophil counts increase.
CMV infection can cause adrenalitis with or without resulting adrenal
Renal & ureteral infections:
Candida, which has a predilection for the kidney, can invade either
from the blood stream or in a retrograde manner via the ureters or
bladder in immunocompromised patients.
Fever – Onset, duration, severity
Associated localizing symptoms : Ear, Nose, Throat, Respiratory
tract, Gastrointestinal tract, Musculoskeletal , CNS, Urinary
Phase of chemotherapy ( Intensive vs. non intensive)
Duration since last chemotherapy
Recent hospitalisation and antibiotics received
Vitals- in every patient of suspected febrile neutropenia is very
important. The patient may appear well despite being in a state of
Detailed physical examination focusing on possible sites of
infection must be undertaken. Sites that are commonly
overlooked include oral cavity, ear, sinuses, skin , nails , perianal
area, intravascular catheter insertion sites and the site of bone
First line investigations- to be performed in every cases.
1. Complete blood count including Differential Leucocyte count and
2. Serum electrolytes
3. Blood urea & Serum Creatinine
4. Blood cultue & sensitivity : obtain as early as possible and always before
the adminstration of antibiotics. Two sets of blood culture from separate
venipuncture sites should ideally be drawn. In the presence of central
venous catheter, a blood culture should be obtained from each lumen of
the catheter and another from peripheral vein.
5. Cultures from any other site, as clinically relevant. This includes stool,
urine, cerebrospinal fluid, skin, respiratory secretions or pus.
6. Chest radiograph: mandatory for all. Initial x-ray may be non
informative but must be taken as a baseline for comparison with later
Second line investigations- Dictated by clinical course.
1. Serum Galactomannan test & CT scan of chest/ paranasal sinuses may
be indicated in patients with suspected fungal infection. Do not order
CT scan in a neutropenic patient with a normal CXR initially.
2. In clinical practice if patient remains febrile for 3 to 5 days then the next
step is HRCT. ( 50 % of patients with positive imaging have a normal
3. Bronchoalveolar lavage : If Pneumonia is non- resolving/ non
responding. Should be cultured for Mycoplasma, Chlamydophilia,
Legionella, Nocardia, more common bacerial pathogens, and fungi.
4. CT abdomen for Necrotizing Enterocolitis or Typhilitis
5. CT brain R/o ICH / MRI of the spine or brain - more for evaluation of
metastatic disease than FN.
6. Examination of CSF specimens is not recommended as a routine
procedure but should be considered if a CNS infection is suspected and
thrombocytopenia is absent or manageable.
7. Skin biopsy, from skin nodules, if any
Approach if ANC < 1000/ cu mm
Repeat blood counts in 3-4 wks
Serology and cultures for infectious agents
Discontinue drugs associated with neutropenia
Test for antineutrophil antibodies
Measure quantitative Ig (G,A and M), lymphocyte subsets
Approach if ANC< 500/cu mm on 3 separate tests
Bone marrow aspiration & biopsy, with cytogenetics
Glucocorticoid stimulation test
Serial CBCs (3/wk for 6 wks)
Exocrine pancreatic functions
-Blood cultures (peripheral and all central line lumens)
-Oral ulcers or sores –send swabs
-Exit site swabs
-Stool Cultures and CDiff Toxin/PCR
Paediatric patients weighing <40 kg, proportionately smaller volumes
of blood culture samples are suggested. Some centres limit blood
draws to no more than 1% of a patient’s total blood volume.
Because total blood volume is approximately 70ml/kg, the total
sample limit would be 7 ml for a 10-kg patient and 28 ml for a 40-kg
Despite advances in diagnostic methods, infection is documented only in
30 - 40% patients.
Risk stratification is crucial in determining the appropriate
Choice of antimicrobials
Route of administration ( IV or Oral )
Setting ( inpatient vs. outpatient )
Duration of treatment
The patient can be classified as low or high risk.
Low risk High risk
Neutropenia is expected to resolve in about
Afebrile for 24 hours, Temperature <39˚ C
Clinically well, haemodynamically stable
Sterile blood culture
Lack of any focus of infection, eg:
pneumonia,abscess, sinusitis or diarrhoea
Lack of medical comorbidities
Evidence of bone marrow recovery with
rising polymorphs count/ platelets / ANC
Non- intensive phase of chemotherapy .e.g.
maintenance phase of chemotherapy
Malignancy in remission
ANC > 100/ cu mm and likely to rise within
the next 7 days.
Absolute monocyte count > 100/mm3
Neutropenia > 7 days
Any focus of infection,eg: cellulitis,
abscess, pnemonia, diarrhoea
No evidence of bone marrow recovery
Recent intensive chemotherapy
Profound neutropenia ( ANC < 100/cu
mm ) anticipated to extend for > 7 days
Evidence of hypotension, respiratory
distress or hypoxemia.
Mucositis interfering with oral intake or
resulting in diarrhea.
Presence of fever > 39 ° c, associated with hypotension, ANC <
100/ cu mm, duration of neutropenia > 7 days are frequently
associated with bacteremia.
Studies have found that serum CRP more than 90 mg/ L ,
hypotension, relapsed leukemia, platelet count <50,000/cu
mm and recent chemotherapy are useful predictors of serious
Studies have found that an absolute monocyte count <100/ cu
mm, co-morbidity and abnormal chest radiograph correlate
with high risk for bacterial infection.
Risk scoring :
For adults- The Multinational Association of Supportive
Care in Cancer
( MASCC ) score is used for risk stratification. Patient with
score with ≥21 are at lower risk of complication.
Clinical Index of Stable Febrile Neutropenia (CISNE)
The Multinational Association for Supportive Care in Cancer
Risk-Index Score (The American Society for Clinical
Burden of illness(no/mild)----------------------------------5
Burden of illness(moderate)---------------------------------3
Burden of illness (sever)--------------------------------------0
No Hypotension ----------------------------------------------5
Solid Tumor/ Lymphoma,
no previous Fungal infection-------------------------------4
Outpatient Status (onset of fever)---------------------------3
Age < 60 years--------------------------------------------------2
Clinical Index of Stable Febrile Neutropenia (CISNE)
Specific of patients with solid tumors and seemingly stable
Able to discriminate patients who are at low, intermediate & high
risk of complications
With CISNE scoring, the complication rate was determined to be
1.1% for low risk patients, 6.2% for intermediate risk patients and
36% for high risk patients.
Prime purpose of this scoring is to avoid complications from an
early hospital release.
IV MONO THERAPY
IV DUAL THERAPY
Mono or dual therapy + VANCOMYCIN
Anti-pseudomonal β-lactam agents:
Monotherapy with anti-pseudomonal β-lactam agents such
as anti-pseudomonas penicillin(Piperacillin-tazobactum),
sulbactum) or carbapenems(Meropenem or Imipinem-
cilastatin) or Cefepime is recommended as first line by
Infectious Disease Society of America.
Carbapenems can be reserved as second line antibiotics to
prevent the emergence of drug resistant organisms.
Colistin is reserved as third line drug.
No significant differences in treatment failure, including
antibiotic modification, infection related mortality, or
adverse events were observed while comparing anti
pseudomonas Penicillin± Aminoglycoside regimen with
Carbepenem monotherapy in a recent meta analysis.
Empirically, combination of antipseudomonal antibiotic
(Ceftazidime, Cefoperazone -sulbactum) + an Aminoglycoside is
used as First line of defence.
Swich to second line drugs : Vancomycin and Carbepenems
(Meropenem, Imipenem- Cilastatin) after 48- 72 hours, if fever is
unrelenting and there is no improvement in clinical condition.
If the culture yields a specific pathogen, the regimen should be
For low risk patients, oral Amoxicillin- Clavulinate with Ofloxacin
OR Ceftriaxone with Amikacin combiation is preffered.
Indications for need of Vancomycin in initial regimen
if patient has
Hypotension or evidence of septic shock.
Obvious catheter related infection
H/O colonisation with MRSA
High risk for viridans Streptococci (severe mucositis/ AML / prior
use of Quinolone prophylaxis)
If indwelling line in situ or no response in 48 hours →
antistaphylococcal antibiotic should be added.
Radiographically confirmed pneumonia
In hemodynamically unstable patient, an adequate coverage for drug
resistant gram negative & gram positive organisms as well as for
anaerobes should be given.
Hence, second line drugs should be administered upfront.
Combination of anti-pseudomonal carbapenem, as well as addition
of an aminoglycoside, together with vancomycin provides this cover.
Emperical or presumptive anti-malarial therapy is not
• Consideration in antibiotics selection in case of organ dysfunction-
(renal and liver) Cisplatin, amphotericin B, cyclosporine,
vancomycin, and aminoglycosides should be avoided in
If fever persists for 4-5 days→ antifungal ( e.g. Amphotericin B )
should be added.
Discontinuation should always be kept in mind to minimise
development of bacterial resistance.
Antibiotic stopping guide
Minimum 1 week of therapy if
. Afebrile by day 3
. Neutrophils >500/mm3 (2 consecutive days)
. Cultures negative
. Low risk patient, uncomplicated course
> 1 week of therapy based if
. Temps slow to settle (>3 days)
. Continue for 4-5 days after neutrophil recovery (>500/mm3 )
Minimum 2 weeks
. Bacteraemia, deep tissue infection
. After 2 weeks if remains neutropenic (< 500/mm3)
BUT afebrile, no disease focus, mucus membranes, skin intact, no
catheter site infection, no invasive procedures or ablative therapy
planned…. Cease antibiotics and observe.
Duration Of Neutropenia and response rates
< 7 days of neutropenia ~ response rates to initial
antimicrobial therapy was 95%, compared to only 32% in
patients with more than 14 days of neutropenia
Patients with intermediate durations of neutropenia
between 7 and 14 days had response rates of 79%
(When temperatures do not go away)
Evaluate for source of persistent fever
Resistant pathogen or slow response to therapy
Emergence of second infection (overgrowth, superinfection,
Inadequate serum or tissue level of antibiotic(s)
Abscess, obstruction, foreign body infection
Role of Empirical or Pre-emptive Antifungal therapy
Candida species are the most common fungal pathogens during
neutropenia, typically occurring during neutropenic episodes
lasting > 1 week, and Aspergillus species are less common,
usually occurring with prolonged neutropenia lasting > 2–3
Past studies have shown that use of empiric antifungal therapy in
neutropenic patients with persistent fever reduced mortality
compared with patients who did not receive empiric antifungal
Until recently, Amphotericin B was the drug of choice for febrile
neutropenia not responding to broad-spectrum antibiotics .
A small study comparing Itraconazole and AmphotericinB
demonstrated higher rates of clinical success (composite of
defervescence, absence of breakthrough fungal infections, and
absence of adverse drug events) with itraconazole.
Voriconazole , a second-generation triazole with an extended
spectrum that includes molds.
No indication for empirical use of antiviral agents
Treat HSV or VZV lesions
Consider acyclovir (famiciclovir or valacyclovir) for
suppression of HSV.
Consider with profound neutropenia, dysfunctional
neutrophils and failure to control bacterial infection despite
optimal antibiotics and G-CSF, and for severe uncontrollable
1 unit contains 1 1010 granulocytes
Rate : 10 to 15 mL/kg . May be repeated after 12 to 24 hrs
Hematopoietic growth factor:
G-CSF (Filgrastim) @ 2-5mcg/kg/day in addition to antibiotics is
useful in children with complicated febrile neutropenia (
Pneumonia, hypotension, invasive fungal infection or multi organ
It results in – more rapid neutrophil recovery.
- relatively fewer days of antibiotic use.
- shortens length of hospial stay.
- reduces mortality and morbidity.
But G-CSF has no role in the management of children
with uncomplicated neutropenia.
MYELOID RECONSTITUTION SYNDROME
Clinicians should be aware of the myeloid reconstitution
syndrome, in which there may be onset or progression of an
inflammatory focus defined clinically or radiologically that
manifests at the time of neutrophil recovery.
Because such processes appear in the context of a persistent
neutropenic fever syndrome, the likelihood of superinfection
must be considered with respect to the antimicrobial spectrum
of the patient’s current empiric antibacterial therapy.
Approach to catheter infections in immunocompromised
Pro active steps must be taken to reduce incidence of hospital
Barrier nursing practice – frequent hand washing, the use alcohol
based hand rub in between patients and wearing gloves must be
Use of IV fluids, central lines, foley’s catheter et. Must be
restricted, if possible.
Care-takers are advised not to administer paracetamol at home
as it may mask fever and can delay in seeking medical care.
Adminstration of IV fluids for minor reasons should be avoided.
Nasogatric feeding should be encouraged in patients with
anorexia or mucositis.
Rectal enema, suppositories and rectal examinations are
contraindicated in neutropenic patients.
High risk patients are to be hospitalised and administered broad
spectrum intravenous antibiotics.
Empirical treatment should begin as soon as possible, even before
the results of culture are available.
Knowledge of locally prevailing bacteriological profile &
antimicrobial susceptibility data is crucial for choice of antibiotics
Non-invasive intermittent positive pressure ventilation should be
attempted in case of acute respiratory failure.
Hemoglobin < 8g/dl is generally an indication for blood
transfusion in a stable patient.
Indication for platelet transfusion: in a stable patient without any
comorbidities and bleeds, prophylactic transfusions are
recommended at a count below 10000. Transfusion threshold of
20000 recommended in patients with minor
bleeds(mucosal,epistaxis) and 1,00,000 in major
bleeds(hemoptysis, GI, or CNS bleeds)
P. jiroveci can cause pneumonia regardless of neutrophil count.
Prophylaxis with Trimethoprim- Sulphamethoxazole against PCP is
an effective preventive strategy and should be provided to all children
undergoing active treatment for malignancy.
Clinicians recommend giving splenoctomised patients a small supply
of antibiotics effective against
S. pneumoniae, N. meningitidis and H. inflenzae to avert rapid,
overwhelming sepsis in the event that they can not present for
medical attention immediately after the onset of fever or other
symptoms of bacterial infection. A few Amoxicillin/Clavulanic acid
tablets are a reasonable choice for this purpose.
Vaccination of cancer patients receiving