FEBRILE NEUTROPENIA

SHAMEEM FARHATH

INTRODUCTION• Most common emergency encountered in children on

treatment for a malignancy• Significant cause of morbidity & mortality• Occurs in children diagnosed to have a/c

leukemia,lymphoma,solid tumor or aplastic anemia• It may result from underlying malignancy per se or

typically due to effect of chemotherapy• Fever may be the sole manifestation

• Definition: a single oral temp of ≥38.3˚C(101˚F) or a temp of ≥ 38.0˚C(100.4˚F) for ≥ 1 hour, with an absolute neutrophil count(ANC=mature granulocytes+neutrophil band or stab cells) of <500/mm3, or an ANC is expected to decrease to <500cells/mm3 during the next 48 hrs.

• Profound neutropenia- ANC < 100cells/mm3• Prolonged neutropenia- neutropenia lasting >7days

EVALUATION• History: should include following points:• Fever onset,duration & severity• Asso. localizing symptoms: ear, nose, throat, respiratory,

gastrointestinal, musculoskeletal and urinary system• Phase of chemotherapy(intensive or non intensive)• Duration since last chemotherapy• Recent hospitalizations & antibiotic received, if any.

POTENTIAL CAUSES OF INFECTION IN PATIENTS WITH FEBRILE NEUTROPENIA

• EYES- conjunctivitis,orbital cellulitis• ENT- otitis media, sinusitis, tonsillitis, pharyngitis, oral candidiasis• TEETH- dental caries/abscess• CHEST- pneumonia• ABDOMEN- diarrhea,dysentery, neutropenic enterocolitis,

pseudomembranous colitis• PERINEUM- perianal candidiasis, perianal abscess• SKIN- cellulitis,abscess,nodular or target lesions s/o fungal

infections, varicella rash, purpura fulminans• CNS- meningitis, meningoencephalitis, cavernous sinus

thrombosis• URINARY TRACT- uti• INTRAVASCULAR CATHETERS- exit site infection, tunnel

infection

• Majority of infections in febrile neutropenia are caused by gram negative organisms,eg: pseudomonas aeruginosa, E.Coli, klebsiella pneumonia, acinetobacter species

• Common gram positive organisms are staphylococcus aureus, coagulase negative staphylococcus & enterococcus

• Common Fungal infections are candida, aspergillus, or mucor

INVESTIGATIONS• First line investigations: • Complete blood count, including differential leukocyte

count & ANC• Serum electrolytes, urea & creatinine• Blood culture: before administration of antibiotics. Two

sets of blood cultures from separate venepuncture sites• Chest radiograph: in patients with respiratory symptoms &

signs• Cultures from any other site, as clinically relevant: stool,

urine, csf, skin, respiratory secretions ,pus.

• Second line investigations: • Serum Galactomannan test, CT Scan of chest/ paranasal

sinuses may be indicated in patients with suspected fungal infection

• Bronchoalveolar lavage: if pneumonia is non-resolving or non responding

• Skin biopsy ,from skin nodules, if any.

RISK STRATIFICATION• Low risk patients: • Clinically stable & well looking• Temperature <39˚ C• Non-intensive phase of chemotherapy• Malignancy in remission• Lack of any focus of infection, eg: pneumonia,abscess,

sinusitis or diarrhoea• Lack of medical comorbidities• ANC ≥ 100/mm3 & likely to rise within the next 7 days• Absolute monocyte count > 100/mm3• Not fulfilling any criteria for high risk category

• High risk patients: • Recent intensive chemotherapy• Profound neutropenia( ANC < 100cells/mm3) , anticipated

to extend for > 7days• Any focus of infection,eg: cellulitis, abscess, pnemonia,

diarrhoea• Evidence of hypotension, respiratory distress or

hypoxemia• Mucositis interfering with oral intake or resulting in

diarrhoea

MANAGEMENT(PGIMER MANAGEMENT PROTOCOL ON ONCOLOGIC EMERGENCIES)

MANAGEMENT• High risk patients are to be hospitalized & administered

broad spectrum i.v. antibiotics• Knowledge of locally prevailing bacteriological profile &

antimicrobial susceptibility data is crucial for choice of antibiotics

• Antibiotics: • It is important to administer first dose of antibiotics without

any delay. Delay in initiating antibiotics significantly increases the morbidity & mortality

• Caretakers are advised not to administer paracetamol at home as it may mask fever & lead to delay seeking medical care

• Anti-pseudomonal β-lactam agents:• Monotherapy with anti-pseudomonal β-lactam agents

such as anti-pseudomonas penicillin(piperacillin-tazobactum), anti-pseudomonal cephalosporin(cefoperazone-sulbactum) or carbapenems(meropenem or imipinem-cilastatin) or cefipime 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.

• 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.

• Specific gram positive cover is added only if patient has evidence of any of the following:

-Hemodynamic instability

-Severe sepsis

-Radiographically confirmed pneumonia

-Clinically suspected catheter related infection

-Skin or soft tissue infection

-Known colonisation with MRSA, Vancomycin

resistant enterococcus(VRE), Penicillin resistant

streptococcus

-Severe mucositis, if fluroquinolone prophylaxis has

been given & ceftazidime is employed as emperical

therapy• Emperical or presumptive anti-malarial therapy is not

recommended.

GENERAL CONSIDERATIONS & SUPPORTIVE CARE• Pro-active steps must be taken to reduce incidence of

hospital acqired sepsis• Use of alcohol based handrub in between patients must

be ensured by each medical & nursing personnel• Use of iv fluids, central line, foleys catheter,etc must be

restricted if possible• Administration of iv fluids for minor reasons should be

avoided• Nasogastric feeding is encouraged in patients with

anorexia or mucositis• Rectal enemas,suppositories & rectal examinations are

contraindicated in neutropenic patients

• Non-invasive intermittent positive pressure ventilation should be attempted in case of a/c 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)

• Growth factors: administration of G-CSF has no role in management of children with uncomplicated febrile neutropenia. Might be useful in reducing duration of neutropenia & length of hospital stay in children with complicated febrile neutropenia(pneumonia, hypotension, invasive fungal infection, multiorgan dysfunction)

SUBSEQUENT MANAGEMENT• Patient who is without a focus of infection, afebrile within 2-

3days of first line antibiotics, along with a rising ANC, with negative cultures, may be discharged after 24-48hrs or may be shifted to oral antibiotics, till ANC exceeds 500/cumm

• In case of documented infections, including soft tissue infection, pneumonia or bacterimia, appropriate antibiotics should be given for 10-14days

• Persistent fever beyond 3days, despite antibiotic therapy should prompt a thorough search for source of infection:

-relevant investigations include repeat blood/urine

cultures,stool for clostridium difficle,fungus & atypical

organisms in case of diarrhea & CT Scan of chest/sinuses

-antibacterials should be upgraded in high risk patients

with persistent fever after 48-72hrs, or earlier in case of

any hemodynamic instability

-empirical antifungal therapy(Amphotericin) and

investigations for invasive fungal infections should be

considered for patients with persistent or recurrent

fever after 4-7days of antibiotics and whose overall

duration of neutropenia is expected to exceed 7days

THANK YOU