UPDATE ON FEBRILE NEUTROPENIA

Clinical approach and management

Dr.Shafiq A. Alimad

Head of medical department at university of science and technology hospital

YICID 15-December-2014

INTRODUCTION

Cancer patients receiving cytotoxic antineoplastic therapy sufficient to adversely affect myelopoiesis and the developmental integrity of the gastrointestinal mucosa are at risk for invasive infection due to colonizing bacteria or fungi that translocate across intestinal mucosal surfaces.

Since the magnitude of the neutrophil-mediated component of the inflammatory response may be muted in neutropenic patients an elevated body temperature may be the earliest and only sign of infection.

It is critical to recognize neutropenic fever and associated sepsis syndromes early and to initiate empiric systemic antibacterial therapy promptly in order to avoid progression to a sepsis syndrome and possibly death.

Prior to the era of empiric antibiotic therapy, infections accounted for most episodes of neutropenic fever and approximately 70 percent of the mortality in neutropenic acute leukemia patients .

Because of the routine use of prompt empiric antibiotics, infections are documented less frequently today.

Although the majority of patients with neutropenic fever do not have a documented infection, consensus guidelines recommend that all patients with neutropenic fever be promptly evaluated and treated with empiric broad-spectrum antibiotics .

This approach is indicated since it is difficult to distinguish life-threatening infections from less serious infections in this patient population, and infection may progress rapidly in such patients. Furthermore, better outcomes are seen with prompt therapy

DEFINITIONS

FEVER

– Single oral T ≥ 38.3o C ( 101o F ) OR

– T ≥ 38o C ( 100.4o F ) sustained over 1 h

NEUTROPENIA

– ANC < 500 cells/mm3 OR

– ANC expected to decrease to < 500 cells/mm3 during the next 48 hrs

PROFOUND NEUTROPENIA

– ANC < 100 cells/mm3

EPIDEMOLOGY

occurs in: Fever

10 % – 15 % of patients with solid tumors

80 % of hematologic malignancies during ≥ 1 chemotherapy cycle

Most patients have NO infectious etiology

% of cases30 –% 20 occur in Clinically documented infections

Site: GI, Lung, Skin

BACTEREMIA

profound neutropenia especially% , 25 -% 10 Occur in

57 % gram +ve

34 % gram –ve

9 % polymicrobial

Mortality: 18 % gram –ve 5 % gram +ve

1960 – 1970 : gram –ve > gram positive

1980 – 1990 : gram positive > gram –ve

Coagulase-Negative Staphylococci are the most common blood isolates due to increase use of indwelling venous catheters

Resistant Organisms:

ESBL

KPC

MRSA, VRE ≈ 20 % - 50 %

Penicillin resistant strept viridans

Candida:

usually > 1st week of prolonged neutropenia

Molds:

Sinuses

Lungs

Typically ≥ 2 weeks of neutropenia

RISK ASSESSMENT

High-risk and Low-risk Patients with Fever and Neutropenia

Type Of Empirical Antibiotic Therapy ( PO vs IV )

Venue Of Treatment ( Inpatient vs Outpatient )

Duration Of Antibiotic Therapy

PATIENTS WITH NEUTROPENIC FEVER WHO ARE AT HIGH RISK FOR SERIOUS COMPLICATIONS

Patients with any of the following characteristics are considered to be at high risk for serious complications during episodes

of neutropenic fever:

Neutropenia (absolute neutrophil count <500 cells/microL) anticipated to last >7 days*

•Presence of any comorbid medical problems, including, but not limited to:

•Hemodynamic instability

•Oral or gastrointestinal mucositis that interferes with swallowing or causes severe diarrhea

•Gastrointestinal symptoms, including abdominal pain, nausea and vomiting, or diarrhea

•Neurologic or mental status changes of new onset

•Intravascular catheter infection, especially catheter tunnel infection

•New pulmonary infiltrate or hypoxemia

•Underlying chronic lung disease

•Complex infection at the time of presentation

Alemtuzumab use within the past two months

Inpatient status at the time of development of fever

Uncontrolled or progressive cancer•

Evidence of hepatic insufficiency (defined as aminotransferase levels >5 times normal values) or renal insufficiency (defined as a

creatinine clearance of <30 mL/min)

Multinational Association for Supportive Care in Cancer (MASCC) risk index score <21Δ

HIGH RISK PATIENTS

Should be hospitalized for IV antibiotics

Usually :

Acute Leukemia

Hematopoietic Stem Cell Transplantation ( HSCT )

LOW RISK PATIENTS

Anticipated ≤ 7 days duration

No or few comorbidities

Candidates for oral empirical therapy

DETAILED HISTORY

New symptoms

Antimicrobial prophylaxis

Infection exposure

Prior documented infections

Prior pathogen colonization

Non-infectious cause of fever, e.g. blood product

Co-morbid diseases

Recent surgical procedures

PHYSICAL EXAMINATION

Site of previous procedures or catheters

Catheter entry and exit site

BM aspiration site

Oropharynx: periodontium

GI, Lungs, Perineum

ECTHYMA GANGRENOSUM

NECROTIC SKIN LESION OF MUCORMYCOSIS

FUSARIUM SKIN LESIONS ON LOWER EXTREMITIES

DIAGNOSTIC EVALUATION OF PATIENTS WITH FEVER AND NEUTROPENIA

Item Purpose Comments

Targeted history Seek sites suspicious for infection Allows detection of symptoms of

infection

Physical exam with emphasis on skin,

oral cavity, oropharynx, lungs, abdomen,

perianal area*

Detection of sites suspicious for infection;

guides selection of cultures and imaging

Pain and/or erythema may point to

infection; pus is not found due to lack of

neutrophils; chest exam may be

unremarkable even with pneumonia;

abdominal tenderness may suggest

Neutropenic enterocolitis; perianal or

hemorrhoidal tenderness may point to

gram-negative or anaerobic infection

Complete blood count with differential Defines the depth of neutropenia

The lower the initial neutrophil count, the

greater the likelihood of serious infection

or bacteremia; daily counts allow

prognostication

NEUTROPENIC ENTEROCOLITIS (TYPHLITIS)

Creatinine, liver function tests,

electrolytes Defines comorbid conditions

Allows optimal selection and dose of

antimicrobial agent(s) and serial

monitoring of toxicities

Blood cultures (2 sets, one peripheral and

one from central venous catheter);

antimicrobial susceptibility testing

Detection of bacteremia

Fever may be the only sign of bacteremia;

allows adjustment of antibiotic regimen if

necessary

Cultures and stains of samples from

suspected sites of infection Detection of infectious etiology Bacterial and fungal stains can be helpful

Imaging studies (generally recommended

only if site is suspected from history or

exam)

Detection of infectious site

Computed tomography (CT) scans are

generally more useful than plain

radiographs; pulmonary infiltrates may be

inapparent by plain radiography during

deep neutropenia and may become

manifest only upon neutrophil recovery;

thickened bowel walls are seen by CT

scan with neutropenic enterocolitis

Digital rectal examination is avoided in neutropenic patients

TESTS AND CULTURES

CBC count with differential

Creatinine, urea, electrolytes, hepatic transaminase enzymes and total bilirubin

At least 2 sets of blood cultures:

Each set from each lumen of central venous catheter ( CVC ) if present and from peripheral vein simultaneously

If No CVC : 2 blood culture sets from separate veins

RE-culture: next 48 hrs or refever

20 ml of blood: aerobic and anaerobic blood culture bottle

Blood culture volume should be less than 1% of total blood volume (70 ml/kg)

Cultures from other sites of suspected infection should be obtained as clinically indicated

Chest X-ray is indicated for patients with respiratory signs and symptoms

Stool : if diarrhea → C. diff. toxin assay

Urine culture is indicated if:

Signs or symptoms

Urinary catheter

Abnormal urine analysis

: CSF culture

if meningitis is suspected

aspiration or biopsy for cytology and culture :Skin lesion

Respiratory:

Sputum culture if productive cough

BAL → if abnormal CXR

Nasal wash or BAL for viral detection: adenovirus, influenza A , B , RSV and parainfluenza

:Radiography

CXR if symptoms

CT if clinically indicated

Type of infection Stain Culture Other

Bacteria Gram stain Aerobic and anaerobic culture

Fungi KOH smear• Fungal culture• Aspergillus galactomannan

antigen

Mycobacteria AFB Mycobacterial culture

Pneumocystis

jirovecii (formerly P. carinii)

Fluorescein-conjugated

monoclonal antibodyΔ N/A PCR

Nocardia spp Modified AFB Fungal culture

Legionella spp N/A Legionella culture using BCY

E medium◊

Mycoplasma pneumoniae N/A N/A PCR

Viruses

Cytomegalovirus N/A Shell vial culture, conventional

culture§ PCR, cytology§

Influenza virus N/A Viral culture

Reverse transcriptase PCR,

direct or indirect fluorescent

antibody, rapid antigen test‡

Parainfluenza virus N/A Viral culture Direct or indirect fluorescent

antibody, PCR

Respiratory syncytial virus N/A Viral culture PCR, rapid antigen test‡

Adenovirus N/A Viral culture PCR

Herpes simplex virus N/A Viral culture† Direct fluorescent antibody†

Varicella-zoster virus N/A Viral culture Direct fluorescent antibody

SERUM FUNGAL MARKERS

Checking fungal markers from the serum, such as

the Aspergillus galactomannan antigen and the beta-D-glucan assay,

should also be considered in high-risk patients. Some centers perform serial monitoring of these twice weekly in hematopoietic cell transplant recipients and acute leukemia patients .

The Aspergillus galactomannan antigen is a specific test for invasive aspergillosis, whereas the beta-D-glucan assay is a nonspecific test for several invasive fungal infections, including aspergillosis and candidiasis

EMPIRIC THERAPY Fever in a neutropenic patient should be considered a medical emergency.

Assessment by a physician should occur soon (eg, within 15 minutes) after triage for patients presenting with neutropenic fever within six weeks of having received chemotherapy for malignancy.

Broad-spectrum antibacterials should be given as soon as possible (within 60 minutes of triage) and at full doses, adjusted for renal and/or hepatic function.

Antibiotics should be:

Bactericidal ,Anti-pseudomonal ,Minimal toxicity.

In addition, the diagnostic evaluation should be obtained quickly.

TIMING OF ANTIBIOTICS

In all febrile neutropenic patients, empiric broad-spectrum antibacterial therapy should be initiated immediately after blood cultures have been obtained and before any other investigations have been completed.

Antimicrobial therapy should be administered within 60 minutes of )1algorithm presentation (

WHAT EMPIRIC ANTIBIOTIC THERAPY AND IN WHAT VENUE

LOW RISK PATIENTS

Initial oral or IV antibiotic doses in clinic or hospital

May be transitioned to outpatient IV/PO treatment if they have specific clinical criteria

ORAL EMPIRICAL TREATMENT

Ciprofloxacin+Amoxicillin-Clavulanate

Others: less well studied and NO enough data

Levofloxacin or Ciprofloxacin as monotherapy

Ciprofloxacin+Clindamycin

ELIGIBILITY CRITERIA FOR OUT PATIENT MANAGEMENT

[ANC] <500 cells/microL) for ≤7 day.

No active comorbidities or evidence of significant hepatic or renal dysfunction.

Normal finding on CXR.

Hemodynamic stability.

Solid malignancy.

No documented bacterial, viral, or fungal infection.

No evidence of VAD related infection.

No abdominal pain, nausea, vomiting or diarrhea

ELIGIBILITY CRITERIA FOR OUT PATIENT MANAGEMENT

No neurological or mental-status changes.

Ability to swallow oral medications.

The patient was not on quinolone prophylaxis.

The patient can be reliably monitored and has ready

access to appropriate medical care.

The patient needs less than one hour car ride to reach

the center.

High risk patients should be hospitalized for IV empirical antibiotic therapy

Monotherapy with an anti-pseudomonal β-lactam agent:

Cefepime

Carbapenem: meropenem or imipenem-cilastatin

Piperacillin-tazobactam

Other antibiotics: aminoglycoside, fluoroquinolones, vancomycin:

May be added to initial regimen For

1. Treatment of Complications

( hypotension, pneumonia ) or

1. If antimicrobial resistance is suspected or

proven

β-lactam monotherapy:

Ceftazidime is NO longer used

Aminoglycoside monotherapy should NOT be used

Vancomycin is NOT recommended as a standard part of initial regimen for febrile neutropenia

Modifications to initial empirical therapy may be considered for patients at risk for infection with the following antibiotic-resistant organisms:

1.Risk factors include previous infection or colonization or hospital with high rate of endemicity

2.MRSA: Vancomycin, Linezolid, or Daptomycin

3.VRE: Linezolid, or Daptomycin

4.ESBL: Carbapenem

5.KPCs: Polymyxin-colistin or Tigecycline

PENICILLIN-ALLERGIC PATIENTS:

SEVER FORM

Ciprofloxacin+ Clindamycin

OR

Aztreonam+Vancomycin

ANTIBIOTIC MODIFICATIONS DURING THE COURSE OF FEBRILE NEUTROPENIA

Modifications to the initial antibiotic regimen should be guided by clinical and microbiologic data

Unexplained persistent fever in a patient who is stable rarely requires an empirical change to the initial antibiotic or adding vancomycin

If an infection is identified, antibiotics should be adjusted accordingly

Documented clinical and/or microbiological infections should be treated with antibiotics appropriate for the site and for the susceptibilities of any isolated organisms:

Pneumonia: health-care acquired infection ( β-lactam+amino OR antipseudomonal FQ ± anti-MRSA )

If vancomycin or other coverage for gram-positive organisms was started initially, it may be stopped after 2 days if there is NO evidence for a gram-positive infection

Patients who remain hemodynamically unstable after initial agents for neutropenic fever should have their antibiotics broadened to include coverage for resistant gram-negative, gram-positive, and anaerobic bacteria and fungi

For Low-risk patients if clinically stable:

Their treatment may be simplified

IV to Po switch if clinically stable and adequate GI absorption

If fever persists or recurs within 48 hrs in outpatient, readmit and treat as high risk patient

HOW LONG SHOULD EMPIRICAL ANTIBIOTIC THERAPY BE GIVEN

In patients with clinically or microbiologically documented infections, the duration of therapy is dictated by the particular organism and site and antibiotics should be continued for at least the duration of neutropenia (until ANC is ≥ 500 cells/mm3) or longer if clinically necessary

Blood stream infection, soft tissue infection and pneumonia: 10 – 14 days of antibiotics

In Patients with Unexplained Fever:

Continue the initial antibiotics until there are signs of marrow recovery (ANC exceeds 500 cells/mm3)

OR

If an appropriate treatment course has been completed and all signs and symptoms of a documented infection have resolved, patients who remain neutropenic may resume oral fluoroquinolone prophylaxis until marrow recovery

EMPIRICAL OR PRE-EMPTIVE ANTIFUNGAL THERAPY

Empirical antifungal coverage should be considered in high-risk patients who have persistent fever after 4–7 days of a broad-spectrum antibacterial regimen and no identified fever source

In low risk patients:

routine use of antifungal therapy is NOT recommended

Treatment:

1) Ampho B

2) Lipid soluble Ampho B

3) Voriconazole

4) Caspofungin

EMPIRICAL OR PRE-EMPTIVE ANTIFUNGAL THERAPY

The choice of antifungal agent for empiric therapy depends upon which fungi are most likely to be causing infection, as well as toxicity profiles and cost:

•For persistently febrile patients who have not been receiving antifungal prophylaxis and who have no obvious site of infection, such as pulmonary nodules, start caspofungin (or another echinocandin) since Candida spp is the most likely cause in such patients.

•For persistently febrile patients with pulmonary nodules or nodular pulmonary infiltrates, invasive mold infection should be strongly suspected. In such patients, start voriconazole or a lipid formulation of amphotericin B.

•For persistently febrile patients who have been receiving anti-mold prophylaxis, a different class of antifungal agent with activity against molds should be used for empiric therapy

EMPIRICAL OR PRE-EMPTIVE ANTIFUNGAL THERAPY

Dosing — The dosing of the various antifungal agents recommended above is as follows:

●Caspofungin – Loading dose of 70 mg IV on day one, then 50 mg IV once daily

●Voriconazole – Loading dose of 6 mg/kg IV every 12 hours on day one, followed by 4 mg/kg IV every 12 hours

●Amphotericin B lipid complex – 5 mg/kg IV once daily

●Liposomal amphotericin B – 3 to 5 mg/kg IV once daily

TREATMENT OF CATHETER-RELATED INFECTION IN NEUTROPENIC PATIENTS

CATHETER REMOVAL for CLABSI Caused By:

S. aureus

P. aeruginosa

Fungi

Mycobacteria

Tunnel Infection

Port Pocket Site Infection

Septic Thrombosis, Endocarditis

Sepsis with Hemodynamically Unstable

Blood Stream Infection Persists ≥ 72 hrs after therapy with appropriate antibiotics

TREATMENT OF CATHETER-RELATED INFECTION IN NEUTROPENIC PATIENTS

CLASBI caused by Coagulase-Negative Staphylococci (CONS):

the catheter may be retained using systemic therapy with OR without antibiotic lock therapy

Prolonged treatment (4–6 weeks) is recommended for complicated CLABSI:

Deep tissue infection

Endocarditis

Septic thrombosis

Persistent bacteremia or fungemia occurring > 72 h after catheter removal in a patient who took appropriate antimicrobials

TREATMENT OF CATHETER-RELATED INFECTION IN NEUTROPENIC PATIENTS

Hand hygiene

Maximal sterile barrier precautions

Cutaneous antisepsis with chlorhexidine during CVC insertion

are recommended for all CVC insertion

PREVENTION ENVIRONMENTAL PRECAUTION

Hand Hygiene is the most effective means of preventing transmission of infection in the hospital

Standard barrier precautions and infection-specific isolation should be used for patients with certain signs or symptoms

HSCT patients: in private single-patient room

Allogeneic HSCT: room with > 12 air exchanges/hr and high efficacy particulate air(HEPA) filtration

ENVIRONMENTAL PRECAUTION

Plants and dried or fresh flowers should not be in the rooms of neutropenic patients

Health-Care Workers (HCWs) to report their illnesses or exposures

ANTIBIOTIC PROPHYLAXIS

Fluoroquinolone prophylaxis: should be considered for high-risk patients with expected durations of prolonged and profound neutropenia (ANC ≤ 100 cells/mm3 for > 7 days)

Levofloxacin vs Ciprofloxacin: EQUIVALENT

Levofloxacin is preferred in situations with increased risk for oral mucositis-related invasive viridans group streptococcal infection

Monitoring for the development of fluoroquinolone resistance among gram-negative bacilli is recommended

ANTIBIOTIC PROPHYLAXIS

Addition of a gram-positive active agent to fluoroquinolone prophylaxis is generally NOT recommended

Antibacterial prophylaxis is NOT routinely recommended for low-risk patients who are anticipated to remain neutropenic for < 7 days

ANTIFUNGAL PROPHYLAXIS

Candida Prophylaxis

Allogenic HSCT

Intensive remission-induction or salvage induction chemotherapy for acute leukemia

Prophylaxis:

Fluconazole Itraconazole

Voriconazole Posaconazole

Micafungin Caspofungin

ANTIFUNGAL PROPHYLAXIS

Aspergillus Prophylaxis

Intensive chemotherapy for AML

MDS

FOR BMTX

1)Prior invasive aspergillosis

2)Anticipated prolonged neutropenia

3)Prolonged neutropenia prior to HSCT

Antimold antifungal is recommended At least 75 days after transplantation OR Stopping of immunosuppressive therapy

ANTIFUNGAL PROPHYLAXIS

LOW RISK PATIENTS

Antifungal is NOT recommended for prophylaxis in whom the anticipated duration of neutropenia is < 7 days

ANTIVIRAL PROPHYLAXIS

Acyclovir Prophylaxis

Herpes simplex virus (HSV)-seropositive patient for allogenic HSCT

Leukemia induction therapy

Till ↑ WBC or resolution of mucositis

Antiviral treatment for HSV or varicella-zoster (VZV) infection is ONLY indicated if there is clinical or laboratory evidence of active viral disease

ANTIVIRAL PROPHYLAXIS

If symptoms of upper respiratory tract (coryza, cough):

Should Do

CXR

Respiratory virus testing: influenza, parainfluenza, adeno, RSV, human metapneumovirus

Yearly Influenza Vaccination

Inactivated vaccine is recommended for all patients treated for cancer

Between cycles of chemotherapy: > 7 days after last treatment or > 2 wks before chemo or > 6 months after HSCT

ANTIVIRAL PROPHYLAXIS

Influenza Infection

Treatment with neuraminidase inhibitors if susceptible

Post-Exposure Treatment: antiviral REGARDLESS of vaccination

Routine treatment of RSV Infection in neutropenic patients with upper respiratory disease should NOT be given

Adenovirus Infection

Supportive

Ribavirin?? Cidofovir?

ROLE OF G-CSF OR GM-CSF

Primary prophylaxis :

Consider prophylactic use of G-CSF/GM-CSF for patients in whom:

%20≥anticipated risk of fever and neutropenia is the

20 and 10 fever is between neutropenicWhen the estimated risk of percent :

•Age 65 and older

•Poor performance status

•Prior episodes of neutropenic fever

•Large radiation portals

•Cytopenias due to marrow involvement

•Poor nutritional status

•Open wounds or active infection

•Advanced cancer or other serious comorbidities

ROLE OF G-CSF OR GM-CSF

Secondary prophylaxis:

●For patients who had an episode of neutropenic fever after an earlier cycle of palliative chemotherapy, they suggest dose reduction or delay as the primary therapeutic option rather than routine administration of CSFs (Grade 2C).

●However, in keeping with ASCO guidelines , when the risk of neutropenic fever would prevent the administration of full doses of potentially curative chemotherapy, they suggest the use of granulocyte CSFs for secondary prophylaxis rather than dose reduction (Grade 2C)

MYELOID RECONSTITUTION SYNDROME

Clinicians should be aware of the myeloid reconstitution syndrome, a circumstance 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 may 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 and the microbiologic differential diagnosis applicable to those circumstances

HOME MESSAGES febrile neutropenia is an emergency especially high risk

You should manage your patient based on risk assessment (individualization).

Neutropenic patient commonly to present atypically .

Treat empirically but follow guidelines and continue or change management according patient response.

Prevention better then cure

THANK YOU