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FEBRILE NEUTROPENIA

Saima Abbas M.D Infectious Diseases Fellow-PGY5. FEBRILE NEUTROPENIA. Why is this an Oncologic emergency ??. Infection + ABX + Immune system = cure. Normal Gross Anatomy Skin Integrity Intact mucous membranes Intact ciliary function Absence of Foreign Bodies. Innate Immunity

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FEBRILE NEUTROPENIA

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  1. Saima Abbas M.D Infectious Diseases Fellow-PGY5 FEBRILE NEUTROPENIA

  2. Why is this an Oncologic emergency ??

  3. Infection + ABX + Immune system = cure • Normal Gross Anatomy • Skin Integrity • Intact mucous membranes • Intact ciliary function • Absence of Foreign Bodies • Innate Immunity ( PMN, Macrophages, NK cells, Mast cells and basophils) • Complement • Adaptive immunity T cells CD 4 and CD 8 B cells

  4. Case 1July 10th 2009 - NF 1 You are paged at 5:00am by the nurse taking care of Mr. Thomas on 4 AB He spiked a fever of 38 C (100.4F) one hour ago. -There is no order for Tylenol.

  5. ~ You check your Hem Oncology List . Per sign out: The patient was recently diagnosed with AML is S/P chemotherapy and is stable. • You can • Order Tylenol and take the next page. • OR…..

  6. OR Am I missing febrile Neutropenia??? • If you are alert, you think…

  7. What are the facts you need to know? • Does 38  C define febrile neutropenia? • What’s his Absolute Neutrophil Count? • Any transfusion in the last 6 hours?

  8. Definition of Fever in FN • A single oral temp  38.3  C (101  F) or • A temperature of  38  C (100.4F) on two occasions separated by 1 hour

  9. You request her to repeat the temperature and she reports 38. 2 C (100.8 F)

  10. Don’t be tricked • If temperature 37  38 C , repeat temperature in 1 hour to see if the above criteria for treatment are met • Clinical signs of septicemia • Good history of fever detected by patient before admission and afebrile when you evaluate the patient.

  11. Definition of Neutropenia • ANC  500/mm3 or • 1000/mm3 and predicted decline to  500/mm ~ Clin Inf Dis, 2002;34:730-51

  12. ANC : Mr. Thomas • WBC 0.7 • Segs = 38% • Bands = 2%

  13. Absolute Neutrophil Count (Total # of WBC) x (% of Neutrophils) = ANC • Take the percent of neutrophils (may also be polys or segs) + percent bands • Convert percent to a decimal by dividing by 100 (Example 40% = 40/100 = 0.40) (*move the decimal 2 points to the left) • Multiply this number by the total White Blood Cells (WBC)

  14. Calculation 0.7 X 1000 = 70040% =40/100=0.40 700 X 0.40 = 280

  15. Neutropenia • Normal ANC 1500 to 8000 cells/mm³ • Neutropenia: ANC < 1500 cells / mm3 • Mild Neutropenia: 1000-1500 cells / mm3 • Moderate Neutropenia: 500-999 cells / mm3 • Severe Neutropenia: < 500 cells / mm3 • Profound Neutropenia: <100 cells/ mm³

  16. When Does Neutropenia Occur? • Most chemotherapy agents/protocols cause neutropenia nadir at 10-14 days • But can see anytime from a few days after chemotherapy to up to 4-6 weeks later depending on the agents used

  17. Risk of Infection as Absolute Neutrophil Count Declines

  18. Epidemiology • Up to 60% febrile neutropenia episodes = infection (microbiological or clinical) • ~20% patients with ANC <100 cells/mm³ with febrile neutropenia episodes have bacteremias.

  19. Epidemiology --NEJM, 1971;284:1061 Retrospective data have shown that • ~ 50 % of Pseudomonas Aeruginosa Bacteremia result in death within 72 hours when ANC is < 1000 • Early trials aimed at Pseudomonas showed thatCarbapenicillin /Gentamicin decreased Mortality by 33 % ~Journal of Infectious diseases, 1978;147:14

  20. Epidemiology Viscoli et al, Clin Inf Dis;40:S240-5 • Changing etiology of bacteremia IATG-EORTC 1973-2000 trials of febrile neutropenia • Gram positive dominant since mid 1980s • 1) More intensive chemoTx • Mucositis • 2) In-dwelling catheters • Cutaneous-IV portal • 3) Selective antiBx pressure • Fluoroquinolones • Co-trimoxazole • 4) Antacids • Promote oro-oesophageal colonisation with GPC Gram negative resurgence

  21. Duration of Neutropenia • < 7 days LOW risk • 7 to 14 days INTERMEDIATE RISK • > 14 days HIGH RISK

  22. Duration Of Neutropenia 1988,Rubin and colleagues • < 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 ( <.001) ~ patients with intermediate durations of neutropenia between 7 and 14 days had response rates of 79%

  23. Common Microbes Gram-positive cocci and bacilli • Staph. aureus • Staphylococcus epidermidis • Enterococcus faecalis/faecium • Corynebacterium species Gram-negative • bacilli and cocci • Escherichia coli • Klebsiella species • Pseudomonas aeruginosa FUNGI • Candida- Non albicans emerging • Aspergillus >> in HSCT

  24. Initial evaluation Ensure Hemodynamic Stability and No NEW ORGAN DYSFUNCTION • History • Underlying disease, remission and transplant status- spleen +/- • Chemotherapy • Drug history (steroids, any previous antibiotics) • Allergies • Focused Review of systems • Transfusions • Can cause fevers • Lines or in-dwelling hardware

  25. THINK Strep. Pneumoniae Neisseriameningitidis HemophilusInfluenzae • Splenectomy

  26. Exam (be prepared to find no signs of inflammation) • HEENT Look in the mouth any oral sores – periodontium, the pharynx • Lungs • Abdomen for tenderness- RLQ (signs of Typhilitis) • Perineum including the anus -No rectal exam !

  27. Skin Exam- Ask the patient for any area of tenderness? Skin – • Bone marrow aspirations sites, • vascular catheter access sites • and tissue around the nails • Rashes (Drug eruptions/herpes zoster reactivation / Petechial rashes all are common in these patients)

  28. Febrile neutropeniaInvestigation • Complete Blood Count (with Differential) -White cells, haemoglobin, platelets • Biochemistry -Electrolytes, urea, creatinine, Liver function • Microbiology -Blood cultures (peripheral and all central line lumens) -Oral ulcers or sores –send swabs ( Viral Cx and fungal Cx ) -Exit site swabs -Wound swabs -Urine Cultures (SSx/Foley Catheter) [- pyuria ?? UA] -Stool Cultures and CDiff Toxin/PCR • Radiology -Chest Xray +/- CT abdomen/pelvis

  29. Lumbar puncture- • 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.

  30. Skin lesions • Aspiration or biopsy of skin lesions suspected of being infected should be • performed for cytologic testing, Gram staining, and culture

  31. IMAGING in FN • CXR if Symptomatic or if out pt Rx considered • High resolution CT Chest Indicated ONLY if persistent fevers with pulmonary symptoms after initiation of empiric Abx • CTA if suspect PE • CT abdomen for Necrotizing Enterocolitis or Typhilitis • CT brain R/o ICH / MRI of the spine or brain - more for evaluation of metastatic disease than FN

  32. Stratify risk of complications 1. Neutropenia •  with severity of neutropenia (< 50/mm3) •  with duration of neutropenia (>7 days) 2.Bacteremia • Gram negative > gram positive 3.Underlying malignancy and status • Acute Leukemia • Relapsed disease • Solid malignancies: Local effects eg obstruction, invasion 4.Co-morbidities, age >60

  33. HIGH risk Patients • • Prolonged Neutropenia (>14 days) • Haematological malignancy/ Allogenic HSCT • • Myelosuppresive chemotherapy • • Concurrent chemotherapy and radiotherapy • • Age >60 • • Co-morbidities eg. Diabetes, poor nutritional status. • • Bone marrow involvement of cancer • • Delayed surgical healing or open wounds • • Significant mucositis • • Unstable (eg hypotensive, oliguric) • • On steroid dose >20mg prednisone daily • • Recent hospitalization for infection

  34. a Concomitant condition of significance (e.g.,shock, hypoxia, pneumonia, or other deep organ infection, vomiting, or diarrhea).

  35. Risk model • Model 2 • (Klatersky et al MASCC 2000 J Clin Onc) • No or Mild symptoms 5 • Moderate symptoms 3 • No Hypotension 5 • No COPD 4 • Solid tumour / 4 • Haem malignancy • (no fungal infection) • Outpatient 3 • No dehydration 3 • Age <60 yrs 2 • LOW RISK=score>20

  36. ORAL vs IV • For patients who are low risk for developing infection-related complications during the course of neutropenia, ~ Oral ciprofloxacin plus amoxicillin/clavulanate ~ Oral ciprofloxacin plus clindamycin for PCN allergy

  37. If inpatient and high risk • EMPIRIC ANTIMICROBIAL THERAPY after Blood Cultures.Must be initiated within 1 hour

  38. THREE approaches for IV EMPIRIC therapy • IV MONO THERAPY • IV DUAL THERAPY • COMBINATION THERAPY Mono or dual therapy + VANCOMYCIN

  39. Monotherapy IV • Extended spectrum Antipseudomonal Cephalosporins • Cefepime • Ceftazidime • Carbapenem • Imipenem –Cilastatin • Meropenem • Anti –Pseudomonal PCN • Piperacillin- Tazobactam • Ticarcillin- Clavulanic acid

  40. DUAL therapy 1. an aminoglycoside plus an antipseudomonal penicillin (with or without a beta-lactamase inhibitor) or an extended-spectrum antipseudomonal cephalosporin,

  41. Dual therapy (2) ciprofloxacin plus an antipseudomonal penicillin. • Indications • Unstable patient • H/O P. aeruginosa colonization or Invasive disease

  42. 5 Indications for Vancomycin 1. clinically suspected serious catheter-related infections 2. known colonization with penicillin- and cephalosporin-resistant pneumococci or MRSA, 3. positive results of blood culture for gram-positive • hypotension or other evidence of cardiovascular impairment 5. H/O ciprofloxacin or trimethoprim-sulfamethoxazole

  43. vancomycin resistant enterococcus • Linezolid • Daptomycin (avoid for pneumonia) • Quinopristin- Dalfopristin

  44. PCN allergy • NON – ANAPHYLACTIC If not allergic to cephalosporins ~ Cefepime • ANAPHYLACTIC and allergic to cephalosporins- ~Aztreonam +/- Aminoglycoside or a FQ +/- Vancomycin if indicated

  45. MAINTAIN BROAD SPECTRUM ACTIVITY FOR A MINIMUM OF 7 DAYS OR UNTIL ANC >500

  46. Antibiotic stopping guideIDSA, Clin Infect Disease, 2002 • 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, mucous membranes, skin intact, no catheter site infection, no invasive procedures or ablative therapy planned…cease antibiotics and observe

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