Febrile Neutropenia presentation by Dr Omer Abdelgader internal medicine consultant.pptx

comprehensive presentation about febrile neutropenia

1. Febrile Neutropenia Presented by Dr. Omar Abdelgader

2. Introduction Febrile neutropenia is a potentially life-threatening medical emergency characterized by the rapid onset of fever in patients with neutropenia. Prompt medical attention and immediate intervention are crucial to prevent severe complications and improve outcomes. Neutrophils create host responses, especially to bacterial and fungal infections. The depth and duration of neutropenia determine the degree of immunocompromise. The course of febrile neutropenia can be fulminant, often with signs and symptoms of bacterial infection absent, leading to a mortality rate as high as 50% in patients presenting with severe sepsis or shock .

3. Definitions Fever : Defined as a single oral temperature of ≥38.3°C or a temperature of ≥38.0°C sustained over one hour. Neutropenia: absolute neutrophil count (ANC) ≤500 cells/mm 3  OR ANC predicted to decrease to ≤500 cells/mm 3  in 48h. Definitions

4. Common Causes Of Neutropenia Chemotherapy-Induced Bone Marrow Suppression (the most common cause) Hematologic Malignancies (e.g., leukemia, lymphoma, myelodysplastic syndromes) Solid Tumors (especially with bone marrow involvement or treated with myelosuppressive chemotherapy) Bone Marrow Disorders (e.g., aplastic anemia, myelofibrosis, congenital neutropenia)

5. Severe Infections Medications (e.g., certain antibiotics, antithyroid drugs, immunosuppressants) Radiation Therapy (especially to large areas of bone marrow) Bone Marrow Transplantation Autoimmune Disorders (e.g., systemic lupus erythematosus) Nutritional Deficiencies (e.g., vitamin B12, folate) Primary Immunodeficiencies (e.g., severe congenital neutropenia) Other Causes Of Neutropenia

6. Alarm Signs and Symptoms Chemotherapy-induced neutropenic fever in and of itself is a medical emergency that warrants prompt evaluation and initiation of empiric antibiotic therapy. Patients with hemodynamic instability and multiorgan failure have a high risk for death. Presence of multiple comorbidities increases likelihood of complications. Patients with relapsed or refractory disease are at higher risk for complications.

7. PATHOGENS A causative pathogen is identified in 20% to 30% of cases The majority of infections likely originate from endogenous flora within the gastrointestinal tract, lungs, or skin

8. PATHOGENS frequent pathogens seen in this population: Gram-positive pathogens Coagulase-negative  Staphylococci Staphylococcus aureus  (including MRSA) Viridans streptococci (especially in patients with mucositis) Enterococcus spp.  (including VRE) Streptococcus pneumoniae Streptococcus pyogenes Other Gram-positive bacilli:  Corynebacterium jeikeium ,  Bacillus spp .,  Propionibacterium  spp. Gram-negative bacilli consider antibiotic-resistant GNB, e.g., ESBLs, carbapenemase -producers (KPCs) Enterobacteriaceae: E.coli ,  Klebsiella  spp . ,  Enterobacter  spp . Pseudomonas spp. Citrobacter spp . Acinetobacter spp . Stenotrophomonas maltophilia M. tuberculosis  and non-tuberculous mycobacteria

9. PATHOGENS Fungal: Candida spp.  (including fluconazole-resistant strains) Aspergillus  spp . , Mucorales,  Fusarium spp, Scedosporium   spp. Anaerobes: less commonly implicated (e.g., periodontal or perirectal abscess,  intra-abdominal infection ) Viral: Influenza Other respiratory viruses such as  adenovirus ,  RSV ,  parainfluenza

10. Work-up

11. History A detailed history must be obtained and should include the following: Complete history of present illness Major comorbidities Type of and time since last chemotherapy Prior documented infections in the past 3 months Recent antibiotic therapy/prophylaxis Medications Presence of invasive devices Epidemiologically relevant exposures. ( eg , injection drug use, sick contacts, zoonotic exposures, and recent travel).

12. Examination A comprehensive physical examination; with particular attention to the following anatomical sites: Skin, including vascular access sites Oral cavity Oropharynx Lungs Abdomen Perianal region Avoid digital rectal examination of patients with neutropenia

13. Investigations Routine labs: obtain CBC w/differential, LFTs, electrolytes, UA w/micro and cx, blood cxs (2 sets: one catheter + one peripheral), sputum for Gram stain and cx, consider stool for  C. difficile  toxin assay, and  VZV  or HSV PCR, DFA or viral cx of vesicular lesions. Throat or nasopharyngeal swabs for respiratory virus panel, especially during respiratory season and outbreaks. Assess for focal infection: CXR, CT or other scans, bronchoscopy… as per signs/symptoms. Consider occult fungal infection : Serum or BAL galactomannan in patients at increased risk for invasive  aspergillosis  (e.g., hematological malignancies, HSCT). For suspected viral infection , use PCR.. or culture, if PCR unavailable.

14. Treatment The treatment of febrile neutropenia (FN) focuses on early detection of infection and rapid initiation of treatment. The first step is to decide whether the patient requires hospital admission or can be managed as an outpatient, based on clinical evaluation and risk assessment tools. Low-risk patients can be treated with oral antibiotics as outpatients, while intermediate- or high-risk patients need intravenous (IV) antibiotics in a hospital. Empiric antibiotics should be administered within one hour of FN identification, ideally after blood cultures are taken. The choice of antibiotics should consider local resistance patterns and the patient's history of multidrug-resistant infections. If a specific pathogen is identified, treatment should be tailored accordingly. The duration of antibiotic therapy depends on the patient's clinical progress and specific indications. Central venous catheters should be removed in certain clinical scenarios .

15. Risk Stratification High-Risk Features Profound neutropenia (ANC < 100 cells/µL) Duration of neutropenia > 7 days Hemodynamic instability Comorbidities (e.g., uncontrolled cancer, renal or hepatic insufficiency) Low-Risk Features Neutropenia expected to resolve within 7 days No comorbidities or stable clinical condition

16. Step 1: Risk Stratification Using MASCC Score Calculate the MASCC score ( Multinational Association for Supportive Care in Cancer score) to assess the risk of mortality and complications: mild or no symptoms: 5 points No hypotension (systolic BP > 90 mmHg): 5 points No chronic obstructive pulmonary disease: 4 points Solid tumor or no previous fungal infection: 4 points No dehydration requiring parenteral fluids: 3 points moderate symptoms: 3 points Outpatient status: 3 points Age < 60 years: 2 points Interpretation : Low risk : MASCC score ≥ 21 High risk : MASCC score < 21

17. Step 2: Initial Antibiotic Therapy Initiate antibiotics within 1 hour of diagnosis. The early use of empirical antimicrobial treatment as part of the management of fever and neutropenia decreases the risk of progression to sepsis, septic shock, acute respiratory distress syndrome, organ dysfunction, and death. Continue antibiotics for at least 3-5 days, adjusting based on culture data or clinical deterioration.

18. Step 3: Determine Empirical Therapy Low-risk patients (MASCC ≥ 21) Oral antibiotics : Ciprofloxacin 500-750 mg PO BID + Amoxicillin/Clavulanate 875 mg PO q12h Alternative (beta-lactam allergy) : Moxifloxacin 400 mg PO daily Levofloxacin 500-750 mg PO daily

19. High-risk patients (MASCC < 21) Empiric monotherapy (IV) : Cefepime 2 gm IV q8h Meropenem 1-2 gm IV q8h Imipenem/ Cilastatin 500 mg - 1 gm IV q6h Piperacillin/Tazobactam 4.5 gm IV q6h or extended infusion 3.375 gm IV q8h Combination therapy ( if MRSA, MDR organisms, or ESBL coverage needed ): Add Vancomycin 15 mg/kg IV q12h or Linezolid 600 mg q12h for Gram-positive coverage Add Amikacin, Gentamicin, or Tobramycin for additional Gram-negative coverage

20. Isolation Purpose: Isolation is essential to protect febrile neutropenic patients from infections due to their severely compromised immune system. Types of Isolation: Includes protective (reverse) isolation to shield the patient from external pathogens and contact isolation if multidrug-resistant organisms are involved. Practices: Patients should be placed in private rooms, ideally with HEPA filtration. Strict hand hygiene, limited visitors, and environmental controls (e.g., no fresh flowers or raw foods) are crucial. Duration: Isolation continues until the patient’s neutrophil count recovers to safer levels and they are afebrile. Psychosocial Support: Regular communication is needed to address feelings of loneliness or depression due to prolonged isolation. Staff Training: Healthcare providers must be trained in infection control to ensure compliance with isolation protocols.

21. Step 4: Specific Considerations Suspected catheter-related infection : Include coverage for Gram-positive organisms (e.g., Vancomycin ). Remove the central line if cultures positive for certain pathogens (e.g . S. aureus, VRE, Pseudomonas ). Pneumonia : Add Azithromycin or Fluoroquinolone (e.g., Levofloxacin ) for atypical coverage. Consider TMP/SMX for P. jirovecii . Diarrhea : Evaluate for C. difficile . Add Oral Vancomycin if confirmed or Metronidazole for intra-abdominal concerns. Sinusitis : Urgent ENT evaluation and possible antifungal treatment. Meningitis : Use an anti-pseudomonal β-lactam (e.g., Cefepime, Meropenem) plus Vancomycin and Ampicillin.

22. Step 5: Persistent Fever Management Reassess after 3-5 days of persistent fever : If stable, consider continuing current therapy. If worsening, adjust antibiotics or add antifungal therapy. Empiric antifungal therapy after 4-7 days if no cause identified: Liposomal Amphotericin B 3-5 mg/kg/day Voriconazole 6 mg/kg IV q12h x 2, then 3-4 mg/kg IV q12h Posaconazole 300 mg IV/PO daily Echinocandins (e.g., Caspofungin , Micafun ).

23. Step 6: Duration of Treatment If infection identified : Continue targeted therapy for standard infection duration. If afebrile for 3-5 days: If ANC > 500 , consider stopping antibiotics if no infection found. If ANC < 500 , continue antibiotics for at least 7 days or until ANC > 500.

24. Step 7: Special Considerations Routine antivirals not indicated unless specific lesions (e.g., herpes, VZV). (consider acyclovir IV, or if stable, famciclovir or valacyclovir ). G-CSF (Granulocyte Colony-Stimulating Factor: consider G-CSF for severe neutropenia not responding to antibiotics or prolonged marrow recovery delay. ASCO restrict use of CSFs to patients at high risk for infection-associated complications or who have prognostic factors that are predictive of a poor clinical outcome. High-risk factors include: Prolonged (>10 days) or profound (<100 cells/ microL ) neutropenia Age >65 years Clinically documented infections (e.g., pneumonia) Sepsis syndrome or invasive fungal infections Prior febrile neutropenia episodes Hospitalized at fever onset

25. Antimicrobials Commonly used in empiric treatment of febrile neutropenia Amoxicillin/clavulanate In combination with  ciprofloxacin , considered as part of PO combination treatment in low-risk pts. Liposomal amphotericin B FDA-approved for use in febrile neutropenia. Caspofungin Active against  Candida spp.  and  Aspergillus . Cefepime Approved for use as a single agent in febrile neutropenia; increased frequency of resistance of GNR in some centers, not active against anaerobes or  Enterococcus . Ceftazidime No longer a reliable agent for empiric monotherapy because of increased resistance among gram-negative rods and poor activity against many gram-positive pathogens, such as streptococci. Ciprofloxacin In combination with  amoxicillin/ clavulanate ,  considered a PO treatment in low-risk pts without hx of FQ prophylaxis. Fluconazole Useful in most  C. albicans  infections.  C. glabrata  and  C. krusei  may be resistant. I would avoid routine empiric treatment of fever in the setting of neutropenia since many patients are azole-experienced.

26. Gentamicin It may be a synergistic agent with a β-lactam to treat Gram-negative infections. Imipenem/ cilastatin Approved for use as a single agent in febrile neutropenia; drug of choice for ESBL organisms. Isavuconazole Novel triazole with broad-spectrum antifungal activity, including mucormycetes . Consider potential drug interactions. Linezolid A potential alternative to  vancomycin , it has bone marrow suppression potential. Meropenem Single agent in febrile neutropenia; active against ESBL organisms. Micafungin Alternative to caspofungin , not FDA-approved for neutropenic fever, small studies of pts with hematologic malignancy suggest efficacy. Posaconazole FDA-approved for preventing invasive fungal infections, including  Candida  and  Aspergillus  in HSCT with GVHD and hematological malignancy pts with prolonged neutropenia. Although a delayed-release tablet is better absorbed than a liquid formulation, recommended taking with food. Vancomycin Consider in patients with chronic indwelling catheters or pts known to be MRSA colonized. Voriconazole FDA-approved for invasive aspergillosis ,  Scedosporium apiospermum  and  Fusarium  spp. Antimicrobials Commonly used in empiric treatment of febrile neutropenia

27. Pitfalls in febrile neutropenia Fever as the Only Sign : Fever is often the only indicator of infection in febrile neutropenia due to the patient's inability to mount a full inflammatory response, particularly when neutrophil counts are very low. Some may not even present with fever due to factors like chronic prednisone therapy or bone marrow transplants. Afebrile Patients : Some neutropenic patients may have serious infections without fever. Oral temperatures can be unreliable, and rectal temperatures are contraindicated. Instead, other signs like unexplained tachypnea, tachycardia, mental status changes, and metabolic acidosis should be considered. Misleading Physical Examination : Localized infections in febrile neutropenia may not show typical signs like induration, redness, or purulent drainage. Tenderness might be the only indicator in some infections, and peritoneal signs may be absent despite surgical pathology. Non-Infectious Causes of Fever : Non-infectious causes, such as drug reactions, transfusion reactions, or pulmonary emboli, should also be considered in febrile neutropenic patients. Diagnostic Testing Limitations : Diagnostic tests may not always be reliable; for example, pneumonia might not show on initial chest radiographs, and urinary tract infections may not present with pyuria. Leukocytosis Misinterpretation : Patients receiving colony-stimulating factors may show marked leukocytosis, which should not mislead clinicians into thinking the patient is not neutropenic. Avoid Rectal Temperatures : Rectal temperature measurements are avoided in neutropenic patients due to the risk of bacterial translocation; oral temperature measurements are preferred. Pitfalls

28. Febrile neutropenia ( T 38.3 ANC <0.5) is a medical emergency that requires prompt diagnosis and initiation of empirical antibiotic therapy within one hour. MASCC score can be used to determine patient risk and guide treatment decisions. Low-risk patients may be managed with oral antibiotics, while high-risk patients need inpatient IV therapy. Choose Empirical antibiotics based on the risk category, local resistance patterns, and patient's medical history. Adjust treatment based on clinical response and culture results . Monitoring: Regularly reassess the patient, especially after 3-5 days of persistent fever. Consider adding antifungal therapy if no improvement is seen. Duration of Therapy: Continue antibiotics until the patient is afebrile for 3-5 days and the ANC is above 500 cells/µL. Tailor the duration of therapy based on the identified infection and clinical progress. summary

29. Questions

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