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Neutropenic Fever.pptx

  1. Management of Neutropenic fever Dr. G/yesus E. Moderator : Dr. G/Hiwot (Pediatrician) 1-Apr-23 1 Febrile neutropenia
  2. Presentation Out lines • Introduction • Definition • Etiology of fever • Clinical manifestations • Approach Neutropenic fever • Investigations • Risk stratification • Management • Modified Guideline for ACSH 1-Apr-23 Febrile neutropenia 2
  3. Questions • What clinical features and laboratory markers can be used to classify FN ? • What clinical, laboratory, and imaging studies are useful at the initial presentation of FN? • What empirical antibiotics are appropriate for children with high-risk FN? • When and how should the initial empirical antibiotic therapy be modified ? • When can empirical antibiotics be discontinued in low- and high-risk FN? 1-Apr-23 Febrile neutropenia 3
  4. Introduction • Infection is a major cause of morbidity and mortality in cancer patients. • Fever may be the first manifestation of a life-threatening infection, particularly during periods of neutropenia. • Febrile episodes occur in approximately one-third of Neutropenic episodes in children with chemotherapy-induced neutropenia or after hematopoietic cell transplantation . Up-to-date,2018 1-Apr-23 Febrile neutropenia 4
  5. Introduction … • Fever occurs frequently during chemotherapy-induced neutropenia: • 10%–50% of patients with solid tumors • >80% hematologic malignancies with >/=1chemotherapy cycle associated with neutropenia • Most patients will have not documented infectious etiology. • Clinically documented infections ~ 20%–30%. • Bacteremia occurs in 10%–25% of all patients. • Most episodes occur in prolonged or profound neutropenia (ANC<100 ne/mm) • common sites of tissue-based infection include the intestinal tract, lung, and skin. • Clinical Practice Guideline for the Use of Antimicrobial Agents in Neutropenic Patients with Cancer , IDSA, 2010 1-Apr-23 Febrile neutropenia 5
  6. Introduction ….. • In a 2yr retrospective study of 226 cancer patients in ACSH 2018-20 • 55 episodes of FN among 40 oncologic patients were analyzed • Hematologic malignancy 96.3% of episodes • Febrile neutropenia was common in descending order • Lymphocytic leukemia, AML, NHL, brain tumor ,HL and retinoblastoma respectively • Common during induction and consolidation Kiros T. Treatment outcome and associated factors of febrile neutropenia among pediatric patients with cancer in ACSH, Northern Ethiopia,sep,2020. 1-Apr-23 Febrile neutropenia 6
  7. Definitions • Fever is defined as a single oral temperature >/= 38.3°C or oral temperature >/= 38°C for 1 hour or more. • Oral temperatures are preferred. • However, when axillary temperatures are the only option, fever is defined as a single axillary temperature of >/= 37.8°C or axillary temperature >/= 37.5°C for 1 hour or more. 1-Apr-23 Febrile neutropenia 7
  8. Definition … • Neutropenia • Neutropenia is defined as an absolute neutrophil count (ANC) <1500 cells/mm3 • Neutropenia • ANC of <500 cells/mm3 or an • ANC that is expected to decrease to <500 cells/mm 3 in the next 48 h • Profound neutropenia: ANC is <100 cells/mm 3 • The ANC is calculated using the following formula: ANC = total WBC count (cells/ cells/mm3 ) x (percent neutrophils + % bands) ÷ 100 1-Apr-23 Febrile neutropenia 8
  9. Introduction … • First Neutropenic fever: first febrile episode occurring during a given period of chemotherapy-induced neutropenia • Persistent Neutropenic fever: • a febrile episode without defervescence after at least 5 days of initial empiric broad-spectrum antibacterial therapy in high-risk Neutropenic patients • Recrudescent fever: febrile episode that recurs following initial defervescence during a course of broad-spectrum antibacterial therapy 1-Apr-23 Febrile neutropenia 9
  10. Introduction … • Neutropenic fever syndromes • The International Immunocompromised Host Society has classified initial Neutropenic fever syndromes into three categories . • Microbiologically documented infection ( 10-20%) • Neutropenic fever with a clinical focus of infection and an associated pathogen • Clinically documented infection ( 20-30%) • Neutropenic fever with a clinical focus (cellulites) • No isolated pathogen • Unexplained fever (50-60%) • Neutropenic fever without clinical focus or identified pathogen Up-to-date ,2018 1-Apr-23 Febrile neutropenia 10
  11. Etiology of fever • The etiology of initial fever may be non-infectious, bacterial, viral or less commonly due to other pathogens. • Viral pathogens are common and evaluation should be directed at specific signs and symptoms. 1-Apr-23 Febrile neutropenia 11
  12. 1950s &early 1960s • Common pathogens were gram-positive organisms, Late 1960s &1970s • Common pathogens were gram-negative organisms- E.coli, Klebsiella, Pseudomonas sp. 1980s • TMP/SMZ started being used for prophylaxis in neutropenic patient 1990 • IDSA Guidelines recommended TMP/SMZ for patients with profound neutropenia for > 1 weeks • Common pathogens -gram-positives (e.g .s. aureus, & gram- negatives (E. coli, Pseudomonas sp.) • early 1990s, the increased use of fluoroquinolones for prophylaxis in neutropenic patients began. 1997& 2002 • IDSA Guidelines did not recommend the routine use of TMP/SMZ or quinolones for prophylaxis. 2010 • Increase in drug-resistant pathogens ~ MRSA, VRE, ESBL-producing Enterbacteriaciae • IDSA Guidelines recommended the use of fluoroquinolones in high-risk patients with prolonged and profound neutropenia 1-Apr-23 12 Febrile neutropenia
  13. Etiology of fever… • ETIOLOGY OF FEVER • The rate of documented infection, when a child presents with fever and therapy-induced neutropenia, ranges between 10 and 40 percent. • No clinical or microbiologic evidence of infection will be established in the remainder. • Bacteremia is the most common form of documented infection (20 to 50 %) • Other sites of infection • GIT oral or intestinal mucositis or diarrhea caused by Clostridium difficile and Salmonella spp • Upper and lower respiratory tract • Urinary tract • Skin and soft tissues 1-Apr-23 Febrile neutropenia 13
  14. Etiology of fever… • In a 2yr retrospective study of 226 cancer patients in ACSH 2018-20 • 55 episodes of FN among 40 oncologic patients were analyzed • 17 pathogen was isolated • Most of isolated bacteria were gram negatives ~ 88.2 % • ESBL positive ~ 40% • Klebsiella pneumonia • Escherichia coli • Enterobacter cloacae • Acinobacter species • Microbiological confirmed FN -27.2 % • Gram negatives are sensitive to meropenem and amikacin but highly resistant to cephalosporins • Mortality rate of febrile neutropenia was 21.8%. . 1-Apr-23 Febrile neutropenia 14 Kiros T. Treatment outcome and factors of febrile neutropenia among pediatric patients with cancer in ACSH, sep,2020
  15. Etiology of fever … • Fungi • Typically Candida spp, are more likely to be recovered after prolonged courses of broad-spectrum antibiotics but occasionally may be the primary pathogen • Aspergillus spp, Zygomycetes, and Cryptococcus spp • Antifungal prophylaxis shift the distribution from Candida spp and toward mold infections. • Viral etiologies • Most significant are HSV and VZV • Respiratory viruses are also frequently detected in nasopharyngeal aspirates 1-Apr-23 Febrile neutropenia 15
  16. Clinical manifestations FN • Fever often is the sole sign of occult infection in the neutropenic host • This sign may be absent in some infected patients may present with hypothermic, hypotensive, listless, or confused • Infected children who are receiving glucocorticoids • May present with a lower and/or intermittent temperature elevation or may be afebrile 1-Apr-23 Febrile neutropenia 16
  17. Clinical manifestations FN  Signs and symptoms of inflammation are often attenuated or absent in neutropenic patients • Bacterial infections of skin and soft-tissue • Lack induration, erythema, warmth, or pustulation • Pulmonary infection • No discernible infiltrateon a radiograph • Meningitis • CSF pleocytosis might be modest or absent • Urinary tract infection may demonstrate little or no pyuria 1-Apr-23 Febrile neutropenia 17
  18. Patient approach • Detailed HX and P/E with special attention to clues • Suggesting etiology or focus of infection • Try to identify any features that may help to risk stratify the patient 1-Apr-23 Febrile neutropenia 18
  19. Patient approach … • Detail History • Important aspects of HX include : • New site-specific symptoms • Antimicrobial prophylaxis • Infection exposures • History of documented infections or colonization • Concomitant noninfectious cause of fever (eg, receipt of blood products) • Underlying co morbid conditions (eg, diabetes, recent surgery) • Previous chemotherapy, agents used, and the stage of therapy (to anticipate the length of the Neutropenic episode) • Intravascular catheters or other devices 1-Apr-23 Febrile neutropenia 19
  20. Patient approach … • Physical examination • A careful P/E particular attention paid to most commonly infected sites : • Abnormal vital signs, particularly tachycardia (even without hypotension) • HEENT • Sinus tenderness or nasal ulcerative lesions • Oral mucosa and periodontium • Pharynx • Lower esophagus 1-Apr-23 Febrile neutropenia 20
  21. Patient approach … • Lungs • Tachypnea & saturation • Abdomen • Retrosternal burning pain • Decreased bowel sounds • Typhilitis/colitis • Acute abdomen (RLQ pain) • Hypotension • Bloody diarrhea 1-Apr-23 Febrile neutropenia 21
  22. Patient approach … • Perineum, particularly the perianal and labial regions • Perirectal abscess • Erythema • Induration • Anorectal pain, tenderness and painful bowel movements. • In the neutropenic patient, pus will be absent and the patient will present with a brawny edema and dense cellulitis. 1-Apr-23 Febrile neutropenia 22
  23. Patient approach … • Skin • Skin folds • Areas surrounding nail beds, • Central venous line exit sites and subcutaneous tunnel • Sites of bone marrow aspiration and lumbar puncture • Mild Erythema or tenderness should not be ignored • Visual signs of inflammation may become evident only when neutrophil counts are recovering. 1-Apr-23 Febrile neutropenia 23
  24. Investigations of FN • CBC • Liver and renal function • Obtain peripheral blood cultures • Consider urinalysis and urine culture in patients where clean catch midstream specimen is readily available. • Obtain chest X-ray only in symptomatic patients 1-Apr-23 Febrile neutropenia 24
  25. Investigations of FN… • Blood culture • Obtaining a blood culture of an adequate volume from all lumens of the CVC is important. • Utility of peripheral blood cultures in addition to CVC cultures is controversial. • Seven studies evaluated concurrent peripheral and CVC cultures in adults and children with cancer and/or undergoing HSCT • The proportion of Bacteremia detected by peripheral blood cultures alone (CVC cultures were negative) was 13% (95% CI 8-18%). 1-Apr-23 Febrile neutropenia 25 IDSA 2010
  26. Investigations of FN… • Variables influence blood culture yield • Blood culture volume • Choice of media type • Number of culture bottles inoculated • 2 retrospective studies found that • 2 blood culture sets detect 80%–90% of bloodstream pathogens • whereas >3 sets are required to achieve >96% detection • Accordingly, at least 2 sets of blood culture specimens should be obtained 1-Apr-23 Febrile neutropenia 26 CPG guideline for use of antimicrobial agent in neutropenic cancer patients , 2010
  27. Investigations of FN… Urinalysis and Urine Culture • Pyuria was found in only 4% of UTI • Nitrite testing in younger children to be less effective • Urine culture if symptoms or abnormal urinalysis present • Avoid invasive methods • Clean-catch or midstream urine collection is recommended. • Urine should be obtained prior to commencing antibiotics • Urine collection should not delay treatment. 1-Apr-23 Febrile neutropenia 27
  28. Investigations of FN… • CXR: • Routine CXRs are not recommended in asymptomatic children • Had been advocated as part of the routine, initial assessment of pediatric FN • Four studies that included 540 episodes of FN examined the value of routine CXR • Frequency of pneumonia in an asymptomatic child was 5% or less each of them • Asymptomatic children who do not receive a CXR had no significant adverse clinical consequences • Findings • New focal lesion in patient recovering from neutropenia • New focal lesion in patient with continuing neutropenia • New interstitial pneumonitis • induced sputum or Bronchoalveolar lavage 1-Apr-23 Febrile neutropenia 28 Guideline for mgt of PNF ,IDSA 2010
  29. Investigations of FN… • Fungal • Serial serum tests for fungal antigens or DNA • D glucan test sensitivity (63%–90%) and specificity (>95%) • Candida species • Aspergillus species • Pneumocystis species • Fusarium species • Galactomannan test ( 58-65 vs 65-95%) • Aspergillus species • BAL fungal culture • PCR of blood and BAL fluid • High-resolution chest CT • Macronodules with or without a halo sign  Aspergillosis • Halo sign represents edema or blood surrounding the nodule • nodular, wedge-shaped, peripheral, multiple, or cavitary lesions. 1-Apr-23 Febrile neutropenia 29
  30. Risk stratification • Risk stratification at the time of a child’s presentation with FN • May allow for intensification of therapy • Monitoring for those at higher risk for serious infections and/or complications • De-escalation of therapy for those at lower risk for severe FN outcomes. • Patients with fever and neutropenia can be divided into high- and low-risk categories based upon • Presenting signs and symptoms • ANC • Underlying cancer • Type of therapy and the anticipated length of neutropenia • Medical comorbidities. 1-Apr-23 Febrile neutropenia 30
  31. Risk stratification… • Use of a risk stratification strategy is important, and individual institutional standards of care for risk assignment should be based on one of the six validated schemas. • Each institution should maintain records of which specific strategy was used and evaluate the performance of the chosen rule to ensure accuracy and safety within the specific clinical setting 1-Apr-23 Febrile neutropenia 31
  32. Risk stratification… 1-Apr-23 Febrile neutropenia 32 ICON 2016 , guideline for mgt of FN
  33. Risk stratification… High-risk • Patients with FN with the following criteria , but not limited to: • Hemodynamic instability • Oral or GI mucositis that interferes with swallowing or causes diarrhea • GI symptoms (abdominal pain, nausea, vomiting, or diarrhea) • New-onset neurologic or mental status changes • Intravascular catheter infection • New pulmonary infiltrate or hypoxemia or underlying chronic lung disease • Hepatic/renal insufficiency • Patients with ALL, AML, or within 30 days of HCT • NB • High-risk patients should be admitted to the hospital for empiric antimicrobial therapy. 1-Apr-23 Febrile neutropenia 33
  34. Risk stratification… • Low-risk FN Low-risk patients are those with : • Neutropenia expected to resolve within seven days • Stable and adequate hepatic and renal function • No active comorbidities • Nontoxic appearance • No identifiable source of fever • Normal chest radiograph • Malignancy in remission status. 1-Apr-23 Febrile neutropenia 34
  35. Management of FN • Factors to be considered in Initial management of pediatric FN • Patient characteristics • Clinical presentation • Local infrastructure to support different models of care • Drug availability and costs • Local epidemiology of resistance patterns 1-Apr-23 Febrile neutropenia 35
  36. Management of FN… • Goal of empiric therapy • To provide coverage for virulent organisms and prevent serious morbidity and mortality • Minimizing exposure to unnecessary antibiotics and prevent antibiotic resistance rates 1-Apr-23 Febrile neutropenia 36
  37. Cont… • The cornerstone of therapy for the febrile, neutropenic patient is prompt initiation of empiric broad-spectrum antibiotics with antipseudomonal activity to reduced the mortality rate for Gram-negative infections significantly. • Administration of antibiotic therapy more than 60 minutes after presentation has been associated with increased adverse outcomes and length of stay . • In an observational study in pediatric cancer patients, receipt of antibiotics within 60 minutes of presentation was associated with decreased rates of ICU consultation or admission among. 1-Apr-23 Febrile neutropenia 37
  38. Empirical Treatment options • Monotherapy • Ticarcillin/clavulanate • Piperacillin/tazobactam • cefepime • Imipenem or meropenem • Two-drug regimen: • cefepime, or ceftazidime AND gentamicin (or tobramycin or amikacin). • Ticarcillin/clavulanate or Piperacillin/tazobactam and gentamicin (or tobramycin or amikacin). • NB • Imipenem or meropenem should not be prescribed routinely as empiric therapy. 1-Apr-23 Febrile neutropenia 38
  39. Cont… • Recommendations on empirical antibiotics use in pediatric HR FN • Monotherapy with an anti-pseudomonal ß-lactam or a carbapenem ( strong recommendation, high-quality evidence) • Result from 2 meta-analyses compared monotherapy versus an aminoglycoside- containing regimen in FN and in immunocompromised patients with sepsis in adults • Non-inferiority of monotherapy regimens • Higher toxicity with combination regimens 1-Apr-23 Febrile neutropenia 39 Guideline for mgt of PNF, IDSA 2010
  40. Cont… • In review of 68 randomized trials, which includes 30 more trials than the 38 randomized trials. • Found that monotherapy is similar in efficacy and safety in comparison with aminoglycoside-containing combination regimens • Reduce costs , toxicity, and the need for therapeutic drug monitoring • Fourth-generation cephalosporin monotherapy is an appropriate option for empirical pediatric high-risk FN management if institutional factors support its use. 1-Apr-23 Febrile neutropenia 40 Paula D. robinson etal , Strategies for Empiric Management of Pediatric FN in Patients With Cancer and HSCT Recipients,, journal of clinical oncology ,2016
  41. Cont… • A pediatric meta-analysis found included only 4 trials with patients younger than 14 years of age show • Fewer treatment failures with monotherapy (OR 0.88, 95% CI 0.78-0.99) • Aminoglycoside-containing combination treatment did not improve clinical outcomes in comparison to monotherapy. • Limitation – limited trials 1-Apr-23 Febrile neutropenia 41 Guideline for mgt of PNF, IDSA 2010
  42. Cont… 1-Apr-23 Febrile neutropenia 42 ICON 2016 , guideline for mgt of FN
  43. Modification of treatment: after 24-72 hr empirical RX If responding to empiric therapy • Do not modify based solely on persistence of fever if clinically stable • Discontinue double gram-negative, or empiric glycopeptides coverage (if initiated) after 24-72 hours UNLESS combination is justified by specific microbiologic indication If NOT responding to empiric therapy • If persistent fever and clinically unstable • Escalate initial empiric antibacterial regimen to include coverage for • Resistant gram negative • Gram-positive • Anaerobic bacteria 1-Apr-23 43 Febrile neutropenia
  44. Cont… • MRSA: addition of Vancomycin, linezolid, or daptomycin • VRE: Consider early addition of linezolid or daptomycin • ESBLs: Consider early use of a carbapenem • penicillin-allergic patients can be treated with ciprofloxacin plus clindamycin or aztreonam plus vancomycin 1-Apr-23 Febrile neutropenia 44
  45. Treatment Cessation :After 24-72 hr empirical RX For all patients • Discontinue empiric antibiotics if: • blood culture negative at 48 hrs • Afebrile for at least 24 hours, and • There is evidence of bone marrow recovery For low-risk FN • Consider discontinuation of empiric antibiotics in low-risk patients at 72 hours irrespective of marrow recovery status, if: • Blood culture negative, • Afebrile for at least 24 hours, as long as careful follow-up is ensured 1-Apr-23 45 Febrile neutropenia
  46. Treatment Cessation :After 24-72 hr empirical RX For all patients • Discontinue empiric antibiotics if: • blood culture negative at 48 hrs • Afebrile for at least 24 hours, and • There is evidence of bone marrow recovery For low-risk FN • Consider discontinuation of empiric antibiotics in low-risk patients at 72 hours irrespective of marrow recovery status, if: • Blood culture negative, • Afebrile for at least 24 hours, as long as careful follow-up is ensured 1-Apr-23 46 Febrile neutropenia
  47. Cont… 1-Apr-23 Febrile neutropenia 47 ICON 2016 , guideline for mgt of FN
  48. Indication for vancomycin consideration • Suspected central venous catheter-related infection • Patients with AML because of the increased risk of infection with alpha hemolytic streptococcus such as Streptococcus mitis • Prior history of alpha hemolytic streptococcus Bacteremia • Patients colonized with resistant organisms only treatable with vancomycin • Recent history of Bacteremia or venous catheter-related infection requiring vancomycin • Intensive chemotherapy causing mucositis (such as high-dose cytosine arabinoside) • Hypotension • Patients who have developed fever despite quinolone prophylaxis. 1-Apr-23 Febrile neutropenia 48
  49. Management of fungal infection • The risk of fungal infections is related to the cytotoxicity of the chemotherapeutic regimen and the duration of neutropenia. • The major cause IFIs • Aspergillus and Candida with a mortality approaching 30–60% with. • Higher among post-hematopoietic stem cell transplantation patients. • Prompt diagnosis and treatment is paramount to improving outcomes in these patients. • Difficulty in diagnosing fungal infections is caused by • Absence of localizing signs and symptoms • High likelihood of negative blood cultures. 1-Apr-23 Febrile neutropenia 49
  50. Risk stratification of IFIs • High risks invasive fungal infection • Acute myeloid leukemia • Relapsed acute leukemia • Highly myelosuppressive chemotherapy • Allogeneic hematopoietic cell transplant recipients • Children with prolonged neutropenia • Children receiving high-dose corticosteroid • Low-risk of IFIs - if do not fulfill the above three criteria 1-Apr-23 Febrile neutropenia 50
  51. Empiric Treatment IFD High risk IFIs • Start empiric antifungal therapy if persistent or recurrent fever of unclear etiology at or beyond 96 hours of broad-spectrum antibacterial treatment. Low risk IFIs • consider empiric antifungal therapy if persistent or recurrent fever of unclear etiology at or beyond 96 hours of broad-spectrum antibacterial treatment. 1-Apr-23 51 Febrile neutropenia
  52. Management … • Choice of antifungal: • Caspofungin, or liposomal Amphotericin B • Amphotericin-B in places with limited resources • Prophylactic antifungal therapy in children with IFD high risk • No studies evaluating the safety of this approach in pediatric patients found • Research needed to evaluate its safety and effectiveness in children. 1-Apr-23 Febrile neutropenia 52
  53. Management … • Cessation of antifungal therapy: • No data exists to guide this decision • International pediatric FN guideline panel agrees that empiric therapy should be continued until absolute neutrophil count rises to100-500/µL, and no documented or suspected IFD. 1-Apr-23 Febrile neutropenia 53
  54. Management … • Antiviral therapy • Antiviral treatment for HSV or VZV is only indicated if there is clinical or laboratory evidence of active viral disease . • Respiratory virus testing ( influenza, parainfluenza, adenovirus) and CXR are indicated for patients with URT symptoms ( coryza, cough). 1-Apr-23 Febrile neutropenia 54
  55. Typhilitis/Neutropenic Enterocolitis • Necrotizing colitis localized in the cecum, occurs in the setting of severe neutropenia, particularly in patients with leukemia and in stem cell transplant recipients. • Should be strongly suspected in patients with right lower quadrant pain or the development of a partially obstructive right lower quadrant mass. • Result of bacterial or fungal invasion of the mucosa and can quickly progress from inflammation to full-thickness infarction to perforation, peritonitis and septic shock. 1-Apr-23 Febrile neutropenia 55
  56. Typhilitis … • Responsible pathogens include • Pseudomonas species, Escherichia coli, other Gram negative bacteria • Staphylococcus aureus, a-hemolytic Streptococcus, Clostridium, • Aspergillus, and Candida. • Typhilitis in patients receiving chemotherapy is linked to mucosal injury caused by cytotoxicity chemotherapeutic agents. • The cecum is usually affected ...> its distensibility and its diminished vascularization relative to the rest of the colon. • Extends into the ascending colon and terminal ileum 1-Apr-23 Febrile neutropenia 56
  57. Clinical manifestations of typhilitis • Neutropenic enterocolitis must be considered in any severely neutropenic patient (ANC <500 cells/microL) who presents with fever and abdominal pain. • The location of abdominal pain right lower quadrant. • fever, frequently appear during the 3rd week (median 17 days) after receiving cytotoxicity chemotherapy • At a time when neutropenia is most profound. • Abdominal distension, cramping, tenderness, nausea, vomiting, watery or bloody diarrhea, and frank hematochezia. • Paralytic ileus may occur but is uncommon. • Peritoneal signs and shock suggest the possibility of bowel wall perforation. • Stomatitis and pharyngitis, suggesting the presence of widespread mucositis, may be present. 1-Apr-23 Febrile neutropenia 57
  58. Cont… • Diagnosis • Typhilitis is usually diagnosed clinically when a neutropenic patient presents with right lower quadrant pain. • Physical examination may reveal an • Absence of bowel sounds • Bowel distention • Tenderness on palpation maximal in right lower quadrant • A palpable mass in right lower quadrant. • Serial abdominal examinations are required • Blood and stool cultures and C. difficile toxin assays 1-Apr-23 Febrile neutropenia 58
  59. Cont… • Imaging studies may aid in the diagnosis of typhlitis: • Radiograph of the abdomen • Reveal pneumatosis intestinalis • free air in the peritoneum • Wall thickening • US • Thickening of the bowel wall in the region of the • cecum and is becoming a • More commonly used non-radiation modality to image for typhlitis • CT scan • definitive imaging study and may • demonstrate diffuse thickening of the cecal wall • Barium enema • show severe mucosal irregularity, rigidity, loss of haustral markings and occasional fistula formation 1-Apr-23 Febrile neutropenia 59
  60. Cont… • Medical management is the initial treatment: • Discontinuation of oral intake • Nasogastric tube suctioning • Broad-spectrum antibiotics (anaerobic , Gram-negative and anaerobic) • Piperacillin-tazobactam /Cefepime/Meropenem with/out metrodazole • Vancomycin with indication • Intravenous fluid and electrolytes • Packed red cell and platelet transfusions, as indicated • Vasopressors, as needed (hypotension is associated with a poor outcome). 1-Apr-23 Febrile neutropenia 60
  61. Cont… • Indications for surgical intervention: • Persistent GI bleeding despite resolution of neutropenia and thrombocytopenia • Evidence of free air in the abdomen on abdominal radiograph • Uncontrolled sepsis from bowel infarction requiring fluid and pressor support • Mortality is related to bowel perforation, bowel necrosis and sepsis. 1-Apr-23 Febrile neutropenia 61
  62. Cont… • Fungemia and fungal invasion of the bowel can occur • Candida spp are the most common cause of fungal bloodstream infection in patients with neutropenic colitis. • Protracted fever (>72 hours) despite broad-spectrum antibiotics. • Voriconazole and amphotericin B formulations. 1-Apr-23 Febrile neutropenia 62
  63. Management … • Myeloid CSFs • Are not recommended as adjuncts to antibiotics • Minimally (but statistically significantly) decreased • Days of neutropenia • Duration of fever • Length of hospital stay • The actual clinical benefit of these reductions is not convincing. • None of the studies demonstrated a survival benefit associated with therapeutic CSFs. • Given the cost of and adverse effects and lack of consistent clinical data associated with the CSFs routine use is not advocated 1-Apr-23 Febrile neutropenia 63 Guideline FN IDSA 2010
  64. Management … • Prevention of febrile neutropenia • Hand hygiene • Standard barrier precautions and infection specific isolations. • HSCT recipients should place in private room • Allogeneic HSCT recipients should placed in private room with >12air exchange /hr and high efficacy particulate filter room • Plants and dried or fresh flowers should not allowed in the room of hospitalized neutropenic patients • Hospital work exclusion policies should be designed to encourage health workers to report their illness or exposure. 1-Apr-23 Febrile neutropenia 64
  65. Summery • Fever is frequently the only clinical manifestation of serious infection in a neutropenic cancer patient, • Infection is the major cause of treatment related mortality for children with cancer • Prompt initiation of empiric, broad-spectrum, intravenous antibiotic therapy is the single most important life-saving intervention in these patients and should Treated as an emergency. • Vital sign Q1hr until stable then Q4hror as indicated • Acetaminophen is the preferred antipyretic agent. 1-Apr-23 Febrile neutropenia 65
  66. Guidelines for the management of febrile neutropenia in ACSH, 2021 ACSH Hemato-oncology unit 1-Apr-23 Febrile neutropenia 66
  67. Definition • The neutropenic patient • ANC < 500 x 109 /L or ≤1 x 109 /L with predicted fall to < 0.5 x 109 /L) must be admitted and given intravenous antibiotics in the event of a single temperature spike of >37.8°C axillary or a temperature of ≥37.5°C axillary taken on two occasions at least one hour apart 1-Apr-23 Febrile neutropenia 67
  68. Cont… Please do • CBC and Differential immediately • Liver and renal function • Obtain 2 blood culture sets from separate peripheral vein puncture • IV antibiotics should be started within 1 hour • Provide blood transfusion if indicated • Consult pediatric hemato-oncologist 1-Apr-23 Febrile neutropenia 68
  69. Risk stratification Low risk features • Vitally stable • No evident focus of infection • ANC>100 and anticipated to rise within 7days • Solid tumors and ALL during maintenance • No abdominal pain High risk features • AML, MDS, ALL(during induction, consolidation , re-induction), NHL • ANC<100, and/or anticipated to extend > 7 days • Presence of any co-morbid medical problem including: vital instability, GIT manifestation, pneumonia, altered mental status • Vital instability: Hypotension, tachypnea, Hypoxia (O2 sats < 94% in room air) 1-Apr-23 69 Febrile neutropenia
  70. Management of FN Low risk features • Start with ceftriaxone and gentamicin • 2nd line: Ceftazidime &Vancomycin • Outpatient management • who refused inpatient management • Do blood culture • first dose of ceftriaxone and gentamicin IV at PEOPD • Ciprofloxacin and Augmentin PO • Phone number High risk features • Start ceftazidime and gentamicin • 2ndline: cefepime • Ciprofloxacin if microbiological documented • Vancomycin can be used as first line based on indications • Metronidazole for abdominal symptoms or suspected C. difficile infection • 1-Apr-23 70 Febrile neutropenia
  71. Treatment Cessation :after 24-72 hr empirical RX For all patients • Discontinue empiric antibiotics if: • blood culture negative at 48 hrs • Afebrile for at least 24 hours, and • There is evidence of bone marrow recovery For low-risk FN • Consider discontinuation of empiric antibiotics in low-risk patients at 72 hours irrespective of marrow recovery status, if: • Blood culture negative, • Afebrile for at least 24 hours, as long as careful follow-up is ensured 1-Apr-23 71 Febrile neutropenia
  72. Treatment Cessation :after 24-72 hr empirical RX For all patients • Discontinue empiric antibiotics if: • blood culture negative at 48 hrs • Afebrile for at least 24 hours, and • There is evidence of bone marrow recovery For low-risk FN • Consider discontinuation of empiric antibiotics in low-risk patients at 72 hours irrespective of marrow recovery status, if: • Blood culture negative, • Afebrile for at least 24 hours, as long as careful follow-up is ensured 1-Apr-23 72 Febrile neutropenia
  73. Empiric Treatment IFD High risk IFIs • start empiric antifungal therapy if persistent or recurrent fever of unclear etiology at or beyond 96 hours of broad-spectrum antibacterial treatment. • Liposomal Amphotericin B Low risk IFIs • consider empiric antifungal therapy if persistent or recurrent fever of unclear etiology at or beyond 96 hours of broad- spectrum antibacterial treatment. 1-Apr-23 73 Febrile neutropenia
  74. Reference • Up to date 2018 • Clinical practice Guidelines for the use of antimicrobial Agents in neutropenic patients with cancer :2010 update by Infectious Disease Society of America • Manual of Pediatric Hematology &Oncology,5th edition • Guideline for the management of fever and neutroprnia in children with cancer and HSCT recepient ,2017 • Nelson text book of pediatrics ,21st edition • Febrile neutropenia current guidelines for children, ICON 2016 • CPG guideline for use of antimicrobial agent in neutropenic cancer patients , 2010 1-Apr-23 Febrile neutropenia 74
  75. Thank you! 1-Apr-23 75 Febrile neutropenia