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Approach to Infections in the Immunocompromised Host

Approach to Infections in the Immunocompromised Host. PEDIATRIC RESIDENT AHD Rupesh Chawla MD MSc FRCPC October 11, 2012. Objectives. 1. Describe challenges in infections in immunocompromised host 2. Evaluation of the immunocompromised host for infectious etiologies

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Approach to Infections in the Immunocompromised Host

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  1. Approach to Infections in the Immunocompromised Host PEDIATRIC RESIDENT AHD Rupesh Chawla MD MSc FRCPC October 11, 2012

  2. Objectives • 1. Describe challenges in infections in immunocompromised host • 2. Evaluation of the immunocompromised host for infectious etiologies • 3. Therapy of the cancer patient with febrile neutropenia

  3. Definitions • Immunocompromised host: individuals with impairment of either or both natural and specific immunity to infection (impaired host defenses) leading to increased risk of infection by a variety of microorganisms • Opportunistic infection: invasive infection due to non-pathogens or to infections with sometime or even true pathogens of a type and/or severity rarely encountered in normal hosts

  4. Challenges to Infections in the Immunocompromised Patient • Many infectious agents can lead to lethal infection. Treatment has improved but prevention should be the first goal. Need better epidemiological protection and preemptive and prophylactic strategies. • Impaired inflammatory response attenuates symptoms and signs till disease far advanced.

  5. Challenges to Infections in the Immunocompromised Patient • Diagnostic techniques are not optimal. • Prolonged therapy often necessary with associated increased toxicity. • Differential diagnosis include a multitude of non-infectious entities making diagnosis more difficult

  6. Risk factors for infection include disease process and treatment. • Specific deficiencies theoretically increase pt susceptibility to infection to organisms they are responsible for eradicating. • Single isolated deficiencies never encountered and malfunction of one part affects other components.

  7. Host Defences • Physical Barriers • Skin • Alimentary Tract • Mucous Membranes • Humoral Immunity • Nonspecific: Lysozyme and lactoferrin, Complement, Fibronectin, Interferons, Interleukins • Specific: Immunoglobulins (B-cell) • Cellular Immunity • Nonspecific: Neutrophils, Eosinophils, Mononuclear phagocytes, NK cells • Specific: Cell-mediated immunity T-cells and macrophages

  8. Management of Fever and Neutropenia in Patients with Cancer(Hughes W.T et al CID 2002;34:730-41) • ≥ 50% febrile neutropenic patients have an established or occult infection and ≥ 20% with neutrophil counts <100 cells/mm3 have bacteremia. • Bacterial Causes of febrile episodes • Gram-positive cocci and bacilli • Gram-negative bacilli and cocci • Anaerobic cocci and bacilli

  9. Fungi are common causes of secondary infection in patients who have received courses of broad-spectrum antibiotics but they may also cause primary infection • Primary anatomic sites of infection: • Alimentary tract • Integument damage by vascular access devices allow portal of entry

  10. Definitions • Fever: Single oral temperature ≥ 38.3oC (101oF) or a temperature of ≥ 38.0oC (100.4oF) for > 1 hour • Neutropenia: Neutrophil count <500 cells/mm3 or a count of <1000 cells/mm3 with predicted decrease to 500 cells/mm3 • Degree and duration of neutropenia are important determinants of infection

  11. Evaluation/Diagnosis

  12. Evaluation • Symptoms and signs of inflammation may be minimal or absent ( No induration/erythema/pustulation, infiltrate, CSF pleocytosis, pyuria)

  13. Evaluation • History and careful examination critical • Look for pain at commonly infected sites: peridontium, pharynx, lower esophagus, lung, perineum (anus), eye (fundus), and skin (including BMA sites, vascular catheter sites, and tissue around nails)

  14. Evaluation: Laboratory • CBC and differential, urea, creatinine, electrolytes and liver function tests (transaminases and total bilirubin) as an initial baseline and can also be helpful diagnostically A-III • Acute phase reactants such as ESR, CRP, IL-6 and 8, and procalcitonin have NOT been shown to have specificity for determining nature of infection • Obtain specimens for bacterial and fungal culture (≥ 1 set of blood cultures from each device lumen and peripheral vein) A-III Penel N et al Support Care Cancer 2004 Persson I et al Eur J Hematol 2005;74:297-303 von Liienfeld-Toal M et al Eur J Clin Micro Infect Dis2004;23:539-44 von Liienfeld-Toal M et al Support Care Cancer 2006;14:1241-5

  15. Evaluation: Laboratory • Culture urine if: Sx and signs UTI, urinary catheter in place, or abnormal urinalysis • CSF specimens: if suspected, not routine • Stool specimens: for Clostridium difficile toxin and other studies if clinically indicated

  16. Evaluation: Laboratory • If catheter site inflamed or draining: gram stain and culture for bacteria and fungi • Aspiration/biopsy of skin lesions: • 1/2 for histopathologic evaluation and special stains for fungi, mycobacteria, and bacteria • 1/2 to microbiology for culture aerobic/anaerobic bacteria, mycobacteria, and fungi (stains: Gram’s stain, acid-fast, modified acid-fast, and direct fungal stain)

  17. Evaluation: Laboratory • CXR: Sx and signs of RTI (high resolution CT will reveal evidence of pneumonia in ≥ 50% febrile neutropenic pts with normal CXR) A-III • CT more sensitive and provides precise anatomic localization which can result in earlier localization, diagnosis, and treatment

  18. Evaluation: Laboratory • Other • Abdominal U/S or CT • Sinus (radiograph) or CT • Other imaging studies or diagnostic procedures as clinically indicated

  19. Virology 101 • The ability of viral diagnostics is limited in the neutropenic patient because….. • And the survey says….. • NO WBC… • The foundation of diagnosing most viruses is determining an antibody response which is not present with neutropenia and therefore serology is not useful

  20. Virology 101 • However, all is not lost…. • We have other methods: • Electron Microscopy • Viral culture • Antigen testing: DFA, EIA • Polymerase Chain Reaction

  21. Virology 101 • With patients who continue to have fever once neutropenia resolved serology is an important diagnostic tool • Should send for viruses such as HSV, VZV, EBV, CMV, parvovirus, HHV-6, Hep B, Hep C depending on clinical circumstance

  22. Advanced Mycology 303 • For fungal infection a high index of suspicion is important • Look for signs of colonization even prior to chemotherapy • Signs during period of neutropenia can be muted/subtle and get markedly worse with the return of the immune response

  23. Advanced Mycology 303 • Biopsy of suspicious lesions and aggressive diagnostic procedures are often needed to make the definitive diagnosis • On the horizon new testing for early detection of fungal infection are becoming available • Galactomannan assay for aspergillus • β-D Glucan for fungi other than zygomycetes • PCR for both aspergillus and candida

  24. CBC and renal function (urea and creatinine) for supportive care and monitoring for drug toxicity at least every 3 days • Serum transaminase monitoring for patients with complicated course or suspected hepatocellular injury

  25. Case #1 • Clinical History: 15-year-old female with neutropenia and right-sided abdominal pain and diarrhea.

  26. Findings: CT scan demonstrates bowel wall thickening and enhancement involving the cecum and ascending colon from the level of hepatic flexure to the appendix. There is also thickening and edema of the adjacent fat. No free air or abnormal extraluminal fluid collections or masses are seen. • Diagnosis: Typhlitis

  27. Therapy

  28. Therapy • Risk stratification is a recommended starting point for managing pts with febrile neutropenia • Signs and symptoms • Underlying cancer • Type of therapy • Medical comorbidities

  29. High Risk • Anticipated prolonged (> 7 days duration) and profound neutropenia (ANC ≤ 100 cells/mm3) • Medical co-morbid conditions: hypotension, pneumonia, new onset abdominal pain, or neurologic changes • ADMIT pts for empirical Rx

  30. Low Risk • Brief (≤ 7 days duration) neutropenia • Few or no co-morbidities • CANDIDATE for oral Rx

  31. MASCC Score Characteristic Point score Burden of illness *No or mild symptoms 5 *Moderate symptoms 3 No hypotension 5 No COPD 4 Solid tumor or no previous fungal 4 Infection in hematologic tumor Outpatient status 3 No dehydration 3 Aged <60 years 2 •  The maximum value in this system is 26, and a score of >21 predicts a <5% risk for severe complications and a very low mortality (<1%) in febrile neutropenic patients.

  32. Who is a Low Risk Febrile Neutropenic Pediatric Oncology Patient? • Identify risk factors predictive of severe bacterial infection in FN pts • Adult studies: Lower risk of complications • Pts younger than 60 yrs • Solid tumors • Outpatient status at onset of fever • No symptoms of illness • Absence of comorbidities or other reason for hospitalization Talcott JA et al. Arch Intern Med 1988;148:2561-8, Uys A et al. Support Care Cancer 2004; 12:555-60

  33. Recently pediatric specific risk stratification models have been developed: Low risk • Absolute monocyte count (AMC) >100/mm3 • C-reactive protein (CRP) ≤ 90 mg/L • Temperature < 390C • Absence of co-morbidity or significant focal infection • Goal of risk stratification identify children at low risk to offer less aggressive therapeutic approaches: shortened Abx treatment, early hospital discharge, oral antibiotic therapy, and outpatient management Boragina M et al. Pediatr Blood Cancer 2007;48:521-6, Ammann RA et al. Med Pediatr Oncol 2003;41:436-43, Klassen RJ et al. J Clin Oncol 2000;18:1012-9, Santolaya ME et al. J Clin Oncol 2001;19:3415-21. Santolya ME et al. CID 2002;35:678-93, Rackoff WR wt al. J Clin Oncol 1996;14:919-24, Baorto EP et al. Cancer 2001;92:909-13

  34. So...What’s new in Low Risk Kids?? • Po antibiotics (cipro/clavulin and cefixime) have been used with success in low risk pediatric FN pts (from the onset and after 48 hour –ve cultures): in hospital, and outpatient (Paganini) • Study of outpt therapy of low risk FN pediatric pts with IV (ceftazidime) and po (ciprofloxacin) meds • 63/73 episodes (86%) successfully managed as outpt • 31/33 ceftaz, 32/40 cipro not statistically different • Seen daily till afebrile 48 hrs and rising AGC >500 cells/μL Freifeld A et al. NEJM 1999;341:305-11, Shenep JL et al. CID 2001;32:36-43, Paganini HR et al. Cancer 2000;88:2848-52 Mullen CA et al. Cancer 1999;86:126-34

  35. Other studies have examined early discontinuation of antibiotics in low risk FN pediatric pts • One study till afebrile >24 hrs and treated minimum of 72 hrs: 106 episodes84 D/C  no death/complication none rehospitalized for recurrent fever or infection • Another study after afebrile >24 hrs, -ve BC at 48 hrs, and LR randomized 37 to po cloxacillin and cefixime and 36 placebo5 pt in abx arm and 2 in placebo readmit with recurrent F+N, 1 pt in placebo + BC, no fatalities • Edmonton study retrospective review: 276 episodes FN • 59 micro defined infection (21%) • 217 FUO 112/199 (56%) with known neutrophil counts D/C’d Abx prior to ANC ≥ 500/mm3 Lehrnbecher T et al. Infection 2002;30:17-21 Klaassen RJ et al. Jour Ped Hem Onc 2000;22:405-11 Hodgson-Viden H et al. BMC Pediatrics 2005,5:10

  36. One study has looked at withholding antibiotics in LR FN pediatric patients • 196 episodes: 76 (39%) HR, 84 (43%) MR, 36 (18%) LR • HR: pt with signs bacterial infection, +/- abnormal vital signs indicating sepsis • IL-8 level determinant of MR vs LR 40 ng/Lchanged to 60 ng/L after 75 episodes without failure • HR and MR standard Abx • LR no Abx and discharged after 12hrs of febrile observation •  one pt received Clavulin for severe mucositis • No failures (No +BC, nor persistent or recurrent fever, nor discontinuation assigned strategy before neutropenia resolved) Nijhuis CO et al. Jour of Clin Oncol 2005;23:7437-44

  37. Therapy • What is currently happening?? • Recent study reviewed management of Febrile Neutropenic (FN) Pediatric Oncology patients Boragina M et al. Pediatr Blood Cancer 2007;48:521-6 • Mailed questionnaire to chiefs of Hem/Onc of every tertiary pediatric centre in Canada • 16/17 completed survey: 94% response

  38. Boragina M et al. Pediatr Blood Cancer 2007;48:521-6

  39. Boragina M et al. Pediatr Blood Cancer 2007;48:521-6

  40. I. Complete outpatient management • 120 episodes (16% of total FN/year at 4 centers) • 81% success (failure readmit) • IIa. Discharge home without Abx • 6 centers 250 pts/year • Readmit rate 6% • IIb. Discharge home with Abx (IV or po) • 1 center ?readmit or number of pts • IIc. D/C Abx observe in hospital for 24 hrs • 4 centers 150 pts/year (1 center IIa and IIc) • Readmit rate 3% Boragina M et al. Pediatr Blood Cancer 2007;48:521-6

  41. 14 centers: resolution neutropenia not necessary for early discharge but 3 mentioned waiting for some evidence of BM recovery (increased plt, monos, or neuts) lead to early discharge of 42% of FN pts initially admitted to hospital • 2002 IDSA guidelines  • Initial Abx therapy consistent with guidelines • BUT length of therapy and treatment setting majority deviate from guidelines Boragina M et al. Pediatr Blood Cancer 2007;48:521-6

  42. Therapy • Administer empiric antibiotics promptly to all neutropenic pts at onset of fever and in afebrile pts with signs/symptoms compatible with infection • Progression of infection is rapid • Early bacterial infections can not be distinguished from noninfected pts at presentation • Detectable rate of bacteremia 10-30% • Severe bacterial infections in children > adults 20-55% • GP bacteria now account for ~ 60-70% microbiologically documented infections • Selection of initial antibiotic regimen should consider type, frequency of occurrence, and antibiotic susceptibility of isolates recovered from other pts in hospital Hughes W.T et al CID 2002;34:730-41

  43. ACH Febrile Neutropenia Experience(Fric AM ACH Pharmacy Dept) • Retrospective case review of pediatric febrile neutropenic pts at ACH Jan. 2001-Dec. 2002 • 204 febrile neutropenic episodes (260 charts initially identified, 66 excluded: from 181 charts 22 additional febrile neutropenic events) • 48% high risk vs. 52% low risk • GP pathogens 60% GN 32% • Resistance noted to Tazocin, gentamicin, and tobramycin in one blood isolate of K. pneumoniae and an isolate of E. cloacae found four times in the blood during one episode that was resistant to Tazocin • Sites of positive culture: blood 31, urine 6, wound 7, CSF 1, stool 7

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