Approach to Infections in the Immunocompromised Host

PEDIATRIC RESIDENT AHDRupesh 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

• 3. Therapy of the cancer patient with febrile neutropenia

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

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.

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

• 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.

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

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

• 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

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

Evaluation/Diagnosis

Evaluation

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

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)

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;74:297-303von 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

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

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)

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

Evaluation: Laboratory

• Other– Abdominal U/S or CT– Sinus (radiograph) or CT– Other imaging studies or diagnostic procedures

as clinically indicated

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

Virology 101

• However, all is not lost….

• We have other methods:– Electron Microscopy– Viral culture– Antigen testing: DFA, EIA– Polymerase Chain Reaction

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

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

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

• 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

Case #1

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

• 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

Therapy

Therapy

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

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

Low Risk

• Brief (≤ 7 days duration) neutropenia

• Few or no co-morbidities

• CANDIDATE for oral Rx

MASCC ScoreCharacteristic 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.

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

• 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

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

• 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 episodes84 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 placebo5 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

• 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/Lchanged 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

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

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

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

• 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

• 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

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

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

2001 & 2002 Pathogens IsolatedSpecific Pathogens N=50 (%)

CONS 9 (18%)

Streptococcus viridans 6 (12%)

Clostridium difficile 6 (12%)

Enterobacter cloacae 6 (12%)

Klebsiella pneumoniae 6 (12%)

Staphylococcus aureus 4 (8%)

Streptococcus mitis 3 (6%)

Pseudomonas aeruginosa 2 (4%)

Candida krusei 2 (4%)

Enterococcus faecalis 1 (2%)

Stomatococcus mucilaginosus 1 (2%)

Escherichia coli 1 (2%)

Klebsiella oxytoca 1 (2%)

Candida albicans 1 (2%)

Rotavirus 1 (2%)

Summary of Pathogens

Gram positive pathogens 30 (60%)

Gram negative pathogens 16 (32%)

Fungal pathogens 3 (6%)

Viral pathogens 1 (2%)

Clinical Practice Guideline for the Use of Antimicrobial Agents in Neutropenic Patients with Cancer: 2010 Update by

the IDSA

Freifeld AG et al CID 2011;52:e56-93

High Risk: Intravenous Antibiotics

• Monotherapy recommended (A-I)– Antipseudomonal ß-lactam agent

• Cefipime

• Carbapenem

• Piperacillin-Tazobactam

• Other antimicrobial (AG, FQ, and/or vancomycin) for management of complications (eg hypotension, pneumonia) or if antimicrobial resistance suspected or proven (B-III)

Freifeld AG et al CID 2011;52:427-31

High Risk: Intravenous Antibiotics

• Vancomycin not recommended as standard part of initial regimen (A-I)

• Considered for specific clinical indications:– Suspected catheter related infection– Skin or soft tissue infection– Pneumonia– Hemodynamic instability/severe sepsis– Postive BC for GP bacteria– Colonization with MRSA, VRE, PRSP

High Risk: Intravenous Antibiotics

• Modification considered for pts at high risk for ARO, especially if pt’s condition unstable or positive BC suspicious for resistant bacteria (B-III)

• Risk factors: previous infection/colonization with ARO, treatment in hospital with high rates of endemicity

High Risk: Intravenous Antibiotics

• Afebrile neutropenic pts who have new signs or symptoms suggestive of infection should be evaluated and treated as high risk

Low Risk: Intravenous Antibiotics

• Receive initial oral or IV empirical antibiotics in a clinic or hospital setting

• Transition to outpatient oral or IV if meet specific clinical criteria (A-I)

• Ciprofloxacin plus Clavulin recommended for initial treatment (A-I)– Other: levofloxacin or ciprofloxacin monotherapy,

or ciprofloxacin+clindamycin less well studied (B-III)

Therapy

• Vascular devices may be left in place except:– Infection recurrent or persistent after ≥ 72 hours of

therapy– Subcutaneous tunnel or port pocket site infection– Septic thrombosis– Endocarditis – Sepsis with hemodynamic instability– Non-patent catheter– Organism: S. aureus, P. aeruginosa, fungal, Atypical

mycobacteria require removal

Hughes W.T et al CID 2002;34:730-41

Modification of Antibiotic Regimen During First Week of Therapy

• 3-5 days are usually required to determine efficacy of initial regimen

• Time to defervescence for febrile neutropenic pt with cancer with antibiotics 2-7 days (median 5 days)

• Low risk pts: 2 days High risk pts: 5-7 days• Wait 5 days before making change unless

mandated by deterioration in clinical condition or positive culture

Hughes W.T et al CID 2002;34:730-41

Modification of Antibiotic Regimen During First Week of Therapy

• Should be guided by clinical and microbiologic data (A-II)

• If pt stable with unexplained persistent fever rarely require change. If infection identified adjust accordingly (A-I)

• If Vancomycin (other GP coverage) started initially, stop after 2 days if no evidence of GP infection (A-II)

Modification of Antibiotic Regimen During First Week of Therapy

• If pt remain hemodynamically unstable broaden therapy for ARO, anaerobic bacteria, and fungi (A-III)

Modification of Antibiotic Regimen During First Week of Therapy

• IV po switch if pt clinically stable and GI absorption felt to be adequate (A-I)

• Outpt therapy as long as adequate daily f/u ensured (B-III)

• If fever recurs or persists within 48 hrs for outpt, hospital readmit recommended treat a high risk (A-III)

Modification of Antibiotic Regimen During First Week of Therapy

• Consider empirical antifungal coverage in high risk pt with persistent fever after 4-7 days of broad spectrum antibiotic and no source

Case#2

• Clinical History: 12 year old boy with lymphoma Day#3 of febrile neutropenia develops increased abdominal pain and difficulty breathing.

Case #3

• Clinical History: 10 year old girl in day 3 of febrile neutropenia develops increased SOB, indrawing, and hypoxemia.

Duration of Antimicrobial Therapy

• Pts with clinically or microbiologically documents infections, duration is dictated by particular organism and site; antibiotics should continue for at least duration of neutropenia (ANC ≥ 500 cells/mm3) or longer if clinically indicated (B-III)

Freifeld AG et al CID 2011;52:427-31

Duration of Antimicrobial Therapy

• Pts with unexplained fever regimen should continue till clear sign of marrow recovery; ANC ≥ 500 cells/mm3 (B-II)

• Alternatively if appropriate treatment course completed and all signs and symptoms of documented infection resolved pts who remain neutropenic can stop regimen (C-III)

Adjunctive Therapy• Granulocyte transfusions: no specific indications• Colony stimulating factors (CSF): prophylactic

use should be considered for pts in whom risk febrile neutropenia ≥ 20%– Not recommended for treatment of established febrile

neutropenia – Use of CSF does not affect overall mortality but

reduces time spent in hospital and neutrophil recovery period, ? Effect on infection related mortality Clark OAC et al. Cochrane Database of Systematic Reviews 2003

• Antibiotic prophylaxis:– TMP-SMZ all pts at risk for P. carinii

pneumonitis regardless whether neutropenic– No consensus to recommend prophylactic

antibiotics in all afebrile neutropenic pts: concern re-antibiotic resistance

– FQ prophylaxis considered in high risk pt (B-I)• Monitor for FQ resistance among GNB (A-II)

– Addition of GP agent not recommended (A-I)

Hughes W.T et al CID 2002;34:730-41

Summary

• The immunocompromised pt encompasses a heterogeneous population

• Infections in the immunocompromised pt are difficult to diagnose due to poor inflammatory response and imperfect diagnostic tools

• Therapy should concentrate on prevention as well as treatment of presumed/documented infection.