Rontgene M. Solante, MD, FPCP, FPSMID Infections in the Immunocompromised Host.
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Rontgene M. Solante, MD, FPCP, FPSMID
Infections in the Immunocompromised Host
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OverviewDefinitionsDiagnostic approachTreatment and prevention of infectious
complicationsFebrile neutropeniaTransplant recipientsAspleniaHIV/AIDS
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Immunocompromised HostAlteration of the phagocytic, cellular or
humoral immunity that increases the risk of infectious complications or an opportunistic process
Alteration or breaks in the skin or mucosal barriers that permits microorganisms to cause local or systemic infection
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Specific ImmunocompromisedConditions
1. Severe Immunocompromise (Non-HIV) - active leukemia, lymphoma, generalized malignancy, aplastic anemia, graft versus host disease, congenital immunodeficiency, solid organ transplant, or bone marrow transplant within 2 years of transplantation; or persons whose transplants are of longer duration but who are still taking immunosuppressive drugs2. Chronic Diseases with Limited Immune Deficits - asplenia, chronic renal disease, chronic hepatic disease (cirrhosis and alcoholism), diabetes, and nutritional deficiencies
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3. Severe Immunocompromise Due To Symptomatic HIV/AIDS - HIV-infected persons with CD4 counts lower than 200, - history of an AIDS-defining illness, or - clinical manifestations of symptomatic HIV
4. Asymptomatic HIV Infection -Asymptomatic HIV-infected persons with CD4 counts from 200 to 500
Specific ImmunocompromisedConditions
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Approach to an immunocompromised patient suspected to have an infection
CausesPredisposing factors
Underlying diseasesTherapeutic interventions
Anti-infective strategy
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ETIOLOGIC CAUSES:PROBLEMS
Associated signs and symptoms are often muted
Microbiologic confirmation in < 50%
Difficult to treat organisms or unusual pathogens
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Diagnostic Evaluation
Careful history-takingExtensive PE
Blunted inflammatory responseUnusual manifestations
Diagnostic testsMicrobiologic examinationsAntigen detection testsSerologic testsImaging techniques
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Management of Infectious Complications in the
Immunocompromised Host
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Febrile Neutropenia (FN)Granulocytopenia
single most important risk factor for infection in patients with hematologic malignancy
80% of pathogens from the patient’s endogenous microbial flora
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Impact of GranulocytopeniaMost important risk factor for infection
Degree of granulocytopenia is inversely related to risk of infection
Fever develops in nearly all patients with granulocyte count < 100/cu.mm.
Risk of infection and infection-related mortality increases proportionally with time
Bodey GP, Ann Intern Med 1996
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Walter Hughes, Donald Armstrong, Gerald Bodey, Eric Bow, Arthur Brown, Thierry
Calandra, Ronald Feld, Philip Pizzo, Kenneth Rolston, Jerry Shenep, Lowell Young
CID, March 2002
2002 IDSA Guidelines for the Use of Antimicrobial Agents in Neutropenic
Patients with Cancer
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Alison Freifeld, Michael Boeckh, Eric Bow, James Ito, Craig Mullen, Issam Raad, Kenneth Rolston, Kent Sepkowitz, Jo-Anne Van
Burik, John Wingard, Stuart Cohen(For publication, Clin Infect Dis)
Clinical Practice Guideline for the Use of Antimicrobial Agents in Neutropenic
Patients with Cancer 2008 Update
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Guideline comparisonClinical features of
the neutropenic patient
Evaluation of the patient
Initial antibiotic therapy
Clinical featuresRisk assessment:
definitions of high and low risk
Evaluation of the patient
Initial antibiotic therapyHigh riskLow risk
2002 Guidelines
2008 Update
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Guideline comparison Antibiotic prophylaxis Use of antiviral drugs Granulocyte transfusions Economic issues
Antibacterial prophylaxis Antifungal prophylaxis:
empiric and pre-emptive therapy
Antiviral prophylaxis and treatment
Colony-stimulating factors
Catheter infections Environmental
precautions
2002 Guidelines
2008 Update
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Febrile Neutropenia
Guidelines for Empirical TreatmentWho requires empiric antibiotic therapy?
Candidates:ANC < 500/mm3
OR < 1000/mm3 if with evidence of decline (over the next 48 hours)
PLUS Fever (single oral T > 38.3oC or > 38oC
for > 1 hr)
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Febrile NeutropeniaGuidelines for Empirical TreatmentWho requires empiric antibiotic therapy?
Candidates:Afebrile neutropenic patients and have new
onset of abdominal pain, mental status changes, respiratory symptoms or other signs or symptoms compatible with possible infection* Considered high risk candidates for empiric antibiotics
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Febrile Neutropenia
Guidelines for Empirical TreatmentWhat are necessary prior to the initiation of empiric
antibiotic therapy?Pre-antibiotic evaluation
Thorough Hx and PEMicrobiologic examinations of blood, catheter entry
site dischargeLaboratory examinations:
Baseline CXRBlood chemistries
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What constitutes appropriate initial empirical therapy?
Febrile Neutropenia
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Defect in Neutrophil FunctionPathogens:
S. aureus and CoNS Viridans strep and other streptococcal
speciesEnterococcus spp.E. coliP. aeruginosaK. pneumoniaeEnterobacter spp.Citrobacter spp.AnaerobesFungi
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IDSA (Infectious Disease Society of America) risk criteria for fever and neutropenia
High riskNeutropenia anticipated
to extend beyond 7 days
Medical co-morbiditiesHemodynamic
instabilityOral or GI mucositis -
dysphagiaAbdominal or peri-
rectal painNausea/vomitingDiarrhea (6 loose
stools daily)Neurologic/mental
status changes
Low riskNeutropenia
expected to resolve within 7 days
Absence of any co-morbidity listed in high risk criteria
Adequate hepatic and renal function
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High risk
Medical co-morbiditiesIntravascular catheter
infectionNew pulmonary
infiltrate, hypoxemia or underlying COPD
Hepatic insufficiency (aminotransferase levels > 5x normal)
Renal insufficiency (creatinine clearance < 30 ml/min)
IDSA (Infectious Disease Society of America) risk criteria for fever and neutropenia
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Initial empiric antibiotics: High risk patientsMonotherapy with an IV antipseudomonal ß-
lactam: ceftazidime, cefipime, imipenem, meropenem or piperacillin-tazobactam (AI)Ceftazidime may be a less reliable
monotherapyPCN-allergic patients: ciprofloxacin or
aztreonam + clindamycin or vancomycin (CII)Aminoglycoside, FQ and/or vanco may be
added for mgt of complicated cases (i.e., hypotension, pneumonia) or if antimicrobial resistance is suspected/proven (AII)
Paul Cochrane Database 2003; 2: CD003038; Furno Lancet ID 2002; 2: 231;Bow CID 2006; 43: 447; Glasmacher Clin Micro Infect 2005; 11 (S5): 17
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Initial empiric antibiotics: Low risk patientsInpatient IV or oral antibiotics
IV regimens as for high risk patients (AI) OROral regimen: ciprofloxacin +
amoxicillin/clavulanate (AI)Oral regimen for PCN-allergic patients:
levofloxacin, moxifloxacin, ciprofloxacin + clindamycin, ciprofloxacin + azithromycin (CIII)
Freifeld NEJM 1999; 341: 305; Kern NEJM 1999; 341: 312; Rolston CID 1999; 29: 512;Chamilos Cancer 2005; 103: 2629; Cornely Int J Hematol 2004; 79: 74;
Innes Supp Care Cancer Sept 25, 2007 epub.
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How should the initial therapy be modified?
Patient Follow-up
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Modification of initial therapy during the first week
Daily examination while febrile and neutropenic
Modifications based on new findingsIdentified focus of infection Positive initial cultures - specific
antibioticSuperinfections or breakthrough
infections Clinical deterioration
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Empiric antifungal therapyAfter 4-7 days of broad spectrum antibiotics, high
risk patients with continuing or recrudescent fever, should receive antifungal therapy (AII)Amphotericin B (standard tx)Others include: caspofungin, liposomal ampho
B (AI); itraconazole, voriconazole (BII)Investigate for systemic fungal infection
Chest CT scan can be performed on high risk patients with prolonged FN, to evaluate evidence of invasive mould infection (BIII)
Winston Am J Med 2000; 108: 282; Walsh NEJM 2004; 351: 1391; Booegarts Ann Intern Med 135: 412; Maertens CID 2005; 41: 1242;
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How long should empirical antibiotic therapy be continued?
Treatment Duration
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Duration of empiric antibiotic therapyDocumented infections
Treat for an appropriate length of time for the particular organism and site and continue through the period of neutropenia or beyond, as necessary (CIII)
FUOANC > 500/mm3 for at least one day with a rising
trend; ANDPatient is afebrile for at least 2 days (CIII)
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How do we prevent infection in the neutropenic host?
Prevention of Infection
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Antimicrobial Prophylaxis
Low riskAntibacterial, antifungal, antiviral not routinely recommended (CIII)
Prophylaxis for Pneumocystis cariniiMandatory for patients with ALL and for those who are receiving
glucocorticoid containing chemotherapy regimen
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Antibacterial prophylaxisHigh risk
Ciprofloxacin or levofloxacin for patients with expected duration of neutropenia > 7 days (AI)
Antibiotic prophylaxis has been shown to reduceFebrile episodesGram +/- bacteremiasUse of empiric antibiotics without an
increase in antimicrobial resistanceGafter-Gvill Ann Int Med 2005; 142: 979; Bucaneve NEJM 2005; 353: 977;
Crucianin JCO 2003; 21: 4127; Gimmema Ann Int Med 1991; 115: 7; von Baum JAC 2006; 58: 891;Leibovici Cancer 2006; 107: 1743
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Antifungal ProphylaxisHigh risk
AML induction: posaconazole (AI); itraconazole, fluconazole (CI)
Allogeneic HSCT: fluconazole (AI); itraconazole, micafungin (BI);
Autologous HSCT: fluconazole if patient is anticipated to develop severe mucositis (BI)
Mould-active agent for patients with prolonged neutropenia >14 days (BIII)
Cornely NEJM 2007; 365: 348; Rotstein CID 1999; 28: 331; Winston Ann Int Med 1993; 118: 495;Glasmacher JAC 2006; 57: 317; Goodman NEJM 1992; 326: 845; Slavin JID 1995; 17: 1545;
Winston Ann Int Med 2003; 138: 705; Marr Blood 2004; 103: 1557; van Burik CID 2004; 39: 1407
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Colony Stimulating Factors (G-CSF, GM-CSF)Should not be administered at the onset of
FN, as adjuncts to empiric antibiotics, as they are not clinically useful (EI)
Berghmans Supp Care Cancer 2002; 10: 181
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Environmental PrecautionsNo specific protective gear (gowns, gloves,
masks) for routine care of neutropenic patients (CIII)
Neutropenic patients do not require a single room or special ventilation, except allogeneic HSCT recipients (CIII)
“Neutropenic diet” generally recommended (BIII)
No plants, dried or fresh flowers; no pets (BIII)All HCWs must have updated immunizations,
especially yearly influenza vaccine (AI)
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Infections inTransplant Recipients
Important problem due to its contribution to the failure and rejection of the transplanted organ
Clinical manifestations vary depending on:infecting pathogen prior immune status of the hosttime after transplantationlevel of pharmacologic
immunosuppressionOften occur during the first 4-6 months
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Factors that contribute to infection after transplantationPretransplant host factors
Underlying medical conditionLack of specific immunityPrior colonizationPrior latent infectionPrior medications
Transplantation factors - type of transplantation, surgical stress
Immunosuppression - therapy, infectionsAllograft reactions
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Effects of ImmunosuppresantsSteroids
Inhibit migration of monocytes to areas of inflammation Prevent induction of IL-1 and IL-6 in macrophages Chemotactic activity and adhesion of neutrophils at the site of infection
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Effects of ImmunosuppresantsCyclosporine
Generation of CD4 (T-helper cells) Proliferation of CD4 cells Production of cytotoxic T-cells from the precursors
Mycophenolate mofetilInhibits inosine monophosphate dehydrogenase
Proliferation of B and T lymphocytes
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Infections in bone marrow transplant recipients
Period after transplantation
Infection site Early (<1 month)
Middle (1-4 months)
Late (> 6 months)
Disseminated Bacteria (aerobic gram -/+)
Bacteria (Nocardia, actinomycosis)Fungi (Candida, Aspergillus)
Encapsulated bacteria (S. pneumoniae, H. influenzae, N. meningitidis)
Skin and mucous membranes
HSV HHV 6 VZV
Lungs Bacteria (aerobic gram
-/+)Candida, Aspergillus, HSV
CMV, seasonal respiratory virusesParasites (T. gondii)Fungi (Pneumocystis)
Pneumocystis
GIT CMV
Kidneys BK virus, adenovirus Viruses (BK)
Brain HHV-6 Parasites (T. gondii)Viruses (JC)
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Infections in solid organ transplant recipients
Transplant 1 2 3 4 5 6 MONTHS
UTI: BENIGNUTI: BACTEREMIA, PYELITIS, RELAPSE
Hep BNon-A, Non-B Hep
HEPATITIS
WoundPneumoniaLine-related
BACTERIAL
CNS
FUNGAL TB PNEUMOCYSTIS
Listeria
Aspergillus, Nocardia, Toxoplasma Cryptococcus
VIRALHSV
CMV Onset
EBV VZV PAPOVA ADENOVIRUSCMV chorioretinitis
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Approach to suspected infection in a post-transplant patient
Careful history and PEFocus of infection
Diagnostic Work-upCXRMicrobiologic studiesCBC, LFTs, Renal Function testsViral studies (CMV)
Important to remember:Infections may occur without feverNot all fevers are due to infections
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Diagnosis and Control of InfectionRoutine Lab Tests
Before TransplantationCMV / EBV / HSV /
VZV IgGToxoplasma IgGHep B screeningHep C ELISAHIV AbPPDStool for ova and
parasites
After TransplantationViral
surveillance Antibody
studies (as indicated)
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Prophylactic measuresImmunization
PassiveCMV-specific Ig for seronegative renal transplants
Active – inactivated vaccines
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Prophylactic Agents
Pathogen Prophylactic Agents Protozoa Toxoplasmosis
Pyrimethamine, TMP-SMX
Viral HSV CMV
Acyclovir Acyclovir, Ig, Ganciclovir
Fungal Candida Aspergillus Pneumocystis
Fluco, Nystatin, Clotrimazole Ampho B TMP-SMX
Bacterial UTI Neutropenic infection TB Pneumococcus
TMP-SMX Quinolones Isoniazid Penicillin
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ASPLENIAPostsplenectomy sepsis
Rapid deterioration accompanied by CV collapse, seizures, coma and DICHigh mortality rate
Diagnosis: Microbiologic exams of blood
Microbiology: S. pneumoniae, H. influenzae, N. meningitidisAppropriate antibiotics against these
organisms
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Prevention of Infection in Asplenic PatientsPatient educationVaccination - at least 2 weeks before elective
surgeryProphylactic antibiotics ?
Spleen-sparing treatmentsPotential immunologic measures
GM-CSF - macrophage bactericidal activityCorynebacterium parvum – stimulates RES
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HIVAntiretroviral therapy (HAART)Treatment of concurrent infectionsPrevention of opportunistic infections
General isolation proceduresProphylactic antimicrobials
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NATURAL COURSE OF HIV INFECTIONHIV initiates immunity loss
Fauci et al.
RNA
CD4 T cells
Immunity HIV
Anti-HIV Anti-HIV
OvertAIDS
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Disease and PathogenHIV causes immune deficiency. Other pathogen triggers death.
EventsHIV infection
Loss of immunity
Opportunistic infectionOpportunistic cancer
Death
PathogenHIV
Many pathogens other than HIV
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Loss of immunity leads to opportunistic infection/cancer
• Fauci et al. Harrison‘s Principles of INTERNAL MED
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HIVClinical Category A
Asymptomatic HIV infectionPersistent generalized lymphadenopathyAcute (primary) HIV illness
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HIV
Clinical Category BSymptomatic, not A or C conditionsExamples include (but not limited to):
Bacillary angiomatosisCandidiasis, vulvovaginal; persistent > 1 month,
poorly responsive to treatmentCandidiasis, oropharyngealCervical dysplasia, severe or carcinoma in situConstitutional symptoms, e.g., fever (38.5oC) or
diarrhea > 1 monthMust be attributed to HIV infection or have a
clinical course or management complicated by HIV
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HIV Clinical Category C
Candidiasis, esophageal, trachea, bronhci
Coccidioidomycosis, extrapulmonary
Cryptococcosis, extrapulmonary Cervical cancer, invasive Cryptosporidiosis, chronic
intestinal (> 1 month) CMV retinitis,or CMV in other
than liver, spleen, nodes HIV encephalopathy Herpes simplex with
mucocutaneous ulcer > 1 month, bronchitits, pneumonia
Histoplasmosis, disseminated, extrapulmonary
Isosporiasis, chronic, > 1 month Kaposi’s sarcoma Lymphoma: Burkitt’s,
immunoblastic, primary in brain M. avium, M. kansasii,
extrapulmonary PCP Pneumonia, recurrent (>2
episodes in 1 year) Progressive multifocal
leukoencephalopathy Salmonella bacteria, recurrent Toxoplasmosis, cerebral Wasting syndrome due to HIV
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HIV
CLINICAL CATEGORY
CD4 Cell Category A B C
(1) >500/mm3 A1 B1 C1
(2) 200-499/ mm3 A2 B2 C2
(3) <200/ mm3 A3 B3 C3
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Prophylactic Regimens
Any CD4 levelM. tb: INH 300mg qd or 900 mg 2x/wk
CD4 < 200/mm2
PCP: TMP-SMX DS qd or 3x/wk CD4 < 100/mm2
Toxoplasma gondii: TMP-SX DS qdCMV: Ganciclovir 1g TID; Valganciclovir 900 mg BID
CD4 < 50/mm2
MAI: Clarithro 500 mg qd or Azithro 1.2 g qweek Cryptococcus (for 2ndry prevention): Fluco 200 mg
qd
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SUMMARYHigh index of suspicion
Careful history and thorough PERigorous diagnostic testsImmediate institution of appropriate
therapeutic interventionsAdequate preventive measures