Rontgene M. Solante, MD, FPCP, FPSMID

Infections in the Immunocompromised Host

OverviewDefinitionsDiagnostic approachTreatment and prevention of infectious

complicationsFebrile neutropeniaTransplant recipientsAspleniaHIV/AIDS

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

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

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

Approach to an immunocompromised patient suspected to have an infection

CausesPredisposing factors

Underlying diseasesTherapeutic interventions

Anti-infective strategy

ETIOLOGIC CAUSES:PROBLEMS

Associated signs and symptoms are often muted

Microbiologic confirmation in < 50%

Difficult to treat organisms or unusual pathogens

Diagnostic Evaluation

Careful history-takingExtensive PE

Blunted inflammatory responseUnusual manifestations

Diagnostic testsMicrobiologic examinationsAntigen detection testsSerologic testsImaging techniques

Management of Infectious Complications in the

Immunocompromised Host

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

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

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

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

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

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

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)

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

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

What constitutes appropriate initial empirical therapy?

Febrile Neutropenia

Defect in Neutrophil FunctionPathogens:

S. aureus and CoNS Viridans strep and other streptococcal

speciesEnterococcus spp.E. coliP. aeruginosaK. pneumoniaeEnterobacter spp.Citrobacter spp.AnaerobesFungi

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

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

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

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.

How should the initial therapy be modified?

Patient Follow-up

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

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;

How long should empirical antibiotic therapy be continued?

Treatment Duration

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)

How do we prevent infection in the neutropenic host?

Prevention of Infection

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

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

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

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

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)

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

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

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

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

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)

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

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

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)

Prophylactic measuresImmunization

PassiveCMV-specific Ig for seronegative renal transplants

Active – inactivated vaccines

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

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

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

HIVAntiretroviral therapy (HAART)Treatment of concurrent infectionsPrevention of opportunistic infections

General isolation proceduresProphylactic antimicrobials

NATURAL COURSE OF HIV INFECTIONHIV initiates immunity loss

Fauci et al.

RNA

CD4 T cells

Immunity HIV

Anti-HIV Anti-HIV

OvertAIDS

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

Loss of immunity leads to opportunistic infection/cancer

• Fauci et al. Harrison‘s Principles of INTERNAL MED

HIVClinical Category A

Asymptomatic HIV infectionPersistent generalized lymphadenopathyAcute (primary) HIV illness

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

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

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

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

SUMMARYHigh index of suspicion

Careful history and thorough PERigorous diagnostic testsImmediate institution of appropriate

therapeutic interventionsAdequate preventive measures