Transcript Infections in the Immunocompromised Host

Infections in the
Immunocompromised Host
Rontgene M. Solante, MD, FPCP, FPSMID
Overview
 Definitions
 Diagnostic approach
 Treatment and prevention of infectious complications
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Febrile neutropenia
Transplant recipients
Asplenia
HIV/AIDS
Immunocompromised Host
 Alteration 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 Immunocompromised
Conditions
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 drugs
2. Chronic Diseases with Limited Immune Deficits
- asplenia, chronic renal disease, chronic hepatic disease (cirrhosis
and alcoholism), diabetes, and nutritional deficiencies
Specific Immunocompromised
Conditions
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
Approach to an immunocompromised
patient suspected to have an infection
 Causes
 Predisposing factors
 Underlying diseases
 Therapeutic 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-taking
 Extensive PE
 Blunted inflammatory response
 Unusual manifestations
 Diagnostic tests
 Microbiologic examinations
 Antigen detection tests
 Serologic tests
 Imaging 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 Granulocytopenia
 Most 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
2002 IDSA Guidelines for the Use of
Antimicrobial Agents in Neutropenic Patients
with Cancer
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
Clinical Practice Guideline for the Use of
Antimicrobial Agents in Neutropenic Patients
with Cancer 2008 Update
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)
Guideline comparison
 Clinical features of the
neutropenic patient
 Clinical features
 Risk assessment: definitions of
high and low risk
 Evaluation of the patient
 Evaluation of the patient
 Initial antibiotic therapy
 Initial antibiotic therapy
 High risk
 Low risk
2002 Guidelines
2008 Update
Guideline comparison
 Antibiotic prophylaxis
 Antibacterial prophylaxis
 Use of antiviral drugs
 Antifungal prophylaxis: empiric and
 Granulocyte transfusions
 Economic issues
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2002 Guidelines
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pre-emptive therapy
Antiviral prophylaxis and treatment
Colony-stimulating factors
Catheter infections
Environmental precautions
2008 Update
Febrile Neutropenia
Guidelines for Empirical Treatment
 Who 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 Neutropenia
Guidelines for Empirical Treatment
 Who 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 Treatment
 What are necessary prior to the initiation of empiric
antibiotic therapy?
 Pre-antibiotic evaluation
 Thorough Hx and PE
 Microbiologic examinations of blood, catheter entry site
discharge
 Laboratory examinations:
 Baseline CXR
 Blood chemistries
Febrile Neutropenia
What constitutes appropriate initial empirical
therapy?
Defect in Neutrophil Function
 Pathogens:
 S. aureus and CoNS
 Viridans strep and other streptococcal species
 Enterococcus spp.
 E. coli
 P. aeruginosa
 K. pneumoniae
 Enterobacter spp.
 Citrobacter spp.
 Anaerobes
 Fungi
IDSA (Infectious Disease Society of America) risk
criteria for fever and neutropenia
 High risk
 Neutropenia anticipated to
extend beyond 7 days
 Medical co-morbidities
 Hemodynamic instability
 Oral or GI mucositis dysphagia
 Abdominal or peri-rectal
pain
 Nausea/vomiting
 Diarrhea (6 loose stools
daily)
 Neurologic/mental status
changes
 Low risk
 Neutropenia expected
to resolve within 7 days
 Absence of any comorbidity listed in high
risk criteria
 Adequate hepatic and
renal function
IDSA (Infectious Disease Society of America) risk
criteria for fever and neutropenia
 High risk
 Medical co-morbidities
 Intravascular catheter
infection
 New pulmonary
infiltrate, hypoxemia or
underlying COPD
 Hepatic insufficiency
(aminotransferase levels
> 5x normal)
 Renal insufficiency
(creatinine clearance <
30 ml/min)
Initial empiric antibiotics: High risk
patients
 Monotherapy with an IV antipseudomonal ß-lactam: ceftazidime,
cefipime, imipenem, meropenem or piperacillin-tazobactam (AI)
 Ceftazidime may be a less reliable monotherapy
 PCN-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
patients
 Inpatient IV or oral antibiotics
 IV regimens as for high risk patients (AI) OR
 Oral 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.
Patient Follow-up
How should the initial therapy be modified?
Modification of initial therapy during the
first week
 Daily examination while febrile and neutropenic
 Modifications based on new findings
 Identified focus of infection
 Positive initial cultures - specific antibiotic
 Superinfections or breakthrough infections
 Clinical deterioration
Empiric antifungal therapy
 After 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;
Treatment Duration
How long should empirical antibiotic therapy be
continued?
Duration of empiric antibiotic therapy
 Documented 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)
 FUO
 ANC > 500/mm3 for at least one day with a rising trend; AND
 Patient is afebrile for at least 2 days (CIII)
Prevention of Infection
How do we prevent infection in the neutropenic
host?
Antimicrobial Prophylaxis
 Low risk
 Antibacterial, antifungal, antiviral not routinely
recommended (CIII)
 Prophylaxis for Pneumocystis carinii
 Mandatory for patients with ALL and for those
who are receiving glucocorticoid containing
chemotherapy regimen
Antibacterial prophylaxis
 High risk
 Ciprofloxacin or levofloxacin for patients with
expected duration of neutropenia > 7 days (AI)
 Antibiotic prophylaxis has been shown to reduce
 Febrile episodes
 Gram +/- bacteremias
 Use of empiric antibiotics without an increase in
antimicrobial resistance
Gafter-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 Prophylaxis
 High 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, GMCSF)
 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 Precautions
 No specific protective gear (gowns, gloves, masks) for routine care
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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 in
Transplant 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 host
 time after transplantation
 level of pharmacologic immunosuppression
 Often occur during the first 4-6 months
Factors that contribute to infection
after transplantation
 Pretransplant host factors
 Underlying medical condition
 Lack of specific immunity
 Prior colonization
 Prior latent infection
 Prior medications
 Transplantation factors - type of transplantation, surgical
stress
 Immunosuppression - therapy, infections
 Allograft reactions
Effects of Immunosuppresants
 Steroids
 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 Immunosuppresants
 Cyclosporine
  Generation of CD4 (T-helper cells)
  Proliferation of CD4 cells
  Production of cytotoxic T-cells from the precursors
 Mycophenolate mofetil
 Inhibits inosine monophosphate dehydrogenase
  Proliferation of B and T lymphocytes
Infections in bone marrow transplant recipients
Period after transplantation
Infection site
Early
(<1 month)
Disseminated
Bacteria (aerobic
gram -/+)
Skin and mucous HSV
membranes
Lungs
Middle
(1-4 months)
Bacteria (Nocardia,
actinomycosis)
Fungi (Candida,
Aspergillus)
Encapsulated
bacteria (S.
HHV 6
VZV
Bacteria (aerobic CMV, seasonal respiratory
gram -/+)
viruses
Candida,
Parasites (T. gondii)
Aspergillus, HSV Fungi (Pneumocystis)
GIT
CMV
Kidneys
BK virus, adenovirus
Brain
HHV-6
Late
(> 6 months)
pneumoniae, H.
influenzae, N.
meningitidis)
Pneumocystis
Viruses (BK)
Parasites (T. gondii)
Viruses (JC)
Infections in solid organ transplant recipients
VIRAL
CMV Onset
HSV
CMV chorioretinitis
EBV VZV PAPOVA ADENOVIRUS
FUNGAL TB PNEUMOCYSTIS
CNS
Listeria
Cryptococcus
BACTERIAL Aspergillus, Nocardia, Toxoplasma
Wound
Pneumonia
Line-related
HEPATITIS
Hep B
Non-A, Non-B Hep
UTI: BACTEREMIA, PYELITIS, RELAPSE
Transplant 1
2
3
4
UTI: BENIGN
5
6
MONTHS
Approach to suspected infection in a posttransplant patient
 Careful history and PE
 Focus of infection
 Diagnostic Work-up
 CXR
 Microbiologic studies
 CBC, LFTs, Renal Function tests
 Viral studies (CMV)
 Important to remember:
 Infections may occur without fever
 Not all fevers are due to infections
Diagnosis and Control of Infection
 Routine Lab Tests
 Before Transplantation
 CMV / EBV / HSV
/ VZV IgG
 Toxoplasma IgG
 Hep B screening
 Hep C ELISA
 HIV Ab
 PPD
 Stool for ova and
parasites
 After Transplantation
 Viral surveillance
 Antibody studies (as
indicated)
Prophylactic measures
 Immunization
 Passive
 CMV-specific Ig for seronegative renal transplants
 Active – inactivated vaccines
Prophylactic Agents
Pathogen
Protozoa
Toxoplasmosis
Viral
HSV
CMV
Fungal
Candida
Aspergillus
Pneumocystis
Bacterial
UTI
Neutropenic infection
TB
Pneumococcus
Prophylactic Agents
Pyrimethamine, TMP-SMX
Acyclovir
Acyclovir, Ig, Ganciclovir
Fluco, Nystatin, Clotrimazole
Ampho B
TMP-SMX
TMP-SMX
Quinolones
Isoniazid
Penicillin
ASPLENIA
 Postsplenectomy sepsis
 Rapid deterioration accompanied by CV collapse,
seizures, coma and DIC
 High mortality rate
 Diagnosis: Microbiologic exams of blood
 Microbiology: S. pneumoniae, H. influenzae, N.
meningitidis
 Appropriate antibiotics against these organisms
Prevention of Infection in Asplenic
Patients
 Patient education
 Vaccination - at least 2 weeks before elective surgery
Prophylactic antibiotics ?
 Spleen-sparing treatments
 Potential immunologic measures
 GM-CSF -  macrophage bactericidal activity
 Corynebacterium parvum – stimulates RES
HIV
 Antiretroviral therapy (HAART)
 Treatment of concurrent infections
 Prevention of opportunistic infections
 General isolation procedures
 Prophylactic antimicrobials
INFECTION
HIV initiates immunity loss
Immunity
HIV
Overt
AIDS
CD4 T cells
RNA
Anti-HIV
Anti-HIV
Fauci et al.
Disease and Pathogen
HIV causes immune deficiency. Other pathogen triggers death.
Events
 HIV infection
Pathogen
 HIV
 Loss of immunity
 Opportunistic infection
 Opportunistic cancer
 Death
 Many pathogens
other than HIV
Loss of immunity leads to
opportunistic infection/cancer
•
Fauci et al. Harrison‘s Principles of INTERNAL MED
HIV
 Clinical Category A
 Asymptomatic HIV infection
 Persistent generalized lymphadenopathy
 Acute (primary) HIV illness
HIV
 Clinical Category B
 Symptomatic, not A or C conditions
 Examples include (but not limited to):
 Bacillary angiomatosis
 Candidiasis, vulvovaginal; persistent > 1 month, poorly responsive to
treatment
 Candidiasis, oropharyngeal
 Cervical dysplasia, severe or carcinoma in situ
 Constitutional symptoms, e.g., fever (38.5oC) or diarrhea > 1 month
 Must be attributed to HIV infection or have a clinical course or
management complicated by HIV
HIV
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Clinical Category C
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Candidiasis, esophageal, trachea, bronhci
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Coccidioidomycosis, extrapulmonary
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Cryptococcosis, extrapulmonary
Cervical cancer, invasive
Cryptosporidiosis, chronic intestinal (> 1 

month)
CMV retinitis,or CMV in other than liver, 
spleen, nodes
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HIV encephalopathy
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Herpes simplex with mucocutaneous ulcer >
1 month, bronchitits, pneumonia
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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 level
 M. 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 qd
 CMV: 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
SUMMARY
 High index of suspicion
 Careful history and thorough PE
 Rigorous diagnostic tests
 Immediate institution of appropriate therapeutic interventions
 Adequate preventive measures