The Challenge Stem cell transplant/ Infectious differential is - - PDF document

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Infections in non-HIV Immunocompromised Hosts

Monica Fung, MD, MPH Assistant Clinical Professor UCSF Division of Infectious Diseases

Disclosures

I have nothing to disclose

Non-HIV Immunocompromised patients

Stem cell transplant/ Hematologic malignancy Organ transplantation Treatment for autoimmune diseases Treatment for solid tumors Acquired/genetic immune deficiencies Hyposplenism

The Challenge

Infectious differential is broad Clinical manifestations are often atypical Diagnostic tests are insensitive and slow Treatments have toxicity and drug interactions

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How does this differ from HIV patients?

HIV Non-HIV Immune defect Death of CD4+ T-cells Heterogeneous OI risk stratification CD4+ count No reliable tests available Cell‐ mediated immunity Humoral immunity Innate immunity

• Organ transplant
• Stem cell transplant
• TNF inhibitors
• Steroids
• Other IS Rx
• Rituximab (anti-CD20)
• Hyposplenism
• CVID (Low IgG)
• Cytotoxic chemotherapy
• Chronic granulomatous

disease (CGD)

Non-HIV Immunocompromised patients

Stem cell transplant/ Hematologic malignancy Organ transplantation Treatment for autoimmune diseases Treatment for solid tumors Acquired/genetic immune deficiencies Hyposplenism

The Spleen

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Clinically-important Pathogens

• Bacteria
• Streptococcus pneumoniae (pneumococcus)
• Haemophilus influenzae
• Neisseria meningitidis (meningococcus)
• Capnocytophaga
• Bordetella holmesii
• Parasites
• Babesia
• Malaria (P. falciparum)

ASPLENIA (complete loss of splenic function) HYPOSPLENISM (partial loss of splenic function)

• Iatrogenic
• Surgical removal
• Functional
• Sickle cell
• Congenitally absent
• Thalassemias
• Chronic liver disease
• HIV/AIDS
• Immune disorders
• Malignancy
• Disorders with atrophy,

infarction, engorgement, or infiltration of the spleen HOW CAN YOU TELL?

• Recurrent infections with incapsulated
• rganisms
• Howell-Jolly bodies
• Other laboratory evidence of splenic

dysfunction (low IgM memory B cells)

Asplenia/Hyposplenism and Infection

• Asplenic patients have increased risk infection, sepsis, and

sepsis-related mortality

• Cohort study of 8000 splenectomized patients
• 3.4 relative risk of sepsis
• 3.0 relative risk of sepsis-related mortality
• Increased risk sustained over 10 years (presumably lifelong)
• Similar risk presumed with asplenia/hyposplenism due to

disorders

• History of severe infection predisposes to additional episodes

Preventing Infections in Asplenic Patients

Vaccines Antibiotics Education

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Vaccines

• Streptococcus pneumoniae (pneumococcus)
• 13-valent pneumococcal conjugate vaccine (PCV13)
• 23-valent pneumococcal polysaccharide vaccine (PPSV23)*
• Haemophilus influenzae
• H. influenzae type b vaccine (Hib)
• Neisseria meningitidis (meningococcus)
• Quadrivalent meningococcal conjugate ACWY vaccine series (MenACWY)
• Monovalent meningococcal serogroup B vaccine series (MenB-4C or MenB-FHbp)
• Influenza
• Age-appropriate immunizations

* ≥8 weeks after PCV13; consider every 5 years

Vaccines

• Vaccines provide adequate protection in asplenic patients, but

response may be lower than in healthy individuals

• Timing of vaccines
• If possible, at least 2 weeks prior to splenectomy (ideally 10-12 weeks)
• If not prior to splenectomy, wait until 2 weeks after
• Other caveats
• Asplenia is not a contraindication to live vaccines
• Consider concurrent immunocompromising conditions (e.g. HIV,

malignancy)

Antibiotics

Daily PRN Who

• At least 1 year after splenectomy
• Concurrent

immunocompromising conditions

• History of sepsis caused by

encapsulated bacteria

• High local rates of resistant

pneumococcus

• Antibiotic intolerance

What

• Penicillin V 250mg PO BID
• Amoxicillin 500mg PO BID
• Cephalexin 250mg PO BID
• Azithromycin 250mg PO daily
• Amoxicillin-clavulanate

875mg/125mg PO BID

• Cefuroxime 500mg PO BID
• Levofloxacin 750mg PO daily
• Moxifloxacin 400mg PO daily

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Non-HIV Immunocompromised patients

Stem cell transplant/ Hematologic malignancy Organ transplantation Treatment for autoimmune diseases Treatment for solid tumors Acquired/genetic immune deficiencies Hyposplenism

TNF inhibition

• Rheumatoid arthritis
• Inflammatory bowel disease
• Psoriasis/psoriatic arthritis
• Sarcoidosis
• Uveitis
• Seronegative

spondyloarthropathies

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Granulomas

• Mycobacteria
• Fungi

TNF-⍺ inhibitors: Tuberculosis

• Post-marketing survey of TB cases following release
• f infliximab (1998-2001)
• 70 cases of TB
• Median time to diagnosis: 12 weeks (range 1-52)
• TB characteristics
• Extrapulmonary disease: 40/70 (57%)
• Disseminated disease: 17/70 (24%)

Keane J. NEJM. 2001

• In U.S., majority of TB cases due to TNF-⍺ inhibitors are reactivation
• Clinical history of TB risk
• Birthplace, residence, or prolonged travel (>3mo) to TB endemic area
• Living/working homeless shelter, jail, or prison
• Healthcare worker in facility with TB patients
• Contact with patient with active pulmonary TB

TNF-⍺ inhibitors: TB Screening

• More sensitive in

immunosuppressed patients

• Requires only 1 visit
• Improved specificity when

prior BCG vaccination

• Testing
• No TB risk: 1-stage with IGRA
• TB risk: 2-stage with IGRA followed by IGRA
• r TST if first test is negative
• Rescreening if ongoing TB risk
• All patients on TNF-⍺ inhibitors with latent TB should be treated
• Latent TB is diagnosed
• Positive IGRA or TST (≥5mm) without signs/symptoms of active TB (-CXR)
• Negative IGRA or TST, but prior history of latent TB
• Negative IGRA or TST with strong likelihood of prior TB exposure*

TNF-⍺ inhibitors: Latent TB Management

* Particularly if immunosuppressed at the time testing

• Treatment regimens
• INH for 9 months
• Rifampin for 4 months
• INH x Rifapentine weekly x12 weeks
• Timing of latent TB treatment
• No data on optimal interval: ? same time, ? delay 1-2 weeks

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• Prioritize (start immediately) active TB therapy
• What do do about TNF-⍺ inhibitor?
• STOP (at least temporarily)
• Safe timeframe to restart: Unclear but ? after susceptibility testing and

clinical improvement

• Disseminated TB: watch for IRIS due after stopping TNF-⍺

inhibitor (OR 11.4)

TNF-⍺ inhibitors: Active TB Management

TNF-⍺ inhibitors: Fungal Infections TNF-⍺ inhibitors: Fungal Infections

• Histoplasmosis
• 2008 FDA Alert:
• 240 cases in patients on TNF-⍺ inhibitors
• 21 with delayed diagnosis and antifungal therapy
• 12 fatal outcomes
• Concurrent methotrexate (44%) and prednisone

(34%) common

• Not as well characterized
• Coccidioidomycosis: incidence 2.8% over 5 years on infliximab, RR 5.2
• Cryptococcosis: 19 cases reported 1998-2002
• Aspergillosis: 39 cases reported 1998-2002
• Pneumocystis pneumonia: 84 cases reported 1998-2002

Fungal Pathogen Screening Histoplasmosis

Clinical history

• Travel to endemic regions
• High-risk activities (e.g. spelunking)
• Symptom check

CXR if suspicion for active disease or history

• f prior infection

Coccidioidomycosis

In endemic regions

• CXR
• Serology

Cryptococcosis

No specific recommendations

Aspergillosis

No specific recommendations

Pneumocystis

No specific recommendations

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• Other infectious contraindications to starting TNF-⍺ inhibitor
• Active bacterial infections
• Active herpes zoster infection
• Nonhealed infected skin ulcers
• Acute HBV or HCV
• Untreated chronic HBV infection
• Child-Pugh classes B or C chronic HBV or HCV
• Vaccines
• Pneumococcal vaccination: PCV13 & PPSV23
• No live vaccines!

TNF-⍺ inhibitors: Other considerations

Hepatitis B and Biologics

• Goal: prevent HBV reactivation
• Serologic status
• HBsAg+: active infection
• HBsAg-/HBcAb+: prior resolved

infection

• Immunosuppressing agent
• Rituximab (anti-CD20): reactivation

common

• TNF-⍺ inhibitors: reactivation

reported HBsAg+ HBsAg- HBcAb+ Anti- CD20 Very high Moderate TNF-⍺ inhibitor Moderate Very low

Hepatitis B and Biologics

HBV Risk Prevention Strategy Moderate to Very High risk

Antiviral therapy concurrent with immunosuppression

• Tenofovir
• Entecavir

Low and Very Low Risk

Monitoring for reactivation

• HBV viral load
• LFTs

Antiviral therapy if reactivation occurs

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JC Virus and Biologics

• JC virus
• Polyoma virus
• Asymptomatic primary infection in

childhood

• Progressive multifocal

leukoencephalopathy (PML)

• JC virus reactivation in the setting of

immunosuppression with spread to CNS

• Severe CNS demyelinating disease
• Treatment
• No directed antiviral therapy
• Restoring immune system

JC Virus and Biologics

Immunomodulatory Drug PML Risk Screening Natalizumab Incidence 4.2 per 1000 patients (24% fatal) Risk stratification

• JC virus IgG
• Prior immunosuppression
• Duration of natalizumab

JC virus IgG testing at baseline and after 1 year Baseline MRI Brain Rituximab Case reports No specific recommendations

Non-HIV Immunocompromised patients

Stem cell transplant/ Hematologic malignancy Organ transplantation Treatment for autoimmune diseases Treatment for solid tumors Acquired/genetic immune deficiencies Hyposplenism

5,000 10,000 15,000 20,000 25,000 30,000 35,000 1988 1991 1994 1997 2000 2003 2006 2009 2012 All Transplants Deceased Donor Living Donor

Solid organ transplants in the U.S.

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Depleting antibodies: Thymoglobulin, Campath IL-2 receptor blockers: Basiliximab Antimetabolites (Mycophenolate) Calcineurin inhibitors (Tacrolimus, Cyclosporine) Corticosteroids T‐cell costimulation blocker (Belatacept)

Immunosuppression to prevent rejection

Reactivation

INFECTION

Nosocomial Community-acquired Donor-derived Opportunistic Infections Emerging Pathogens Untransplanted tissue 1 2 3 4 5 6 7 8 9 10 11 12

Degree of immunosuppression Months post-transplant

Timing of infections post-transplant

NOSOCOMIAL TECHNICAL

OPPORTUNISTIC

COMMUNITY ACQUIRED CMV

Aspergillus PCP HSV VZV EBV Nocardia Listeria Toxoplasmosis Tuberculosis Cryptococcus Endemic mycoses

QUESTIONS?

Monica.Fung@ucsf.edu