5/9/2015 Disclosures None Infection in the (non-HIV) - - PDF document

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5/9/2015 Disclosures None Infection in the (non-HIV) - - PDF document

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5/9/2015 Disclosures None Infection in the (non-HIV) Immunocompromised Patient Critical Care Medicine May 2015 Jennifer Babik, MD, PhD Assistant Clinical Professor Division of Infectious Diseases, UCSF Outline Case #1 Infectious

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5/9/2015 1

Infection in the (non-HIV) Immunocompromised Patient

Jennifer Babik, MD, PhD Assistant Clinical Professor Division of Infectious Diseases, UCSF

Critical Care Medicine May 2015

Disclosures

  • None

Outline

  • Infectious Risk in Different Types of Immunosuppression
  • Approach to Pulmonary Infections in the

Immunocompromised Host

  • Infections in the Solid Organ Transplant Recipient
  • Infections in Patient Taking TNF Antagonists

Case #1

72 year old woman with microscopic polyangiitis on prednisone 20mg daily is admitted with 2 days of productive cough and shortness of breath. She rapidly deteriorates and is intubated for hypoxemic respiratory failure. Data: WBC 5.6 LDH 409 Beta-D-glucan >500

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Your empiric antibiotic regimen should include:

  • 1. Ganciclovir
  • 2. Voriconazole
  • 3. TMP-SMX
  • 4. Liposomal amphotericin

General Principles of Immunocompromised Host ID

  • 1. Patients can present without overt signs of infection

(e.g. afebrile, normal WBC count)

  • 2. Patients can get very sick, very fast
  • 3. Threshold for more aggressive diagnostics (imaging,

invasive procedures) and for empiric therapy should be lower

  • 4. The kind of immunocompromise matters – i.e. what

kind of infections is the patient at risk for?

Common States of Immunosuppression

  • Neutropenia
  • Hypogammaglobulinemia
  • Asplenia
  • Cell-mediated immunity dysfunction
  • HIV
  • Solid organ transplantation
  • Stem cell transplantation
  • Autoimmune disorders
  • TNF-alpha inhibition and other biologic agents

Common States of Immunosuppression Can We Quantify Immunosuppression?

  • Infectious risk in HIV-negative patients is hard to

determine

  • HIV  Quantitative CD4 depletion (can measure)
  • Non-HIV immunosuppression  Qualitative CD4

dysfunction (no reliable way to measure this)

  • Are there surrogate markers we can use?
  • Underlying disorder
  • Immunosuppressive drugs: duration and dosage
  • Other OIs

Kowalski, Clin Transplantation, 2003.

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Infectious Risk of Different Immune Defects

Immune Defect Bacteria TB/ NTM Endemic mycoses Molds PCP Herpes viruses HBV Neutropenia +++ + + ++ +/- + ++ HypoIgG ++ Asplenia ++ Cell-mediated immunity + ++ ++ +++ +++ +++ +++ TNF-inhibition + +++ +++ + Rituximab +++

Slide courtesy of B Schwartz

STEROIDS

Approach to Pulmonary Infections in ICH

  • What is the degree/cause of immunosuppression?
  • What is the pattern of the pulmonary infiltrates?
  • What is the tempo of the pulmonary symptoms?

Pattern of Pulmonary Infiltrates

  • Segmental/lobar:
  • Common bacterial pathogens
  • Legionella
  • Nodules:
  • Cryptococcus, Histoplasma, Coccidioides
  • Aspergillus, Zygomyces
  • Nocardia
  • Mycobacteria
  • Malignancy
  • Diffuse:
  • PCP
  • CMV
  • Respiratory viruses (e.g. influenza, RSV, adenovirus, parainfluenza,

metapneumovirus)

  • Drug-induced ALI

Tempo of Pulmonary Symptoms

  • Segmental/lobar:
  • Common bacterial pathogens Acute
  • Legionella Acute
  • Nodules:
  • Cryptococcus, Histoplasma, Coccidioides Subacute
  • Aspergillus, Zygomyces Subacute
  • Nocardia Subacute
  • Mycobacteria Subacute
  • Malignancy Subacute
  • Diffuse:
  • PCP Acute**
  • CMV Subacute
  • Respiratory viruses (e.g. influenza, RSV, adenovirus, parainfluenza,

metapneumovirus) Acute to Subacute

  • Drug-induced ALI Subacute
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PCP in HIV-negative Patients

HIV-positive HIV-negative

Clinical Subacute presentation (weeks) Survival >80% Acute (<1 week) Survival 50-90% Radiology Diffuse bilateral infiltrates Same Beta-D-Glucan 90-95 % sensitive 65-90% specific Same sensitivity 85-90% specific LDH 92-100% sensitive 25-85% specific 64-100% sensitive Same specificity BAL Microscopy >90% sensitive (high organism burden) 62-85% sensitive (low organism burden)

de Boer, J Infect 2011. Tasaka, Chest 2007. Oren, Am J Med Sci 2011. Tia, Clin Microbiol Infect 2011. Vogel, Swiss Med Weekly

  • 2011. Tasaka, J Infect Chemother 2012. Sepkowitz, CID 2002.

68 y/o woman s/p cadaveric renal transplant 5 weeks ago (CMV D+R-) is brought to the ED with progressive shortness

  • f breath over 1 week and

rapidly requires intubation. She had been induced with thymoglobulin and is now taking mycophenolate, tacrolimus, and prednisone.

Case #2 The Most Likely Diagnosis is:

  • 1. CMV
  • 2. Aspergillus
  • 3. Rhizopus
  • 4. S. aureus

Case #2: Diagnosis

KOH stain Gram stain Lactophenol cotton blue stain on culture

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The Effects of Thymoglobulin Last For:

  • 1. 1 week
  • 2. 3 months
  • 3. 6 months
  • 4. >12 months

How to Approach Infectious Risk Post-Transplant

  • Organ type
  • Timing after transplant
  • Induction regimen (if within ~1 year of transplant)
  • Maintenance regimen and doses
  • Augmented immunosuppression because of

rejection?

  • Other OIs?

Timing of Immunosuppression in SOT

Wiesner and Fung, Liver Transplant 2011.

Degree of Immune Suppression Risk of Infection Nosocomial, Technical, Donor-derived

OPPORTUNISTIC COMMUNITY ACQUIRED

1 2 3 4 5 6 7 8 9 10 11 12

Degree of immunosuppression Months post-transplant

Classic Timeline of Infections Post-transplant

  • Opportunistic Infections
  • Anastomotic complications
  • Reactivation of latent infections
  • Cdiff
  • Community-acquired infections
  • Late viral infections or OIs (especially

if  immunosuppression)

  • Cdiff
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Types of Immunosuppression in SOT

  • 1. Methylprednisolone
  • 1. +/- Anti-lymphocyte Ab
  • Thymoglobulin
  • (Alemtuzumab)
  • Basiliximab

Induction Maintenance Rejection

  • 1. Calcineurin inhibitor
  • Tacrolimus > Cyclosporine
  • 2. Antiproliferative
  • MMF > Azathioprine
  • 3. Prednisone
  • 4. Others:
  • Sirolimus
  • 1. Methylprednisolone
  • 1. +/- Anti-lymphocyte Ab
  • Thymoglobulin
  • Alemtuzumab
  • 2. +/- Others
  • Sirolimus
  • Rituximab

Induction Maintenance

Steroid

Antibody

Liver Methylpred None Tacrolimus Mycophenolate Prednisone Renal Methylpred Basiliximab, Thymo,

  • r None

Tacrolimus Mycophenolate Prednisone Lung Methylpred Basiliximab >> Thymoglobulin Tacrolimus Mycophenolate Prednisone Heart Methylpred Thymoglobulin Tacrolimus Mycophenolate Prednisone

UCSF Examples of Induction/Maintenance Infectious Risk in Solid Organ Transplant

Immune Defect Bacteria TB/ NTM Endemic mycoses Molds PCP Herpes viruses HBV Neutropenia +++ + + ++ +/- + ++ HypoIgG ++ Asplenia ++ Cell-mediated immunity + ++ ++ +++ +++ +++ +++ TNF-inhibition + +++ +++ + Rituximab +++

Slide courtesy of B Schwartz

Lymphoctye Antibodies for Induction

Antithymocyte globulin

  • Rabbit polyclonal IgG against T

and B cells

  • Depleting Ab: effect lasts >1 year
  • Also used in refractory rejection
  • Increases risk for many infections

(including viral, PCP, fungal)

Basiliximab

  • Anti-CD25: inhibits IL-2 binding

and T cell proliferation

  • Non-depleting Ab: effect lasts 4-6

weeks

  • Lower potency, less infectious

risk – used for lower risk recipients

Halloran, NEJM 2004. Issa and Fishman, CID 2009.

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Duration of Lymphocyte Depletion: Thymoglobulin

Brennan, Transpl Proc 1999.

Normal Range of ALC

Infectious Risk of Maintenance Drugs

  • Most drugs studied together  hard to assign individual risk
  • Calcineurin Inhibitors (tacrolimus, cyclosporine):  risk viruses (CMV), PCP
  • Antiproliferatives (mycophenolate, azathioprine): risk viruses (CMV, VZV)
  • Prednisone: Dose-dependent risk for wide range of infections
  • The drugs together put SOT recipients at risk for a wide range of

infections (bacterial, fungal, viral, parasitic)

Halloran, NEJM 2004. Thomas et al, Am J Transplant 2009. Singh, Curr Opin ID 2005. Husain and Singh, CID 2002. Ritter et al, Transpl ID 2009.

Meta-Analysis of Glucocorticoids and Infection

  • 63 studies in RA patients, significant heterogeneity
  • Dose dependent risk:
  • <5mg/day

RR 1.37

  • 5-10mg/day

RR 1.93

  • 10-20mg/day

RR 2.97

  • >20mg/day

RR 4.30

Dixon et al, Arthr Res Ther 2011.

Case #3

A 55 y/o man with RA on infliximab and low dose MTX x 9 months presents with 4 weeks

  • f severe fatigue, weight loss,

and multiple painful skin lesions. On admission his vtials are: 39˚C, HR 125, BP 85/50, RR20, SaO2 92% RA. He is admitted to the ICU. He had immigrated to the US from Mexico at the age of 45 and now lives in Fresno.

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The infliximab puts him at high risk for:

  • 1. Tuberculosis
  • 2. Coccidioidomycosis
  • 3. Histoplasmosis
  • 4. All of the above

Case #3: Diagnosis

Skin biopsy positive for Coccidioides 1 out of 4 blood cultures positive for Coccidioides Cocci immunodiffusion positive Cocci comp fix titer 1:256

TNF Antagonists

Wallis, ID Clinics NA 2011.

Soluble TNF receptor Anti-TNF Antibodies (Embrel) (Remicade) (Humira, Simponi) (Cimzia)

TNF Antagonists and Granulomatous Infections

  •  the risk of granulomatous infections by ~5 fold:
  • TB
  • Histoplasma
  • Coccidioides
  • Agents interfere with new granuloma formation and

weaken the integrity of existing granulomas

Wallis, ID Clinics NA 2011.

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5/9/2015 9

TNF Antagonists and Granulomatous Infections

  • TB infection
  • Usually occurs within 3-6 months after starting therapy
  • Thought to be reactivation of latent disease given

clustering of cases early after starting therapy

  • Coccidioidomycosis
  • Cases cluster at 3 and 10 months (likely a split of

reactivation and acute infection)

  • 25% have disseminated disease

Wallis, ID Clinics NA 2011. Keyser, Curr Rheum Rev 2011. Kourbeti et al, CID 2014. Novosad and Winthrop, CID 2014. Smith and Kauffman, Drugs 2009. Winthrop and Chiller, Nat Rev Rhematol 2009.

TNF Antagonists: Not All the Same

  • Risk with infliximab, adalimumab is ~2-7 fold higher than

with etanercept

  • Infliximab and adalimumab have:
  • Higher peak and steady state levels
  • More binding sites for TNF
  • Can cause Ab-mediated cytotoxicty of monocytes and T cells
  • This may lead to a more prolonged and/or robust TNF

inhibition in conjunction with effector cell death

Wallis et al, CID 2004. Wallis, ID Clinics NA 2011.

TNF Antagonists and Other Infections

  • Bacterial infections:
  • Septic arthritis
  • Legionella
  • Listeria
  • Salmonella
  • NTM
  • Viral:
  • HBV reactivation
  • Herpes zoster?
  • PML
  • Other fungal: crypto, candida, aspergillus, PCP?

Wallis, ID Clinics NA 2011. Keyser, Curr Rheum Rev 2011. Bodro and Paterson, CID 2013. Winthrop et al, JAMA 2013.

Take Home Points

  • Always define the specific type of immunocompromise

to better delineate infectious risk

  • For pulmonary infections, consider the pattern of

infiltrates and tempo of symptoms

  • For SOT patients, always check which induction agent

the patient received and remember that thymoglobulin lasts for >1 year

  • TNF antagonists increase the risk for TB and the endemic

mycoses, and the risk is much higher with infliximab and adalimumab

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Thank You

  • Questions?