slides - UCSF Office of Continuing Medical Education

2/3/2014
Infection in the (non‐HIV) Immunocompromised Host
• No financial relationships to disclose
Brian S. Schwartz, MD
UCSF, Division of Infectious Diseases
Lecture outline
Lecture outline
• Background/why is this topic important?
• Background/why is this topic important?
• Solid organ transplantation
• Solid organ transplantation
• Heme malignancy/stem cell transplantation
• Heme malignancy/stem cell transplantation
• Biologics
• Biologics
A challenge: diagnosis and treatment of infection in the non‐HIV IS host? How is this different from HIV immunosuppressed patients?
HIV
1. Infectious DDx is broad
2. Clinical manifestations often atypical
3. Diagnostic tests are insensitive and slow
4. Treatments = toxicity & drug interactions
Non‐HIV
Immune defect
Death of
Heterogeneous
CD4+ T‐cells
OI risk stratification
CD4+ count
No reliable
tests available
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Does CD4 help in non‐HIV populations?
# CD4+ T‐cells
Median 815 (113‐2659)
2,500
2,000
Median 389 (10‐1904)
1,500
Will you be seeing any of these non‐HIV immunosuppressed patients?
1,000
500
0
SOT
Healthy Adults
Kowalski R. Clin Transplantation. 2003
Solid organ transplants in U.S. 1988‐
Stem cell transplants in the US:1988‐2010
2012
35,000
30,000
25,000
All Transplants
Deceased Donor
Living Donor
20,000
15,000
10,000
5,000
0
1988 1991 1994 1997 2000 2003 2006 2009 2012
http://optn.transplant.hrsa.gov/data/
Biologics are increasingly used for many autoimmune diseases
Some biologics used to treat autoimmune diseases
• Rheumatoid arthritis: 1.5 million • Inflammatory bowel disease: 1.4 million
• Psoriasis: 7.5 million
• New ones developed annually!
http://www.cdc.gov/arthritis/basics/rheumatoid.htm; http://www.cdc.gov/ibd/;
http://www.psoriasis.org/about-psoriasis
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Some biologics used to treat autoimmune diseases
Some biologics used to treat autoimmune diseases
Some biologics used to treat autoimmune diseases
Some biologics used to treat autoimmune diseases
Some biologics used to treat autoimmune diseases
Lecture outline
•
•
•
•
Background/why is this topic important?
Solid organ transplantation
Heme malignancy/stem cell transplantation
Biologics
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Immunosuppression in SOT
Depleting antibodies: Thymoglobulin, Campath
90
80
70
60
50
40
30
infection
20
rejection
10
0
1987
1990
1993
Years
1996
Degree of immunosuppression
% of SOT recipients hospitalized
Indication for hospitalization post‐transplantation
IL-2 receptor blockers: Basiliximab
Antimetabolites (Mycophenolate)
Calcineurin inhibitors (Tacrolimus, Cyclosporine)
Corticosteroids
T‐cell costimulation blocker (Belatacept)
1999
1
2
3
4
Dharnidharka VR. AJT. 04
Acquisition of infection to organ transplant recipients
Screening and
treatment of latent
infections
Environmental exposures
• Community vs. Nosocomial
• Opportunistic
7
Donor‐derived infections
• Bacteria
• Viruses
• Fungi
• Parasites
SOT: OI prophylaxis?
• PCP prophylaxis: all; 6 months‐life
• CMV prophylaxis: most; 3 months‐1 year
• Mold prophylaxis: lung, 3 months
OPPORTUNISTIC
NOSOCOMIAL, TECHNICAL
Prophylaxis
Degree of immunosuppression
Surgery‐related infection
• Obstruction and/or leaks
6
8
9
10
11
12
“Timeline” of infection post‐transplant
Treatment of rejection
1
Nocardia
Listeria
Toxoplasmosis
CMV
Aspergillus
Cryptococcus
PCP
Endemic mycoses
HSV VZV EBV
2
3
COMMUNITY ACQUIRED
Tuberculosis
4
5
6
7
8
9
10
11
12
Months post‐transplant
Impact of OI prophylaxis on the post‐
transplant “timeline”
Degree of immunosuppression
Reactivation of latent infections
• Herpesviruses
• TB
• Strongyloides
• Hepatitis B
5
Months post‐transplant
Ganciclovir TMP-SMX
Nocardia
CMV
Listeria
Voriconazole
Toxoplasmosis
Aspergillus
TMP-SMX
PCP
Ganciclovir
HSV VZV EBV
1
2
3
4
5
6
7
8
9
10
11
12
Months post‐transplant
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Case 1
• 65 year‐old Chinese woman 10 months post liver transplant presents w/ ear fullness and pain
• Diagnosed with mastoiditis by MRI
• Mastoid biopsy:
– Bacterial and fungal cultures: negative
– Path: lymphocytic inflammation with no granulomas, bacteria or fungi
Case 1: continued
• Patient was discharged with IV cefepime
What is your diagnosis?
A. Aspergillus fumigatus
• Readmitted with continued ear pain, fatigue
B. Candida albicans
• ID team evaluated the patient and ordered retesting of prior pathology specimens
C. Cefepime‐resistant Pseudomonas
D. Mucormycosis
E. Mycobacterium tuberculosis
Dx: Disseminated TB w/ mastoiditis
Why was the Dx missed on pathology?
• Pathologists did not stain for mycobacteria because there were no granulomas present
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Classic granuloma
in patient with TB
Our patient
Tuberculosis in SOT recipients
• Active TB Risk: > 25x risk vs. gen population
• At Dx‐ 30‐50% will have extrapulmonary disease
• Treatment complicated by drug interactions
• Attributable mortality 9.5‐20%
Singh N. CID. 1998, Torre-Cisneros J. CID. 2009
When do SOT recipients present with TB post‐transplant?
% of TB cases post‐transplant
90
Renal
80
Liver
70
Heart
60
Lung
50
Case 1: Summary
• Pathological (and clinical) manifestations of infection may be atypical in SOT recipients
• Risk of reactivation is >25 fold in SOT
• Treatment for LTBI pre‐transplant or early post‐transplant decreases risk of active TB
40
30
20
10
0
< 6 mo
6‐12 mo
>1 yr
Time post‐transplant at diagnosis
>2 yr
Singh N. CID. 1998
Case 2
Case 2
• 38 y/o F s/p renal transplant 8 mo ago presents with fever and cough progressive over 1 week • No improvement on levofloxacin x 7 days
Medications
• Tacrolimus
• Mycophenolate
• Prednisone 5 mg
• TMP‐SMX DS 3x/wk
• Exam: 39.4, 98, 122/87, 28, 94% on 4L NC
• General: Increased work of breathing • Lungs: scattered crackles
PMH
• Trisomy 21
• Congenital heart dz
• IgA nephropathy
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Case 2: Labs
• WBC: 2.5
• Hematocrit: 25
• Platelets: 75
• Cr: 1.7
• LFTs: WNL
DDx of bilateral ground glass opacities
• Infection
• Infection
– PCP
– Viral infection
– PCP
– Viral infection
• Edema
• Hemorrhage
• Interstitial lung diseases
• Edema
• Hemorrhage
• Interstitial lung diseases
Case 2: Results Our Infectious DDx
PCP
Resp virus
CMV
(flu, RSV, etc.)
Risk?
Yes
Yes
Yes
Pancytopenia?
No
Uncommon
Common
Yes
On prophylaxis?
Other
Empiric Rx?
DDx of ground glass opacities (GGO) on CT scan
No
No
Serum β,D‐glucan: negative
Season? yes
Donor CMV IgG+; recipient IgG‐
No
Oseltamivir
Ganciclovir
• Results:
– Resp virus PCR panel (nasal swab): negative
– CMV PCR blood: 930,000 copies/ml
• Rx: Ganciclovir IV for CMV pnemonitis
• Course
– WBC and platelets slowly normalized
– ICU for 2 weeks
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Diagnosis and treatment of CMV
Spectrum of CMV disease in SOT
• Diagnosis:
– CMV PCR serum (if low viral load consider other Dx)
– Biopsy of infected organ
Asymptomatic
viremia
“CMV syndrome”
• Fever/malaise
• Pancytopenia
• Treatment:
End-organ disease
•
•
•
•
– IV Ganciclovir or PO Valganciclovir
– Treat until PCR undetectable and at least 2‐3 weeks
– Secondary prophylaxis in select cases
GI disease (colitis)
Hepatitis
Pneumonitis
Rare (CNS, retinitis)
Case 2: take home points
• “Ground‐glass” on CT: PCP, CMV, resp virus
• CMV common post SOT, often “late‐onset”
• Fever, pancytopenia +/‐ end‐organ disease
Lecture outline
•
•
•
•
Background/why is this topic important?
Solid organ transplantation
Heme malignancy/stem cell transplantation
Biologics
• Dx: Serum CMV PCR (antigen) +/‐ tissue biopsy
• Rx: Ganciclovir (IV) or valganciclovir (PO)
Risk of infection in patients with hematological malignancies
• Underlying disease: – Hypogammaglobulinemia (MM and CLL)
– Neutropenia due to BM infiltration
• Treatment:
Chemotherapy induced neutropenia
Neutropenia + Mucositis +
Central venous catheters +
Prior antibiotic exposure
– Chemotherapy
– Stem cell transplant
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Neutropenia‐associated infections
• Bacterial pathogens
– Bacteremias (oral and GI flora)
– Typhlitis
– Pneumonia and CRBSI
Management of high‐risk, febrile neutropenic patient?
• Empiric therapy 1st (medical emergency): – Cefepime, carbapenem*, or pip‐tazo
– Add Vancomycin if CRBSI, SSTI, PNA, or critically ill
• Diagnostics: Pan‐culture and image
• Fungal infections
– Candidemia
– Aspergillus (if prolonged)
• No response to empiric therapy?
– Continue work‐up for source – Consider escalate antibiotics  add antifungal
• Viral infections
– HSV
*anti-pseudomonal carbapenem (aka not ertapenem)
Freifeld AG. Clin Infect Dis. 2011
Cell recovery and infection risk post stem cell transplant
Initial management of febrile stem cell transplant recipient?
120
Neutrophils
• Empiric therapy: NK cells
CD 8+
B‐cells
CD4+
– Empiric antibiotics based on likely source
• Diagnostics: – How far post‐transplant?
– GVHD?
– Specific signs/symptoms?
% of normal counts
100
80
60
40
Bacteremia
Candida
Aspergillus
HSV
CMV, VZV
PCP,
Molds
(OIs)
Encapsulated bacteria,
Respiratory viruses
20
0
Freifeld AG. Clin Infect Dis. 2011
Prevention of infection in patients with heme malignancy
• Bacterial infections:
– G‐CSF
– Antibacterial prophylaxis (levofloxacin in high‐risk)
• Fungal infections:
– Antifungal prophylaxis (candida, molds, PCP)
• Viral infections:
– Anti‐viral prophylaxis (Acyclovir for HSV/VZV)
– Preemptive monitoring (CMV)
0
4
8
12
16
20
24
28
32
Weeks post‐transplant
36
40
44
48
52
Mackall C. BMT.2009
Case 3
• 21 year‐old with refractory AML has been neutropenic for over 8 weeks and has been on prophylactic levofloxacin, fluconazole, and acyclovir
• He presents to clinic with 3 days of fatigue, mild cough, and pleuritic chest pain
• LABS: 0.9>33<31, ANC = 0.2
Freifeld AG. Clin Infect Dis. 2011
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Chest CT Chest X-ray: 3 months ago
Chest X-ray: Today
DDx of cavitary lung lesions
• Fungal:
– Molds: Aspergillus >>> mucormycosis
– Endemic mycoses: cocci, histo, etc.
• Bacterial: – Septic pulmonary emboli
– S. aureus, Gram negatives, Nocardia
• Mycobacteria: TB and NTM
Case 3: micro results
Aspergillus diagnostics (sensitivity)
• Galactomannan serum: 0.3 (normal <0.5)
• Biopsy: gold standard
• β‐D‐glucan serum: < 40 (normal < 40)
• Fungal cultures BAL: 25‐50%
• Bronchoscopy
– Bacterial culture: negative
– Mycobacterial: negative
– Fungal culture: negative
– Galactomannan: 10.1 (normal < 0.5)
• Galactomannan (aspergillus specific)
– Serum: 60% – BAL: 70‐95% • Beta‐D glucan (asperg, candida, PCP)
– Serum: 55‐95%
Pfeiffer CD. Clin Infect Dis. 2006; Maertens J. Clin Infect Dis. 2009; Muher B. J Clin Micro.
2004; Seghal B. Am J Respir Crit Care Med. 2006. Husain S. Clin Vaccine Immunol. 2008
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Treatment of invasive aspergillosis: Voriconazole vs. Ampho B
Galactomannan
Patients Surviving (%)
False positives
B‐D glucan
• Piperacillin‐tazobactam
• Amoxicillin‐clav acid
• Fungal cross‐reactivity •
•
•
•
IVIg
Albumin
Select HD filters
Gauze packing
Kędzierska A. Eur J Clin Microbiol Infect Dis. 2007
• Fungal testing limited sensitivity and specificity
• BAL GM has increased sensitivity for aspergillus
Ampho B group
P=0.02
Herbrecht R. NEJM. 2002
Case 3: take home points
• DDx for cavitary nodules: mold>bacteria> AFB
Voriconazole group
Lecture outline
•
•
•
•
Background/why is this topic important?
Solid organ transplantation
Heme malignancy/stem cell transplantation
Biologics (focus on TNF blockers)
• Biopsy is the gold standard for diagnosis
• Voriconazole is 1st‐line treatment of aspergillus
Granuloma
Granuloma post TNF inhibitor
Macrophages
TNF
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TNF inhibition in the treatment of septic shock
TNF inhibition
• Clinical scenarios
– Rheumatoid arthritis
– Inflammatory bowel disease
– Psoriasis/psoriatic arthritis
Fischer CJ. NEJM. 1996
TNF inhibitors used in clinical practice
• TNF‐alpha receptor fusion protein
– Etanercept (Enbrel)
• Fungal infections
– Infliximab (Remicade)
– Adalimumab (Humira)
– Certolizumab (Cemzia)
– Golimumab (Simponi)
• Viral infections
TNF inhib: hospitalization for serious infection
• Retrospective, 1998‐2007, rheum, derm, IBD
• Matched on disease score
• TNF inhib: etanercept, infliximab, adalimumab
All
TNF
8.16
Other IS
7.78 • Overall infection risk?
• Mycobacterial infections (TB)
• Anti‐TNF‐alpha antibody
Hospitalizations for serious infx/100 per yrs
TNF inhibitors and infection
Adjusted Hazard Ratio
TNF inhib: tuberculosis
• Post‐marketing survey of TB cases following release of infliximab (1998‐2001)
• 70 cases of TB
• Median time to diagnosis: 12 wks (range 1‐52)
• TB characteristics
1.05 [95% CI, 0.91‐1.21]
Grijalva CG. JAMA. 2011
– Extrapulmonary disease: 40/70 (57%)
– Disseminated disease: 17/70 (24%)
Keane J. NEJM. 2001
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TNF inhib: fungal infections
• Survey of serious infection on TNF inhib in U.S.
– Non‐tuberculous mycobacteria: 32
– Tuberculosis: 17
– Histoplasmosis: 56
• FDA Alert 2008: 256 cases of histoplasmosis in patients on TNF inhibitors
Case 4
• 43 y/o female with Crohn’s disease on infliximab (Remicade®) presents with 3 weeks of cough and fever. Works as a CPA in Bakersfield, CA. No pets.
• She received 1 week of moxifloxacin without improvement.
Winthrop KL. CID. 2008; http://www.fda.gov/Drugs/DrugSafety/
PostmarketDrugSafetyInformationforPatientsandProviders/ucm124185.htm
Which infections are in the DDx?
• Bacterial, mycobacterial, and endemic mycoses
• Cocci IgM/IgG sent
Coccidioides risk regions
– Negative • Now what?
http://updates.clltopics.org/
KOH stain from BAL fluid
Biologics and viral infections
• Hepatitis B reactivation – Reactivation with TNF inhibitors reported (rare)
– Rituximab (Rituxan®) ‐ common
• JC virus (progressive multifocal leukoencephalopathy)
Coccidioides immitis
– Natalizumab (Tysabri) – must check JCV IgG
– Rituximab (Rituxan®) – reports, less common
Serological testing can be insensitive in immunocompromised patients!
Blair J. Mycopathologia. 2006
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Evaluation prior to TNF inhibitor use?
• Evaluate for LTBI
– Check PPD or IGRA, CXR, take TB history
[email protected]
• Evaluate for recent endemic mycoses infection
– Take travel history, symptom check
• Evaluate for HBV
– Check hepatitis B surface antigen and core antibody
*Many images were obtained from the UCSF Microbiology Teaching Pictures Collection Furst D. Ann Rhuem Dis. 2011; Garden. Lancet ID. 2003
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