autologous serum eye drops€¦ · learning objectives review the current indications for, the...
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Autologous Serum Eye Drops
Jeffrey S. Jhang, MD
System Director, Blood Bank and Transfusion Services
Mount Sinai Health System
Associate Professor of Pathology
Icahn School of Medicine at Mount Sinai
AABB October 14, 2018
Disclosures
▶ Celularity Inc. (Contractor), Cedar Knolls, NJ
Learning Objectives
▶ Review the current indications for, the efficacy of, and the
complications of of autologous serum eye drops for dry eyes.
▶ Review the methods for manufacturing autologous serum eye drops.
▶ Appreciate the potential clinical impact and future research needed
to develop and utilize this products to best treat our patients.
Dry Eyes – Symptoms and Diagnosis
▶ Multifactorial disease of tears & ocular surface
1. Discomfort
– Stinging, burning, foreign body, or scratching sensation
– Dryness or irritation
– Light sensitivity
– Redness
– Crusting in or around eyes
2. Visual disturbance/blurred vision
– Difficulty with contact lenses or nighttime driving
3. Inflammation and potential damage to the
ocular surface
4. Increased tear osmolarity
K. Tsubota et al. Treatment of dry eye by autologous serum application in Sjögren’s syndrome. Br J Ophthalmol 1999;83:390–395
Tests
▶ Tear osmolarity
▶ Tear production (Schirmer’s test)
▶ Fluorescein clearance
▶ Tear-film break up time
▶ Ocular surface damage
tube.medchrome.com
epomedicine.com
Evaporative
▶ Wind, smoke or dry air
▶ Blinking less often (e.g. reading,
driving or staring at a computer)
▶ Eyelid problems (e.g. ectropion,
entropion)
Lack of Production (Keratoconjunctivitis sicca)
▶ Sjögren syndrome very common (“sicca
complex”)
▶ Diabetes
▶ Rheumatoid arthritis
▶ Systemic lupus erythematosis
▶ Age-related lacrimal dysfunction
▶ Hormonal changes (e.g. birth control,
thyroid disease)
▶ Drug side effects (e.g. antihistamines,
decongestants, diuretics, antidepressants)
▶ Surgical intervention (e.g. LASIK)
▶ Long-term contact lens use
Treatments
▶ Artificial tears is the mainstay of therapy
▶ Made of different electrolyte concentrations and osmolarity as well as the
presence of different preservatives and also viscosity
▶ Hyaluronate may be used as an additive
▶ Steroids
– long-term complications of increased intraocular pressure and cataracts
▶ Cyclosporine A
▶ Punctal plugs
▶ ASEs
Background Autologous serum eyedrops (ASE)
▶ Lacrimal substitute to provide something that
mimics natural tears
▶ Second-line therapy for dry eyes
▶ Natural tears are much more complex
– Water
– Salts
– Proteins
– lipids
– Growth factors
▶ Composition resemble those of tears with similar
concentrations except
▶ More vitamin A, lysozyme, TGF-b, fibronectin, IgA,
EGF and vitamin C than tears
Indications
▶ Sjögren syndrome
▶ Graft-versus-host disease s/p allogeneic bone marrow transplantation
▶ Neurotrophic keratitis
▶ Persistent epithelial defects
▶ Superior limbic keratoconjunctivitis
▶ s/p LASIK with dry eyes
Production
▶ No standards developed
▶ Unregulated in most states
▶ FDA does not regulate this product
▶ Manufacturing methods differ
▶ Different storage and administration standards
Serum Tubes – you can make this at home! (but don’t, please!)
https://www.youtube.com/watch?v=a62v6IQf4XE; Neal Matthews
Office Preparation
https://www.youtube.com/watch?v=_tjYfkOrS0w. Orange County LASIK surgeon
Segments – Prepare plasma
Fill tubing & Make Segments
BiomedDevice Col© System
Efficacy
• 28 eyes of 28 patients
• 2 dropped out
• Group 1:
• 15 (58%) chemical agents
• Group 2
• Chronic eye disease
22 +/- 15 weeks duration
F. Semeraro et al. BioMed Research International 2014
Efficacy in Sjögren’s syndrome
▶ 12 patients with Sjögren’s
syndrome
▶ treated with autologous serum
(diluted to 20% with sterile
saline) for 4 weeks
▶ EGF, vitamin A, and TGF-a were
well preserved for up to 1 month
in the refrigerator at 4°C and up
to 3 months in the freezer at
−20°C.
▶ Rose bengal and fluorescein
scores improved significantly from
the initial scores of 5.3 and 5.6 to
1.7 and 2.5 after 4 weeks,
respectively.
K. Tsubota et al. Treatment of dry eye by autologous serum
application in Sjögren’s syndrome. Br J Ophthalmol 1999;83:390–395
Complications
▶ Usually well-tolerated
▶ Bacterial conjunctivitis
▶ Eyelid eczema
▶ Scleral vasculitis and melting in RA
▶ Immunoglobulin depositius in cornea
▶ Corneal peripheral infiltrates
O. Thanathanee Cornea Volume 32, Number 8, August 2013
Bacterial Contamination
SC Leite et al. Bone Marrow Transplantation (2006) 38, 223–227
Bacterial Contamination
▶ Lysozyme and complement and
IgG may be bacteriostatic
R. Lagnado Br J Ophthalmol 2004;88:464–465
Thank you
▶ Donna Strauss and the New York Blood Center, New York, NY
▶ Faculty and Staff of the New York Eye and Ear Infirmary of Mount Sinai,
New York, NY
Seeking safe stool: Enabling access to
Universal Stool Banks
Pratik Panchal MD MPH
AABB 2018 | October 14th 2018
Disclosures
• Special advisor to OpenBiome
I am large,
I contain multitudes
Walt Whitman
What is stool transplant?
• Fecal microbiota transplantation (FMT) involves the transfer of full spectrum microbiotaTM stool from a healthy screened donor to a recipient with the aim of normalizing the perturbed gut microbiome associated with CDI.
• Bacteria from donors help outcompete C. difficile and patient reestablishes normal composition of flora in their GI tract
Mechanism of Action
Bakken et al., 2011
The Growing Threat of CDI
• 453,000 cases per year
• 20% rate of recurrence
• 29,300 deaths per year
• $4.8 billion per year in hospitalization & treatment
Lessa et al., 2015 Campbell et al., 2013Steiner et al., 2014Ma et al., 2018
History of stool transplant
• A 4th century Chinese researcher , Ge Hong, used ‘yellow soup’ to treat his patients with severe diarrhea.
• Dr. Ben Eisenman published first case series in 1950s
• Van Nood et al published first, landmark RCT of FMT for rCDI in 2013
Change in the regulatory landscape
July 15, 2013
Wellington Sun, MD
Director, Division of Vaccines and Related Product Applications
Office of Vaccines Research and Review
CBER
RM 2302
1451 Rockville Pike
Rockville, MD 20852
Re: Current Consensus Guidance on Donor Screening and Stool Testing for FMT
Dear Dr. Sun:
On behalf of the undersigned medical specialty societies, we thank you for the opportunity to
provide guidance on appropriate screening and stool testing of potential stool donors for Fecal
Microbiota Transplantation (FMT). Our consensus guidance on donor screening and stool
testing is attached as an addendum to this letter.
Our organizations are interested in collaborating with the FDA on establishing a protocol for
FMT that balances appropriate oversight of this effective, yet not fully understood, therapy with
reasonable access for patients with recurrent Clostridium difficile infection (CDI), for whom few
alternatives are available. We thank the FDA for the opportunity to provide our clinical input
and we look forward to further collaboration aimed at allowing appropriate access to FMT
therapy. Please contact Andres Rodriguez with any questions at 703-299-5146 or
Sincerely,
David Relman, MD, FIDSA Ronald J. Vender, MD, FACG
President – IDSA President – ACG
Anil K. Rustgi, MD, AGAF Kenneth K. Wang, MD, FASGE
President – AGA President - ASGE
Athos Bousvaros, MD
President - NASPGHAN
Guidelines
Stool donation most closely resembles the
blood donation model
Prior to fecal microbiota transplantation there were predominately two forms of tissue transplantation:
Table: Functional Comparison of Blood and HCT/Ps Donation ProgramsGreen: similar to stool donation; Red: different to stool donation
Blood Donation Human cells, tissues, and cellular and tissue-based products (HCT/Ps)
Supply Continuous On-demand
Indication Discrete Heterogeneous
Recipient Matched or unmatched Matched or unmatched
Collection Minimally invasive Invasive
Donor Alive Alive or cadaveric
Cadence Frequent One-off
Location Decentralized collection centers High-acuity procedure
Head-to-head comparison of regulatory
landscape of human tissue donation
Blood Donation Human cells, tissues, and cellular and tissue-based products (HCT/Ps)
Specifically named protections and services provided to them by clinically trained staff
Donors evaluated by ‘responsible persons’ with no explicit care requirements
Donor health and eligibility is monitored on a dynamic and time dependent scale
Donors health and eligibility is determined at a single point in time
Title 21 CFR 630-640 Requirements for blood and blood components intended for further manufacturing use
Title 21 CFR 1271 Human cells, tissues, and cellular and tissue-based products
Emphasis on donor eligibility and transplant safety, as well as welfare, treatment, and maintenance of donorhealth
Emphasis on donor eligibility and transplant safety, but no specific language about management of donor health
Randomized controlled trials show
FMT is efficacious across delivery modalities
Study Delivery N Clinical Cure Related SAEs
Van Nood et alNEJM 2013
Nasoduodenal 43 81% None
Lee et al JAMA 2016
Enema 232 84% None
Kelly et al Ann Intern Med 2016
Colonoscopy 46 91% None
FMT is more cost-effective than antibiotics
⎼ $1,699 (FMT) vs. $3,788 (vancomycin) according to one study
⎼ Insurance coverage varies, often procedures covered but not
necessarily material
Real-world data from OpenBiome show
FMT is efficacious across modalities
Osman et al., 2016
Allegretti et al., 2016
Barriers to Access
• Of the 330 physicians who did not offer FMT
• 80% reported difficulties with the logistics of preparation and/or delivery
• 45% cited the complexity and cost of donor screening
• A major physician barrier to FMT is preparation and material processing
Bakken et al 2014
Zipursky JS et al 2014
The Universal Stool Bank Model
Donor
Assessment
Stool &
Serological
Testing
• 208-point clinical
assessment
- 45-minute evaluation
by a physician or nurse
overseen by an
internal medicine
specialist
• Stool & serological testing
- 18 stool laboratory investigations
- 14 serological laboratory screens
• 16s microbiome sequencing
• Dual testing & continuous
monitoring
• Safety aliquots
• Process, storage & shipping
controls
• Traceability & quality
assurance program
1 Clinician orders fecal
preparations from a stool bank2 Stool bank provides
rigorously screened,
processed, frozen material
3 The clinician thaws
material and performs FMT
Monitoring &
Re-testing
16
OpenBiome’s Donor Safety Standards
1) Donor Registry
Potential donors answered a pre-
screen survey
Assess for most common reasons for exclusion
- Logistics
- Commitment
- Age
- BMI>30
- Birth country
- Travel history
- Antibiotic use
- Smoking
- Recent vaccination
2) Clinical Assessment
Qualified individuals completed an on-site
clinical assessment
- Transmissible infectious diseases
- Gastrointestinal conditions
- Atopic conditions
- Autoimmune conditions
- Chronic pain syndromes
- Metabolic conditions
- Neurological conditions
- Psychiatric conditions
- Malignancy history
- Medications
- Diet
- Family history
- Vital signs including BMI and waist circumference
3) Laboratory Investigation
Those who passed completed a comprehensive stool and serological
screening panel
Stool: Bacteria
Clostridium difficile, PCR
Salmonella/Campylobacter/
Shigella, Culture-based assay
Vibrio, Culture-based assay
Giardia, EIA
Helicobacter pylori, EIA
VRE, Culture-based assay
CRE, Culture-based assay
ESBL, Culture-based assay
Stool: Parasites
Cryptosporidium, EIA
Cyclospora / Isospora, Acid fast stain
Ova & Parasites, Microscopic exam
Microsporidia, Microscopic exam
Stool: Viruses
Norovirus, PCR
Adenovirus, EIA
Rotavirus, EIA
Nasal: MDRO
MRSA, Culture-based assay
Serological
HIV antibody, type 1 and 2
Hepatitis A (IgM)
Hepatitis B panel (HBsAg, anti-HBc [IgM and Total])
Hepatitis C (HCV antibody)
Treponema palladium, EIA
HTLV I &II
CBC with differential
Hepatic function panel
How is FMT prepared?
• Stool collected on-site in standardized collection kits
• Mixed with an inert cryo-preservative and filtered with microfilter to remove fiber (to ensure it doesn’t damage the scopes
• Homogenized
• Storage –80 deg C
• Transport –20 deg C
2013
0
500
1000
0.00
50.00
100.00
2013 2014 2015 2016 2017
% o
f To
tal U
S Po
pu
lati
on
1 Hour Drive Time
2 Hour Drive Time
4 Hour Drive TIme
No. of Hospital Partners
Drive Time(Hours)
% Population Coverage
1 6.51
2 10.83
4 25.37
Panchal et al. DDW 2018
2014
0
500
1000
0.00
50.00
100.00
2013 2014 2015 2016 2017
% o
f To
tal U
S Po
pu
lati
on
1 Hour Drive Time
2 Hour Drive Time
4 Hour Drive TIme
No. of Hospital Partners
Drive Time(Hours)
% Population Coverage
1 52.95
2 72.16
4 92.36
Panchal et al. DDW 2018
2015
0
500
1000
0.00
50.00
100.00
2013 2014 2015 2016 2017
% o
f To
tal U
S Po
pu
lati
on
1 Hour Drive Time
2 Hour Drive Time
4 Hour Drive TIme
No. of Hospital Partners
Drive Time(Hours)
% Population Coverage
1 77.91
2 92.73
4 98.74
Panchal et al. DDW 2018
2016
0
500
1000
0.00
50.00
100.00
2013 2014 2015 2016 2017
% o
f To
tal U
S Po
pu
lati
on
1 Hour Drive Time
2 Hour Drive Time
4 Hour Drive TIme
No. of Hospital Partners
Drive Time(Hours)
% Population Coverage
1 85.35
2 96.84
4 99.86
Panchal et al. DDW 2018
2017
0
500
1000
0.00
50.00
100.00
2013 2014 2015 2016 2017
% o
f To
tal U
S Po
pu
lati
on
1 Hour Drive Time
2 Hour Drive Time
4 Hour Drive TIme
No. of Hospital Partners
Drive Time(Hours)
% Population Coverage
1 87.54
2 97.74
4 99.89
Panchal et al. DDW 2018
Pediatric access to FMT
Drive Time
(hours)
% Population
Coverage
1 42.96
2 64.54
4 90.06
Panchal et al. IDWeek 2018
• In the US, unlike the adult population,
pediatric access to FMT has not been
universally adopted for rCDI.
• This is partially attributable to lack of a
landmark RCTs and pediatric consensus
guidelines
The disease paradigm has shifted away from infection to immune
mediated diseases
Bach NEJM 2002
Impact of a universal stool bank
• Access
• Safety
• Outcomes
• Research
What does the future look like?
Acknowledgements
• Bharat Ramakrishna
• Carolyn Edelstein
• The Neil & Anna Rasmussen Foundation and the Anna-Maria & Stephen Kellen Foundation.
Novel Banking Modalities: Human Milk
Banking, Fecal Microbiota
Transplantation, and Autologous
Serum Eye Drops
10/14/2018
Faculty Disclosures
The following faculty have no
relevant financial relationships to
disclose:
– Suzanne Arinsburg DO
– Jeffrey Jhang MD
The following faculty have a
relevant financial relationship:
– Pratik Panchal MD, MPH
Finch Therapeutics:
Consultant
www.aabb.org 2
Learning Objectives
• Recognize the current indications for the use of human donor milk, fecal microbiota, and autologous serum eye drops
• Advise clinical departments of the necessary steps needed to be taken to comply with federal, state, and volunteer organization standards
• Appreciate the potential clinical impact and future research needed to develop and utilize these products to best treat our patients
www.aabb.org 3
Volunteer Donor Breast Milk Banking
Suzanne A. Arinsburg, DO
Mount Sinai Hospital
• Financial Disclosures
– None
• Conflicts of Interest
– Medical Advisory Board of the New York Milk Bank –
Volunteer
www.aabb.org 2
Outline
• What is the evidence for donor milk?
• Who can donate milk?
• How is donor milk processed?
• How do I obtain donor milk?
• What are the regulations around donor milk?
www.aabb.org 3
What is the evidence for donor milk?
www.aabb.org 4
Background
• Feeding exclusively human milk consistently demonstrated to improve clinical outcomes in premature infants
• Evidence to support reduced risk of– Late onset sepsis
– Bronchopulmonary dysplasia
– Retinopathy of prematurity
– Improved neurodevelopment
• Decreased risk of necrotizing enterocolitis
www.aabb.org 5Quigley M, Embleton ND, McGuire W. Formula versus breast milk for Feeding Preterm or Low Birth Weight Infants (Review). Cochrane Library; 2018, 6.
Human Milk
• Highly bioavailable macro and micronutrients
• Immunomodulatory molecules (IgG, IgA, interleukins,..)
• Prebiotics
• Probiotics
Superiority of human milk compared to formula has led to
the use of donor human milk when mother’s milk is
unavailable or insufficient
www.aabb.org 6Quigley M, Embleton ND, McGuire W. Formula versus breast milk for Feeding Preterm or Low Birth Weight Infants (Review). Cochrane Library; 2018, 6.
Concerns
• Insufficient amount of protein, calories, and minerals
to support rapid growth
• May require the addition of fortifiers to support
optimal growth
www.aabb.org 7Quigley M, Embleton ND, McGuire W. Formula versus breast milk for Feeding Preterm or Low Birth Weight Infants (Review). Cochrane Library; 2018, 6.
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Endorsed by
• American Academy of Pediatrics
• World Health Organization
• Centers for Disease Control
• The Joint Commission
• Surgeon General Call to Action in 2011
• National Association of Neonatal Nurses
www.aabb.org 14
Who can donate breast milk?
www.aabb.org 15
Milk Donation
• Phone consultation
• Fill out a donor questionnaire
• Medical release forms to obtain information regarding the health of the mother and the baby
• Blood tests
• Education on pumping and milk storage
• Volunteer donors
www.aabb.org 16
Donor Testing
• HIV
• HCV
• HBV
• Syphilis
• HTLV
www.aabb.org 17
Exclusion Criteria
• Smoking or use of tobacco products
• Recreation drug use
• Travel restrictions
• Recent tattoo or piercing unless in a licensed facility
• Blood transfusion within past 6 months
• Certain medications
www.aabb.org 18
Delivery of Milk
• Brought to milk depots
• Coolers provided to ship milk
• Shipped frozen overnight
www.aabb.org 19https://littleheartsbiglove.co.uk/wp-content/uploads/2014/07/express-and-share-02.jpg
Types of Milk
• Colostrum
• Preterm - < 36 weeks gestation
• Term
• Mature > 1 year of age
• Research
• Kosher
www.aabb.org 20
How is breast milk processed?
www.aabb.org 21
Steps in Milk Processing
• Pouring
• Mixing
• Pooling
• Pasteurization
• Culture
• Quarantine
• Delivery
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Holder Pasteurization
• 62.5° C for 30 minutes
• Rapid cooling
• Cultured before distribution
• Quarantined for 48 hours
www.aabb.org 23Lafuente MC et al. A prospective analysis of intake and composition of mother’s own milk In preterm newborns less than 32 weeks’ gestational ge. Journal of Perinatology Medicine. 2018,aop/.
Effects of Pasteurization
Component Maintained >90% Maintained 50-90%
Maintained 10-50%
Abolished
Macronutrients Lactose, Oligosaccharides
ProteinFat
Micronutrients Ca, Cu, Mg, Phos, K, Na, Zn
Fe
Vitamins A Folate, B6, C
CD14, IL-2, Lactoferrin, Lysozyme
IgM, Lymphocytes
Biologically active mediators
IL-8, IL-12, IL13, TGF-⍺, Epidermal Growth Factor, Heparin Binding Growth Factor
Adiponectin, Amylase, Insulin
Erythropoietin, Hepatocyte Growth Factor
Bile salt dependent lipase, Lipoprotein lipase
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Factors Affecting Nutritional Content
• Preprocessing
– Stage of lactation
– Storage
– Containers
– Shipping
– Pooling
• Processing
• Post-processing
• Storage length
• Storage container
• Thawing
• Route of administration
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Processing and Delivery by NY Milk Bank
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Pouring, Mixing and Pooling
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Pasterization
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Testing, Freezing and Storage
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Milk Riders
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Obtaining Donor Milk
• State regulations – California, Texas, Maryland, New York and
New Jersey
• State license if needed
• Contract with either a volunteer donor milk bank or for profit
milk bank
• Develop policy and procedures including logs and consent
• Training and education of staff
www.aabb.org 39
Hospital Receipt and Storage of Donor Milk
• Delivery– Food and nutrition department
– Pharmacy
– NICU
• Inspection
• Designated freezer for frozen milk– Mother’s own milk
– Pasteurized donor milk
• Thawing– Expires at 48 hours post-thaw
www.aabb.org 40
Administration of Donor Milk
• Handled as a blood product
– Parental consent
– Order from a licensed practitioner
– 2 RN verification
– May be aliquoted
• Recorded in distribution log
• Must be tracked
www.aabb.org 41
What are the regulations around donor milk?
www.aabb.org 42
Human Milk Banking Association of North
America (HMBANA)• Accredit nonprofit volunteer donor milk banks in th US
and Canada
• Developed and set international guidelines for pasteurized human milk
• 27 current members:– 24 milk banks in the US
– 3 milk banks in Canada
– 6 developing milk banks
www.aabb.org 43
www.aabb.org 44https://www.hmbana.org/find-a-milk-bank/overview.html
www.aabb.org https://www.hmbana.org/news/blog.html/article/2018/03/14/nonprofit-donor-human-milk-distribution-reaches-record-high-in-2017
European Milk Bank Association
• Promote milk banking and the use of volunteer donor milk
• Cooperation between milk banks throughout Europe and Russia
• Establishment of guidelines
• 233 active milk banks with 14 additional planned banks
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Questions??
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