Patient-reported outcomes of serum eye drops manufactured from Australian blood donations and packaged using Meise vials

Frontiers in Medicine 01 frontiersin.org

Patient-reported outcomes of

serum eye drops manufactured

from Australian blood donations

and packaged using Meise vials

Carley N.Gemelli

, PhillipMondy

, AthinaKakkos

JustineO’Donovan

, PerfectoDiaz

, ElizabethKnight

and

RenaHirani

2,3

Australian Red Cross Lifeblood, Melbourne, VIC, Australia,

Australian Red Cross Lifeblood, Sydney,

NSW, Australia,

Faculty of Science and Engineering, Macquarie University, Sydney, NSW, Australia

Introduction: Serum eye drops (SED) are an eective treatment for dry eye

syndrome. However, autologous serum collection can have challenges. Patient-

tailored (allogeneic) SED (PT-SED) can be made from healthy blood donors.

Australian Red Cross Lifeblood has manufactured both autologous SED (Auto-

SED) and PT-SED and, in May 2021, introduced Meise vial packaging. This study

aimed to explore SED patient-reported outcomes and vial packaging satisfaction.

Methods: A prospective cohort study was conducted with recruitment

between 1 November 2021 and 30 June 2022. Participants completed the dry

eye questionnaire (DEQ5), health-related quality-of-life (SF-8™), functional

assessment of chronic illness therapy-treatment satisfaction-general (FACIT-

TS-G), and general wellbeing surveys. Existing patients completed these once,

and new patients were surveyed at baseline, 3 months post-treatment, and

6 months post-treatment.

Results: Participants who completed all study requirements were 24 existing

and 40 new Auto-SED and 10 existing and 8 new PT-SED patients. Auto-SED

patients were younger [56.2 (±14.7) years] than PT-SED patients [71.4 (±10.0)

years]. Participants used a mean of 1.8 (±1.1) SED, 5.3 (±2.9) times per day. In new

patients, DEQ5 scores improved within 6 months from 14.0 (±2.9) to 10.6 (±3.4)

for Auto-SED and from 12.9 (±3.7) to 11.4 (±2.8) for PT-SED. General wellbeing

measures improved in the new Auto-SED from 7.0 (±1.9) to 7.8 (±1.7) but were

reduced for new PT-SED from 6.7 (±2.9) to 6.1 (±2.9).

Discussion: SED improved dry eye symptoms in most patients, regardless of the

serum source. Patients using PT-SED showed decreases in some quality-of-life

measures; however, recruitment was reduced due to operational constraints, and

concurrent comorbidities were not assessed. General feedback for SED and vial

packaging was positive, with some improvements identiﬁed.

KEYWORDS

blood donation, serum eye drops, transfusion medicine, dry eye, blood

OPEN ACCESS

EDITED BY

Michele Lanza,

University of Campania Luigi Vanvitelli, Italy

REVIEWED BY

José-María Sánchez-González,

Sevilla University, Spain

Michael Thiel,

University of Lucerne, Switzerland

*CORRESPONDENCE

Rena Hirani

[email protected]

RECEIVED 04 July 2023

ACCEPTED 17 August 2023

PUBLISHED 05 September 2023

CITATION

Gemelli CN, Mondy P, Kakkos A, O’Donovan J,

Diaz P, Knight E and Hirani R (2023) Patient-

reported outcomes of serum eye drops

manufactured from Australian blood donations

and packaged using Meise vials.

Front. Med. 10:1252688.

doi: 10.3389/fmed.2023.1252688

Diaz, Knight and Hirani. This is an open-access

article distributed under the terms of the

Creative Commons Attribution License (CC BY).

The use, distribution or reproduction in other

forums is permitted, provided the original

author(s) and the copyright owner(s) are

credited and that the original publication in this

journal is cited, in accordance with accepted

academic practice. No use, distribution or

reproduction is permitted which does not

comply with these terms.

TYPE Original Research

PUBLISHED 05 September 2023

DOI 10.3389/fmed.2023.1252688

Gemelli et al. 10.3389/fmed.2023.1252688

Frontiers in Medicine 02 frontiersin.org

1. Introduction

Severe dry eye disease (also known as dry eye syndrome or

keratoconjunctivitis sicca) is a commonly diagnosed condition and,

within a summary of international prevalence, is noted to aect up to

50% of patients referred to ophthalmologists (1). Dry eye is caused by

the inability to produce enough tears for lubrication or tear

evaporation, resulting in severe quality of life challenges for the

aected person (2, 3). Dry eye is mostly found in older women and

has a range of potential causes, including hormonal changes; medical

conditions, such as autoimmune conditions or rheumatological

diseases; medications; and environment. However, depending on the

denition of dry eye that is used, it is becoming more commonly

reported and is linked with the use of computers and other screen

technologies (4, 5). In Australia, vision problems are reported to aect

9.4% of Australians aged over 55 years (6).

ere are a number of available treatments and surgical

interventions, such as preservative-free ocular lubricants, punctal

occlusion, night-time ointment or moisture goggles, therapeutic

contact lenses, topical anti-inammatory medications (corticosteroids

and cyclosporine), or oral antibiotics (macrolide or tetracycline).

However, one well-tolerated treatment is serum eye drops (SED),

which are reported to have few side eects, including slight eye

irritation, burning, and tearing with the potential for an increased risk

of infection if the eye drop vessel is not handled as directed (7–16).

SED are made by separating the serum from the cellular

components of whole blood (WB) and can bemade from a patient’s

own blood donation (autologous) or using blood donations from

healthy volunteers (allogeneic). SED manufacturing procedures are

not standard internationally and dier between blood collection

agencies, pathology clinics, and other providers. SED manufacture can

dier in the amount of WB collected, concentration, type of diluent,

and packaging systems (17). ese dierences can make eective

comparisons of patient outcomes following the use of SED more

challenging and impact the understanding of which proteins or

growth factors are vital for the most eective SED composition.

In Australia, Australian Red Cross Lifeblood (Lifeblood) is the

national provider of fresh blood and blood products manufactured

from blood donations made by voluntary, non-remunerated donors.

Currently, Lifeblood manufactures both autologous serum eye drops

(Auto-SED) and patient-tailored (allogenic) serum eye drops

(PT-SED) diluted to a concentration of 20% in 0.9% saline. Following

manufacture, SED components are transported using dry-ice to an

approved health provider (AHP) close to the patient’s home, and

patients are notied to collect them. Auto-SED patients receive a

12 months supply, and PT-SED patients receive a 6 months supply,

which are stored by the patients in domestic freezers. Both sources of

SED have a 12 months expiration date following manufacture. Once

opened, SED users are asked to dispose of vials at the end of the day.

For SED provision, patients must have a referral from a consultant

ophthalmologist where there is a reasonable expectation of therapeutic

benet. Suitability for Auto-SED collection is dependent on the

patient meeting general blood donation eligibility criteria, having

reasonable venous access, and having the ability to tolerate

venesection. Prior to the COVID-19 pandemic, blood collection for

Auto-SED was conducted via a Lifeblood blood donation centre or, in

particular cases, using selected AHPs. PT-SED are a desirable

alternative for cases where patients are unable to donate due to poor

venous access, have comorbidities preventing donation, or have

mobility/geographical restrictions, and they also enable the ability to

streamline manufacturing processes (18). As a result of the COVID-19

pandemic in 2020, health service restrictions prevented the collection

of autologous donations from patients within AHPs, and PT-SED

production increased.

Furthermore in May 2020, Lifeblood introduced Meise vial (Meise

Medizintechnik GmbH) packaging for SED (Figure1). Prior to this,

SED were packaged using segmented plastic tubing (Macopharma

VSE4001XK tubing set) (19). e introduction of closed vials is

known to improve eciencies in SED manufacture and assist patients

in the administration of SED onto the ocular surface (20). e

previous segments were reported to bedicult to open, as they had

to becut open with scissors and were dicult to squeeze to get the

drops out. ey were also labour-intensive to manufacture, as they

required manual heat sealing to produce a single-dose segment length

(17). e vials are easier to open, as they have a twist cap, can

berecapped and stored for the day, and are already segmented into

vials, making them more ecient to manufacture. Furthermore, using

vial packaging did not aect the stability of SED composition (19, 20).

Previous studies have shown that Auto-SED has sustained benets

for dry eye in Australian patients (14). However, there are limited

standardised studies on the eectiveness of comparing Auto-SED and

PT-SED, especially for patients who have been swapped between SED

types. One Netherlands study did indicate that autologous and

allogeneic SED have comparable ecacy and tolerability (18).

In this study, weexplore both Auto-SED and PT-SED patient

group perspectives on the eectiveness of SED products on their eye

symptoms and quality of life using standardised dry eye and quality

of life surveys. Views from all SED patients were also explored on the

vial packaging.

FIGURE1

Photograph of the original tubing segments (top) used for serum eye

drops and the Meise vials (bottom) introduced in May 2021.

Gemelli et al. 10.3389/fmed.2023.1252688

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2. Methods

e study was reviewed and approved by the Australian Red Cross

Lifeblood Human Research Ethics Committee (HREC) (Mondy

21092021). e study was conducted in accordance with the National

Health and Medical Research Council’s National Statement on Ethical

Conduct in Human Research (2007, updated 2018).

2.1. Patient enrolment

Eligible SED patients between 1 November 2021 and 30 June

2022, over 18 years of age, who were able to provide written informed

consent and were not current Lifeblood sta members, were identied

through the National Blood Management System (NBMS)

administered by Lifeblood. Potential participants were screened by a

research study nurse to determine study eligibility. Once eligible,

patients were invited to participate in the study via email or postal

letter. Following participant consent, links to the survey were sent, and

data were collected via the online web platform Qualtrics (Qualtrics,

Provo, UT). If a valid email address was not available or if the

participant requested it, paper-based surveys were sent to the recorded

postal address. Participants were also able to complete the surveys

with research team assistance over the telephone if they requested so.

When there was no response, participants received a reminder email

within 10 days. Follow-up telephone calls were also conducted if no

response had been received 2 weeks aer initial contact. If participants

asked for the survey to becompleted via telephone, a research sta

member would read out the questions and complete the form on

Qualtrics. Any feedback provided outside of the survey questions was

not recorded to ensure that the feedback was the same as for

participants who completed the survey online or via paper-

based copies.

Auto-SED and PT-SED participants were divided into two groups:

those receiving the product for the rst time were classied as “New,”

while those who had received SED before this research study were

classied as “Existing.” e groups were identied before the

participant was invited to ensure that the correct survey tools were

provided. All patient research records were managed using REDCap

(Research Electronic Data Capture), a secure web platform supporting

data capture for research studies (21). A research study nurse veried

details regarding patient medications and clinical indications.

2.2. Survey and interview

Existing patients received only a single survey sent at the time

when their next allotment of SED was available. New patients received

surveys at baseline prior to SED treatment to establish a pre-treatment

measure. ey then received two follow-up surveys at 3months and

6months post-SED commencement. Survey questions were removed

or included depending on the timepoint as required to comment on

SED usage where appropriate. Brief outlines of each survey section are

provided below, with a detailed survey questions provided in

Supplementary Figure S1. e survey tools used were chosen because

they are well-reported, simple, and objectively standardised

measurement tools within the medical eld to measure patient-

reported outcomes. ey were chosen to determine not only whether

dry eye symptoms were reduced but also whether the relief of these

symptoms assisted patients with other general wellbeing measures and

provided insight into the wider health status of this patient group.

2.3. Dry eye questionnaire

e dry eye questionnaire (DEQ5) assesses a patient’s experience

of dry eye symptoms on a typical day over a month. Questions were

included to ascertain the severity and degree of eye discomfort, eye

dryness, and excessive wateriness. e ve measures are combined

into a total score ranging from 0 to 22, where the lower the score, the

less severe the symptoms (22).

2.4. Short form health survey

e short form health survey (SF-8™) is a shortened version of

the SF-36™ health survey and provides a generic assessment of

health-related quality of life in adults, including physical health and

functioning, role limitations, bodily pain, vitality, social functioning,

mental health, and emotional challenges (23, 24). Scores range from

0 to 100, with higher totals indicating better health.

2.5. General wellbeing

e National Eye Institute visual function questionnaire (NEI-

VFQ-25) captures vision and health-related quality of life and is one

of the most commonly implemented patient-reported outcomes in

ophthalmology research (25). For this study, two items from the

NEI-VFQ-25 have been used to describe the current level of wellbeing

and distress. Specically, these are “I amoen irritable because of my

eyesight” and “I do not go out of my home alone, because of my

eyesight.” Scores ranged from 2 to 10, with a higher score indicating a

greater level of wellbeing experienced.

2.6. Functional assessment of chronic

illness therapy-treatment

satisfaction-general

e functional assessment of chronic illness therapy-treatment

satisfaction-general (FACIT-TS-G) version 4 measures a patient’s

satisfaction with the treatment they have been administered (26).

Patients are asked to rate the eectiveness of the treatment compared

to expectations, satisfaction with the treatment, physician evaluated

eects of the treatment, whether they would use the treatment again,

and recommendations to others. e responses are combined to

provide a score ranging from 0 to 25, with a higher score indicating

more satisfaction with the treatment.

2.7. Generic SED packaging and satisfaction

questions

SED treatment-related questions, frequency and volume of SED

use, and views on SED were also asked and are outlined in

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Supplementary Figure S2. Text from open elds within the survey was

analysed and coded for inclusion in relevant themes.

2.8. Qualitative interviews

Opt-in participation in a 30 min semi-structured, in-depth phone

interview was also conducted on up to ve selected individuals per

SED group (see Supplementary Figure S2 for a detailed question list).

e participants were invited to a qualitative interview at the time of

enrollment until up to ve individuals had been interviewed per

group. Topics included views on SED packaging, SED usage, and the

impact on quality of life. e interviews were recorded with consent

and transcribed by a contracted transcription service. Participants

received a token gi card to the value of AUD50 to recompense for

their time. Interview transcripts were analysed using an inductive

method, with some sections of the transcript coded.

2.9. Statistical method

Statistical analyses of the quantitative data were performed using

the statistical soware IBM SPSS (IBM SPSS Statistics 28.0; IBM

Corporation). Demographic and donation characteristics were

described by means (±SD) for continuous parametric variables,

medians (Med) [interquartile ranges (IQR)] for non-parametric

variables, and by totals (percentages) for categorical variables.

Independent t-tests were conducted to determine any univariate

means dierences between the timepoints for parametric data, and a

Wilcoxon signed-rank test was used for non-parametric variables.

Statistical signicance was determined as a two-tailed p-value

of ≤0.05.

3. Results

3.1. Patient demographics and dry eye

diagnosis

e number of patients who were provided SED during the study

period was 186, of which 144 were Auto-SED recipients and 42 were

PT-SED recipients. Six Auto-SED and two PT-SED patients did not

meet the study requirements; therefore, a total of 178 potential

participants were invited to participate in the study. Of these, 138 (55

existing and 83 new) were autologous recipients (74.2% of total

patients provided with Auto-SED), and 40 (17 existing and 23 new)

were patient-tailored (allogenic) recipients (95.2% of total patients

provided with PT-SED) (Figure2).

Of those invited, a total of 28 existing (50.9% of existing invited)

and 44 new (53.0% of new invited) Auto-SED patients and 10 existing

(58.8% of existing invited) and 12 new (52.2% of new invited) PT-SED

patients consented to participate in the study. However, participants

who completed all study requirements for analysis consisted of 24

existing (43.6% of existing invited) and 40 new (48.2% of new invited)

Auto-SED recipients (44.4% of total patients provided with Auto-

SED), 10 existing (58.8% of existing invited), and 8 new (34.8% of new

invited) PT-SED patients (42.9% of total patients provided with

PT-SED). Previous autologous SED patients that were now being

provided with PT-SED due to operational and manufacturing reasons

were combined with existing PT-SED patients to enable a more

robust analysis.

Table1 summarises the demographic and clinical indications for

SED requirements. e mean age of existing Auto-SED patients was

58.0 (±12.2) years and 55.1 (±16.0) years for new Auto-SED patients.

PT-SED patients were older than Auto-SED patients, with a mean age

of 70.7 (±11.5) years for existing patients and 72.3 (±8.7) years for new

patients. Most (82.8% for Auto-SED and 94.4% for PT-SED) of the

patients requiring SED were women. SED treatment was required due

to the diagnosis of Sjögren’s syndrome (51.6 and 61.1% for Auto-SED

and PT-SED, respectively). SED were also required for neurotrophic

corneal diagnosis in 17.2% of Auto-SED patients. Dry eye symptoms

were experienced for approximately 5 years or more, and nearly all

patients (82.8% Auto-SED and 88.9% PT-SED) had tried at least one

other treatment prior to SED. Existing Auto-SED patients had

symptoms longer than new Auto-SED patients [15.4 (±14.7) years and

4.9 (±5.5) years, respectively]. Existing PT-SED patients had

symptoms for a shorter time than new PT-SED patients [10.0 (±13.5)

years and 23.3 (±17.3) years, respectively].

3.2. Survey measures

DEQ5 measures were found to change signicantly in new

Auto-SED patients from baseline to 6 months post-treatment [14.0

(±2.9) to 10.6 (±3.4), p < 0.001] (Table2). Although not statistically

signicant in new PT-SED patients, the DEQ5 scores trended down

from baseline to 6 months post-treatment [12.9 (±3.7) to 11.4 (±2.8)],

indicating improvements for some patients. DEQ5 scores were similar

for existing Auto-SED and existing PT-SED at 12.7 (±2.7) and 12.9

(±3.3), respectively.

In new Auto-SED patients, the SF-8™ survey showed no

improvement from baseline to 6 months post-treatment [19.6 (±6.7)

to 18.7 (±6.0)]. In new PT-SED patients, the SF-8™ was slightly

improved at 6 months post-treatment, but this was not signicant

[26.3 (±9.5) to 29.3 (±7.7), p = 0.39]. Overall, for existing patients, the

SF-8™ score was higher for PT-SED users than for Auto-SED users.

General wellbeing improved for new Auto-SED users 6 months

post-SED treatment [7.0 (±1.9) to 7.8 (±1.7), p = 0.002] but not for

new PT-SED users [6.7 (±2.9) to 6.1 (±2.9), p = 0.36]. Overall, the

wellbeing score was higher for existing Auto-SED patients than for

existing PT-SED patients [7.1 (±2.1) and 6.4 (±2.3)].

e FACIT-TS-G surveys did show a slight improvement in new

Auto-SED patients 6 months post-treatment [16.4 (±5.8) to 17.6

(±5.3)] but was not improved in new PT-SED patients [20.1 (±4.1) to

18.4 (±4.6)]. Overall, the FACIT-TS-G surveys were similar between

existing Auto-SED and existing PT-SED patients [21.5 (±3.8) and 19.2

(±4.6)].

3.3. Serum eye drop usage and patient

comments

e number of times SED were used per day and the number of

drops each time were similar between Auto-SED and PT-SED users

with approximately two drops used up to six times per day (Table3).

Notably, 1 to 1.5 vials were used per day. Up to four vials were

Gemelli et al. 10.3389/fmed.2023.1252688

Frontiers in Medicine 05 frontiersin.org

discarded due to damage. Up to 180 vials were reported to bediscarded

due to expiration dates being reached.

Many patients indicated positive sentiments towards their SED

treatment, with many comments indicating that they were considered

“life-changing.”

“It helps me quite a lot because Ihave a lot of eye complications, so

the eyedrops really help my eyes feel comfortable. Because Ihad such

dry eyes that, when Iwould blink, it felt like there were rocks in my

eyes, that’s how weird and dry they were but the eyedrops really,

really help. In fact, Ihave scarring on my corneas, and it turns out

that the serum eyedrops seem to have helped heal that scarring, just

a little bit, so that’s been very pleasant.”

“Prior to using the drops my morning vision for up to 3 h aer

waking was poor. About 3 weeks aer commencing the drops

(miraculously) my morning vision was restored to normal. is has

had a huge positive impact on my life. In addition, my vision

generally has improved such that Ihave less need for reading glasses.

Truly, these drops have helped me enormously and

Iamvery grateful!”

“Serum drops have been life-changing for me. I have multiple

autoimmune conditions and in the last year or more Ihave reacted

badly to every eyedrop that Itried… both over the counter and

prescription. (I also react badly to any oral medications Ihave to

use for my dry mouth). With the serum drops, all the nasty

symptoms of dry eye have eased. I am extremely grateful.

ank you!”

e packaging was well liked, and most feedback was to provide

options to help patients travel with the SED while frozen. Due to

Autologous SED recipients

invited to participate

following assessment of

inclusion criteria

Existing (n = 55)

New(n = 83)

Emailedinvite (n = 138)

Paper survey requested

(n = 6)

Phone assistance

requested(n= 3)

Allocation

Patient-tailored SED

recipients invited to

participate following

assessment of inclusion

criteria

Existing (n = 17)

New (n = 23)

Emailedinvite (n = 40)

Paper survey requested

(n = 22)

Completed baseline

(n = 42)

Completed 3-mth

(n = 40)

Completed 6-mth

(n = 40)

Analysis

New Auto-SED

(n = 44)

Existing Auto-SED

(n = 28)

New PT-SED

(n = 12)

Existing PT-SED

(n = 10)

Survey

completion and

Follow up

Completed baseline

(n = 25)

Completed baseline

(n = 10)

Survey results analysed

(n = 24)

Interviewed

(n = 5)

Excluded from analysis/lost

to follow up/withdrew from

study

(n =4)

Completed baseline

(n = 12)

Completed 3-mth

(n = 11)

Completed 6-mth

(n = 8)

Consented

Survey results analysed

(n = 40)

Interviewed

(n = 5)

Excluded from analysis/lost

to follow up/withdrew from

study

(n =4)

Survey results analysed

(n = 10)

Interviewed

(n = 4)

Excluded from analysis/lost

to follow up/withdrew from

study

(n =0)

Survey results analysed

(n = 8)

Interviewed

(n = 4)

Excluded from analysis/lost

to follow up/withdrew from

study

(n =4)

FIGURE2

Consort diagram of patient enrolment and completion of study requirements.

Gemelli et al. 10.3389/fmed.2023.1252688

Frontiers in Medicine 06 frontiersin.org

natural disasters in Australia, some patients reported that storing SED

during that time was challenging.

e new packaging, which wehave had—I do not know—the last

year, or maybe two; it’s really great. It’s much easier to use than the

old straw… (When asked what they liked) at Ido not have to

sterilise them. And that youcan just snap the top o and use them,

put the lid back on and youare done.

If Igo out somewhere, youcannot take them (Meise vials) with you.

Youcannot take them with youwithout going to a lot of trouble, so

Ijust take over-the-counter eye drops to see me through during

the day.

… I just nd when Ihave used them at room temperature, Ijust nd

them a bit ineective, so Igure, well I’m not going to (take them

out)—it’s too problematic to travel with them that they need to stay

frozen, so no… Even just outings Iwill not take them with.

For overseas Ihave to get a licence to travel with (SED)—because

it’s human blood, youhave to get a special clearance for that, and

Idid not know about that. So… I was unable to travel with them

because Idid not get the clearance in time… I just did not know to

travel with them because Idid not know how to keep them cold on

the ight… When Icalled up my airline, they told me that Ineeded

a special clearance.

I got ooded in February, and Ihad one box le at home—I had two

boxes at work, luckily—and Itook them to the evac(uation) centre

and they had a freezer there that was on a generator, because there

was no power… By the time Igot to the next place they’d all thawed

out, but Irefroze them and Iused them anyway, and Idid not have

any problems. It’s because Iwas desperate… (My eyes were) really

badly irritated from having no sleep and being—probably rubbing

them, aer being in the funky ood water. ey were the worst I’ve

ever had them…

4. Discussion

is study aimed to determine the eectiveness of serum eye

drops in Australian recipients using standardised surveys and

evaluate the patient experience with a vial packaging system that had

TABLE1 Demographics of consented serum eye drop users enrolled.

Autologous patients Patient-tailored

Existing (n= 24) New (n= 40) Existing (n= 10) New (n= 8)

Age (mean ± SD) 58.0 (±12.2) 55.1 (±16.0) 70.7 (±11.5) 72.3 (±8.7)

Gender [n (% of cohort

total)]

Male 4 (16.7) 7 (17.5) 0 (0.0) 1 (12.5)

Female 20 (83.3) 33 (82.5) 10 (100.0) 7 (87.5)

Prior auto donations (mean ± SD) 4.0 (±3.7) 0 (0.0) — —

Clinical indications resulting in dry eye

syndrome [n (% of the cohort total)]

Acute management of corneal injuries 2 (8.3) 1 (2.5) 0 (0.0) 0 (0.0)

Blepharitis and conjunctivochalasis 0 (0.0) 1 (2.5) 0 (0.0) 0 (0.0)

Gra vs. host 1 (4.2) 0 (0.0) 0 (0.0) 1 (12.5)

Inherited ocular surface disease 1 (4.2) 6 (15.0) 0 (0.0) 0 (0.0)

Neurotrophic cornea 5 (20.8) 6 (15.0) 0 (0.0) 2 (25.0)

Ocular mucous 0 1 (2.5) 0 (0.0) 0 (0.0)

Sjögrens syndrome 10 (41.7) 23 (57.5) 7 (70.0) 4 (50.0)

Stevens–Johnson syndrome 2 (8.3) 1 (2.5) 0 (0.0) 0 (0.0)

Supportive 0 2 (5.0) 0 (0.0) 1 (12.5)

Other 4 (16.7) 2 (5.0) 3 (30.0) 2 (25.0)

Number of years with symptoms (mean ± SD) 15.4 (±14.7) 4.9 (±5.5) 10.0 (±13.5) 23.3 (±17.3)

Currently or previously used at least one other

treatment [n (% of cohort total)]

22 (91.7) 31 (77.5) 8 (80.0) 8 (100.0)

Articial tears 19 (79.2) 26 (65.0) 7 (70.0) 7 (87.5)

Topical anti-inammatory drops 17 (70.8) 27 (67.5) 5 (50.0) 6 (75.0)

Tear retention therapies 16 (66.7) 23 (57.5) 6 (60.0) 2 (25.0)

Other 15 (62.5) 18 (45.0) 6 (60.0) 1 (12.5)

Multiple selections could have been made.

Gemelli et al. 10.3389/fmed.2023.1252688

Frontiers in Medicine 07 frontiersin.org

TABLE2 Survey score totals from each group of serum eye drop (SED) users.

Survey

(mean ± SD)

Autologous serum eye drop patients Patient-tailored serum eye drop patients

Existing

(n= 24)

New

(n= 40)

New

3 months

post-SED

Change

when

compared

to baseline

(p-value)

New

6 months

post-SED

Change

when

compared

to baseline

(p-value)

Existing

(n= 10)

New

(n= 8)

New

3 months

post-SED

Change

when

compared

to baseline

(p-value)

New

6 months

post-SED

Change

when

compared

to baseline

(p-value)

DEQ5 discomfort 3.0 (±0.8) 3.4 (±0.7) 2.8 (±0.8) <0.001

2.4 (±0.8) <0.001

3.2 (±1.0) 2.8 (±1.3) 2.3 (±1.2) 0.45 2.8 (±0.7) 1.00

DEQ5 intensity of

discomfort

2.8 (±0.8) 3.1 (±0.8) 2.4 (±1.1) <0.001

2.4 (±1.0) <0.001

2.9 (±1.0) 2.7 (±1.0) 2.0 (±1.1) 0.14 2.0 (±1.4) 0.23

DEQ5 dry 3.0 (±1.0) 3.3 (±0.8) 2.7 (±0.9) <0.001

2.6 (±0.8) <0.001

2.7 (±1.4) 2.9 (±1.1) 2.1 (±0.8) 0.08 2.6 (±0.7) 0.45

DEQ5 intensity of

dryness

3.0 (±0.7) 3.1 (±0.9) 2.4 (±1.1) <0.001

2.3 (±0.9) <0.001

2.9 (±1.4) 3.0 (±0.9) 2.0 (±1.3) 0.07 2.4 (±1.2) 0.18

DEQ5 watery 1.0 (±0.9) 1.1 (±1.1) 1.3 (±1.2) 0.42 1.0 (±1.1) 0.28 1.2 (±1.4) 1.3 (±1.3) 1.1 (±1.5) 0.83 1.6 (±1.3) 0.40

DEQ5 total 12.7 (±2.7) 14.0 (±2.9) 11.5 (±3.7) <0.001

10.6 (±3.4) <0.001

12.9 (±3.3) 12.9 (±3.7) 9.5 (±5.0) 0.10 11.4 (±2.8) 0.32

SF-8™ total

19.5 (±8.1) 19.6 (±6.7) 19.2 (±6.8) 0.59 18.7 (±6.0) 0.33 26.1 (±6.6) 26.3 (±9.5) 25.4 (±9.3) 0.68 29.3 (±7.7) 0.39

General wellbeing

total

7.1 (±2.1) 7.0 (±1.9) 7.5 (±2.0) 0.10 7.8 (±1.7) 0.002

6.4 (±2.3) 6.7 (±2.9) 7.3 (±2.8) 0.92 6.1 (±2.9) 0.36

FACIT-TS-G total 21.5 (±3.8) — 16.4 (±5.8) — 17.6 (±5.3) 0.05

19.2 (±4.6) — 20.1 (±4.1) — 18.4 (±4.6) 0.66

DEQ5, dry eye questionnaire (DEQ5); SF-8™, 2.4 short form health survey; FACIT-TS-G, functional assessment of chronic illness therapy-treatment satisfaction-general.

Two-tailed p-value ≤0.05 is considered signicant.

Gemelli et al. 10.3389/fmed.2023.1252688

Frontiers in Medicine 08 frontiersin.org

been recently implemented. DEQ5 was an eective tool for

measuring dry eye symptoms in patients and we found that for all

patients their dry eye symptoms had reduced in severity aer using

SED, regardless of whether Auto-SED or PT-SED were used. Only

two (2.0%) patients across both cohorts could not use SED or had

adverse reactions. is nding is similar to previously published

studies on SED related outcomes and appears to beconsistent with

whether autologous or allogeneic SED were administered (9, 11, 12,

14, 18, 27).

DEQ5 is a reliable and quick tool to measure SED impact on dry

eye, and we feel this could be routinely used for monitoring

eectiveness in patients who are new to SED treatment (22). e other

survey tools analysing health, wellbeing, and distress were not as

suitable for assessing SED outcomes as there were disparate responses

across users. Disparate ndings were likely due to PT-SED patients

being signicantly older than patients using Auto-SED. erefore,

PT-SED patients may have more associated comorbidities, in addition

to dry eye syndrome, that aect their overall wellbeing. Information

on associated comorbidities and symptom burden for SED users

during the study period was not obtained; therefore, it was challenging

to compare the wellbeing outcomes associated with SED to those that

were extraneous.

Strength of this study was the use of objective, standardised

surveys and following some patients from before SED was applied to

6 months post-treatment. For many SED users, improvements were

gained within 3 months of SED use. Limitations included the lack of

information on comorbidities that may have impacted the overall

wellbeing of the patients. While information on co-treatments was

collected, the regime of these treatments when used in conjunction

with SED was not provided in detail and would not beuseful for any

future studies. ere was also limited recruitment of PT-SED users as

a result of regulatory submissions and operational constraints

following the SARS-CoV-2 pandemic impacting SED production

during the study recruitment period. Further to disruptions caused by

SARS-CoV-2, the study period was additionally impacted by large

geographical areas of Australia experiencing extreme weather events,

such as ooding, that impacted SED users’ distress and wellbeing.

Data biases from telephone interviews were reduced where possible

by using standardised tools and questions. However, some variations

are possible, especially in older patients, where they may bemore

positive when they are able to discuss the survey questions with a

researcher. Existing patients were used to having SED, so their views

on eectiveness may have been diminished. However, their views on

the new vial packaging are particularly valuable, as these patients

would have been exposed to both the new vials and had used

segmented tubing previously. Wechose to assess these patients in

conjunction with new SED users, to determine whether the vial

packaging was preferred.

e use of vial packaging was strongly supported, but there were

challenges identied. Some indicated that too much serum volume

was being discarded from daily vials as the vial volumes were larger

than the previously used segmented tubing. Some patients indicated

challenges with opening the vials due to arthritis and other

comorbidities aecting ne motor skills. Other patients were

frustrated by the lack of solutions to allow travel while keeping the

vials at the appropriate cold storage requirements. However, despite

these, the vials were strongly supported, and overall use of SED,

whether Auto-SED or PT-SED, was seen positively by the patients.

Further to the limited information on patient-reported

outcomes following SED use, there is also limited information on

whether donor factors aect batches of SED that could inuence the

eect on patients (19, 28). Despite this, SED, whether autologous or

patient-tailored, have been shown to beeective and generally well-

tolerated, conrming the ndings of other studies. Using tools such

as DEQ5 routinely to allow regular standardised measures of

associated symptoms and track sustained improvements can

bevaluable. Overall, this cohort of SED users indicated that their

dry eye symptoms were signicantly reduced regardless of the

source of the drops provided and that vial packaging did improve

the patient treatment experience.

Data availability statement

e raw data supporting the conclusions of this article will

bemade available by the authors, without undue reservation.

TABLE3 Summarised results of serum eye drop (SED)-related use and discard.

SED-related

outcome

(mean ± SD)

Autologous serum eye drop patients Patient-tailored serum eye drop patients

Existing

(n= 24)

New 3 months

post-SED

(n= 40)

New 6 months

post-SED

Existing

(n= 10)

New 3 months

post-SED

(n= 8)

New 6 months

post-SED

Use per day (times) 5.2 (±2.2) 5.5 (±3.2) 5.3 (±4.1) 6.0 (±3.8) 3.9 (±1.7) 4.5 (±2.5)

How many drops each

time

2.1 (±1.1) 1.7 (±1.0) 1.9 (±1.7) 2.1 (±1.5) 1.7 (±1.0) 2.1 (±1.3)

How many vials used per

day

1.5 (±1.0) 1.0 (±0.3) 1.1 (±0.4) 1.5 (±0.8) 1.5 (±0.5) 1.1 (±0.4)

How many vials

disposed of due to

damage

1.3 (±1.0) 2.3 (±1.9) 4.0 (±2.2) 1.0

0.0

2.0

How many vials

disposed of due to expiry

37.6 (±27.0) 8.0 (±0.0) 5.0 (±2.8) 180.0

3.0

0.0

Only one patient provided discard information.

Gemelli et al. 10.3389/fmed.2023.1252688

Frontiers in Medicine 09 frontiersin.org

Ethics statement

e studies involving humans were approved by Australian Red

Cross Lifeblood Human Research Ethics Committee. e studies were

conducted in accordance with the local legislation and institutional

requirements. e participants provided their written informed

consent to participate in this study.

Author contributions

PM conceptualised the study. CG, AK, JO’D, and PD performed

project administration, data collection, data analysis, and study

interviews. RH supervised the study, analysed data, designed tables/

gures, and wrote the manuscript. CG, PM, AK, JO’D, PD, EK, and

RH contributed to data interpretation, literature searches/review,

study protocol writing, study design, review of the manuscript, and

had access to the data to assess and verify study results. All authors

contributed to the article and approved the submitted version.

Funding

Australian governments fund Australian Red Cross Lifeblood to

provide blood, blood products and services to the Australian

community.

Acknowledgments

We would like to thank Australian blood donors who provide

blood and blood products for the community to enable this study.

We thank all of the recipients of serum eye drops who participated

in this study. We also thank Rebecca Camenzuli, Grace Davies,

Miriam Hydon, and Kosta ompson who provided study

administration support. Andrew Farrar, Tegan Diep, Lifeblood

Pathology and Clinical Governance administration team, and

Lifeblood Clinical Nurse Advisors for support in patient

identication and SED manufacture support. And we also thank

Abby Edwards who assisted with interviews and Catherine Willis

who assisted with detailed process mapping of serum eye drop

manufacture and distribution.

Conﬂict of interest

e authors declare that the research was conducted in the

absence of any commercial or nancial relationships that could

beconstrued as a potential conict of interest.

Publisher’s note

All claims expressed in this article are solely those of the authors

and do not necessarily represent those of their aliated

organizations, or those of the publisher, the editors and the

reviewers. Any product that may be evaluated in this article, or

claim that may be made by its manufacturer, is not guaranteed or

endorsed by the publisher.

Supplementary material

e Supplementary material for this article can befound online

at: https://www.frontiersin.org/articles/10.3389/fmed.2023.1252688/

full#supplementary-material

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