Impact of Covid‐19 on the therapeutic plasma exchange service within the South East Asian region: Consensus recommendations and global perspectives

1 INTRODUCTION 1.1 Problem statement

The Covid-19 pandemic has disrupted all countries, societies health care systems, and services. The degree of socio-economic and psychological impact varies by region and populations.1 In South East Asia (SEA) made up of 11 member countries with a population of over 600 million, the use of therapeutic plasma exchange (TPE) for both central and peripheral neuroimmunological disorders has been evolving and expanding rapidly over the last decade.2, 3 The South East Asian Therapeutic Plasma Exchange Consortium (SEATPEC) was established in 2018 to promote the clinical provision of education and research in TPE for neuroimmunological diseases regionally.2, 3 The Covid-19 pandemic poses unprecendented challenges for the development and expansion of this service.

However, the true impact of the pandemic on the delivery of hospital-based neuroimmunological TPE services is currently unknown within SEA. Preliminary reports from SEA suggest the redistribution of hospital and human resources to deal with the pandemic had led to temporary discontinuation of neurological TPE services in countries like Malaysia.5 Therefore, investigating the impact of the pandemic on all countries within SEA needs to be ascertained so that country-specific/regional strategies and recommendations can be developed to optimize TPE service delivery during the pandemic and for future health system disruptions.

There are many unknowns with regards to the safety of elective and urgent use of TPE during the pandemic; further short-term and long-term impact of TPE and its timing with the advent of universal vaccination also needs consideration. This uncertainty exists due to a lack of available guidelines on the conduct of TPE during the pandemic for neurological conditions regionally and globally. Consensus statements by organizations such as the European Academy of Neurology (EAN) and the American Academy of Neurology (AAN) suggest careful consideration when starting immune depleting/modifying agents balancing between the risks of Covid-19 infections and the need for treatment.6-8

Similarly, neurologists and regional experts in SEATPEC share concerns about the need for screening of patient's prior to TPE, modification of TPE protocols to ensure the safety of patient's and operators, timing to vaccinations as well as the use of this technology in the treatment of neuroimmunological conditions in Covid-19 patients. TPE and convalescent plasma has also been postulated as possible treatment options in mild to severe Covid-19 patients.4 To answer these questions, 25 clinicians and researchers from SEATPEC countries were engaged.

1.2 Objective

The primary objective of this study was to identify the challenges faced by regional TPE services including describing the adjustments and adaptations needed to minimize service interruptions during the Covid-19 pandemic. The adaptations and best practices amalgamated to form targeted recommendations based on consensus amongst SEATPEC neurologists.

Secondary objectives were to report SEATPEC neurologists experience on the conduct of TPE and occurrence of Covid-19 infections in post TPE patients on follow-up from real-world observations and to see if any developed a severe type of Covid-19.

1.3 Methodology

An explorative qualitative and semi-quantitative survey to study the impact of Covid-19 on TPE services within the SEA region was performed. The questionnaire was designed to address practical issues and explore several main themes experienced by TPE neurologists during the Covid-19 pandemic. The study was done in two phases; Phase 1 from 1st January to 30th June 2020 during the initial phase following the recognition of Covid-19 cases globally and the declaration of the pandemic by WHO and subsequently Phase 2 from 1st July to 31st January 2021 during the later phase of the ongoing pandemic.

The questionnaire was designed by a single Neurologist (SV) and administered to all neurologists who are members of SEATPEC. It comprised 12 questions in Phase 1, with Yes/No answers with explanations for the answers and 16 questions in Phase 2 with Yes/No answers and explanations where necessary. The survey was administered through email and a “Survey Monkey” web-based tool (see Questionnaires for Phase 1 and 2 of study under Supplementary files).

Ethical approval: This study was approved by the Medical Research and Ethics Committee (MREC), Ministry of Health Malaysia as part of retrospective and prospective cross sectional data collection on TPE and neuroimmunological diseases under the Demyelinating disease database (DDD)}: NMRR 11-1049-10 503.

1.4 Inclusion criteria Twenty-one neurologists from 11 SEA countries and one from a South Asian country were contacted as members of SEATPEC. All were working at major referral centers with large neurology services dealing with neuroimmunological diseases and TPE. Only neurologists who were performing TPE for neuroimmunological conditions on a routine basis with either a dedicated “in house team” or outsourced from the Hematology or Nephrology disciplines were included. 1.5 Exclusion criteria

Not a SEATPEC member and not actively prescribing or performing TPE.

1.5.1 Consent for participation

Verbal Consent through emails for the questionnaire-based interviews was obtained from all participating neurologist's prior to emailing the questionnaire/Survey monkey onwards.

1.5.2 Duration of study

All responses were obtained from 1 January 2020 to 31 January 2021.

1.5.3 Statistical analysis

Qualitative and semi-quantitative analysis was performed looking at absolute values and percentages.

2 RESULTS TABLE 1. Showing the total number of participating countries, neurologists, level of knowledge, and types of TPE used Parameter Phase 1 (Jan-June 2020) Number/percentage Phase 2 (July-Jan 2021) Number/percentage 1. Total number of participating countries/n = 12 9/12 (75%) 9/12 (75%) 2. Total number of participating neurologists/n = 21 14/21 (66.7%) 14/21 (66.7%) 3. Awareness of Global or regional guidelines on TPE conduct during Covid-19 pandemic: Yes/No

Yes: 0

No: 14/14 (100%)

Yes: 0

No: 14/14 (100%)

4. Type of TPE being done 4/9 (44%)  • Outsourced to Nephrology/Hematology departments 7/9* (56%) * (some who outsourced also did in house TPE) 5. Type of TPE technology  • Centrifuge technology 8/9 (89%)a  • Membrane technology 8/9 (89%)a 7/9 (78%)  • Other types: Small Volume Plasma exchange 2/9 (22%) Abbreviations: n, number; Jan, January; TPE, therapeutic plasma-exchange. a Some may be performing both centrifuge and membrane type of TPE with dedicated machines. TABLE 2. Showing the total number of Covid cases during Phase 1 and 2 of the pandemic with the mortality rates Country (ASEAN) Total no. of cases (Jan-June 2020) Mortality rates SEA (till June 2020) per million Total No of Cases (July-Jan 2021) Mortality rates, SEA (till 31 January 2021) per million Total cases Brunei 141 7 39 7.0 180 Cambodia 142 0 323 0 465 Indonesia 62 142 10.63 1 016 172 111.1 1 078 314 Laos 19 0 25 0 44 Malaysia 8658 3.88 206 301 22.98 214 959 Myanmar 313 0.11 139 832 0 140 145 Philippines 41 430 11.96 484 188 57.88 525 618 Singapore 44 664 4.63 14 872 5.17 59 536 Thailand 3190 0.84 15 592 1.1 18 782 Vietnam 346 0 1471 0 1817 image

Showing the number of participating countries and the number of neurologists who answered the survey

Respondent details and scope of practice: (see Tables 1 and 2; Figure 1).

The results of the Survey are shown below. The questionnaires/survey monkey were filled up by respondents from eight countries within the SEA region and a South Asian country giving a 75% positive country responder rate. Respondents from three remaining countries (7) were unable to contribute despite email invitations. Fourteen out of twenty-one neurologists (66.7%) approached, participated in the survey. There were three neurologists from Singapore, two each from Malaysia, Thailand, and Myanmar and one neurologist each from Laos, Indonesia, Vietnam, Philippines, and Bangladesh, respectively. All 14 respondents were adult neurologists working at major tertiary referral centers.

Awareness of Global, WHO, regional, or local generic guidelines prior to Survey:

Prior to the survey, all respondents acknowledged the lack of international or regional guidelines on the use of TPE during the pandemic for central and peripheral neuroimmunological disorders. All respondents were utilizing generic country-specific and WHO recommendations on preventive and precautionary measures modified to their local situation when dealing with possible or confirmed Covid-19 patients scheduled for elective or emergency TPE procedures.5-18 All adhered to TPE indications as per ASFA 201918 (Table 1).

From 1 January 2020 to 31 January 2021, the status of Covid-19 cases and mortality rates as reported from ASEAN countries is as shown in Table 2.19 There was a trend towards increasing number of cases and mortality rates in the latter half of the study. Postulated causes were human behavior with lack of observation of masking and social distancing in addition to relaxation of MCO's and increased human movement.8, 12, 19

For ease of review, the survey results are presented sequentially based on the questions and answers in the Questionnaire utilized for Phases 1 and 2 of the study (see Tables 3 and 4). TABLE 3. Results of the survey on health utilization, challenges of therapeutic plasma exchange during the Covid-19 pandemic and the impact of Sars CoV-2 on TPE services during Phases 1 (January 2020 to June 2020) and 2 (July 2020 to Jan 2021) of the pandemic Questions/respondents, n = 14 or countries, n = 9 Phase 1 Phase 2 1. Do you have Covid-19 cases at your hospital? Y/N Y: 14/14 (100%) Y: 14/14 (100%) 2. Is your hospital a Covid-19/Hybrid Covid-19 Hospital? Y/N Y: 11/14 (78.5%) Y: 14/14 (100%) 3. Are you a. (i) Still referring NID (Neuroimmunological disease) cases for TPE? Y/N Y: 14/14 (100%) Y: 14/14 (100%)  (ii) Conducting Virtual Consultation* for TPE Counseling? Y/N

Y: 2/9 (14.2%)

N: 7/9 (85.8%)

Y: 4/9 (28.5%)

N: 5/9 (71.5%)

(n, no. of countries) (For Question 3b and c: see Table 1) 4. Is there a drop/increase in TPE’s between 2019 vs 2020/21? a. TPE patient workloads reduced (electives/urgent) Y/N: Y: 14/14 (100%) Y: 14/14 (100%) b. Percentage reduction in TPE workloads (range, %)  0%-25% 7/14 (50%) 10/14 (71.4%) 25%-50% 3/14 (21.4%) 2/14 (14.2%) 50%-75% 2/14 (14.2%) 1/14 (7.1%) 75%-100% 2/14 (14.2%) 1/14 (7.1%) c. If still doing TPE, how many cases per year in 2020 till end Jan 21 vs 2019? 30% drop (229 cases vs 325 cases) 13% drop (286 vs 327 cases) d. Percentage drop in number of cases 2019 vs 2020-till January 2021 22% drop (overall) e. Commonest type of NID treated by TPE? • NMOSD and related disorders 30% 33% • GBS (Covid-19 related and unrelated) 25% 22% • MG 25% 22% • AIE 15% 20% • others 5% 3% 5. Still doing TPE for patients with or without Covid-19 and NID? a. Performing Elective TPE for Non-Covid-19 patients? Y/N

Y: 13/14 (92.8%)

N: 1/14 (7.2%)

Initial phase: Y: 14/14, 100% Late phase: Y: 12/14, 87.5% (2 countries stopped for 2 months) b. Performed TPE for Covid-19 related neurological complications: Y/N (active vs non active phase) 0 Y: 12/14, 87.5% during active phase Y: 2/14, 12.5% after day 10-14 post Covid-19 in non-active phase. 6. What factors have contributed to reduced TPE workloads? a. Patient-related factors: TPE patients fearful to come to hospital/do Covid-19 testing? Y/N Y: 14/14 (100%) Y: 14/14 (100%) b. Shortage of Staff: Y/N Y: 14/14 (100%) Y: 14/14 (100%) c. Stratification of TPE cases; urgent vs non-urgent: Y/N Y: 14/14 (100%) Y: 14/14 (100%) d. Stratification of patients based on age &comorbidities: Y/N Y: 5/14 (35.7%) Y: 6/14 (42.8%) e. Logistic Issues d/t MCO: Y/N Y: 14/14 (100%) Y: 14/14 (100%) f. Staff Fear of conducting TPE? Y/N Y: 7/14 (50%) Y: 7/14 (50%) 7. Have there been • Interruptions of supply of TPE consumables/replacement fluids? Y/N N: 14/14 (100%) N: 14/14 (100%) • Biomarker Access interruptions N: 9/9 (100%) N: 9/9 (100%) • Biomarker Access Challenges? (in house/outsourced) Y/N (n = 9) Y: 8/9 (88.9%) Y: 8/9 (88.9%) 8. Is it safe to continue TPE during the pandemic? a. Is it safe to continue TPE during pandemic: Y/N Y: 14/14 (100%) Y: 14/14 (100%) b. Do you feel TPE increases the risk of Covid-19 in pts? Y/N N: 14/14 (100%) N: 14/14 (100%) c. Are there concerns about the cost of Covid-19 testing: Y/N Y: 7/14 (50%) Y: 4/14 (25%) d. Have any patients with NID developed Covid-19 post TPE? Y/N (n = 14 respondents) N: 14/14 (100%) N: 13/14 (92.8%) e. With regard to timing of vaccination to TPE, to defer one month Not applicable Y: 14/14 (100%) 9. What precautions are taken prior to initiating TPE and during TPE? i. Pre TPE CSQ*: Y/N Y: 14/14 (100%) Y: 14/14 (100%) ii. Pre TPE Covid-19 screen with Covid-19 PCR/RTk antigen in all pre TPE pts: Y/N Y: 8/14 (57.1%)

Y: 12/14 (85.7%)

(Not 100% due to resource issues in some countries for PCR testing)

iii. Precautions taken during TPE: Mask, PPE, gloves, Face shield/Visor (PPE Level determined by if symptomatic or Covid-19 +ve/−ve): Y/N Y: 14/14 (100%) Y: 14/14 (100%) iv. Screening of Plasma for Covid-19 antibodies: Y/N N: 14/14 (100%) N: 14/14 (100%) 10. Are alternatives to TPE used? Y/N (n:number of respondents)

Y: 11/14 (78.5%)

N: 3/14 (22.5%)

Y: 12/14 (85.7%)

N: 2/14 (14.3%)

i. State types: IVIG Y/N Y: 11/14 (78.5%) Y: 12/14 (85.7%) ii. Others/No treatment: Y/N Y: 7/14 (50%) Y: 7/14 (50%) 11. i. Performing Convalescent Plasma: Y/N N: 0/14 N: 3/14 ii. Affiliated to Global studies: Y/N N: 0/14 N: 3/14 12. What is the impact of Covid-19 on regional TPE in the future? i. Change in TPE protocols with prescreening & PPE for Covid-19 exposure prevention: Y/N Y: 14/14 (100%) Y: 14/14 (100%) ii. Need for Covid-19 dedicated TPE machines/ Covid-19 dedicated neurology wards: Y/N Y: 7/14 (50%) Y: 7/14 (50%) iii. Modify timing of TPE to vaccination timing: Y/N Y: 14/14 (100%) Y: 14/14 (100%) 13. Would you be willing to participate in the development of a regional consensus recommendation for safe & efficient TPE? Y/N Y: 14/14 (100%) Y: 14/14 (100%) 14. Do you agree that a. TPE may be offered to all patients regardless of whether Covid-19 positive or negative if Y: 14/14 (100%) Y: 14/14 (100%) i. There are strong clinical indications for treatment (as per ASFA18) ii. The treatment is urgent and cannot be delayed iii. There are no other alternatives for treatment iv. The center offering TPE is equipped with safe protocols to screen and protect against inadvertent transmission of SARS-CoV-2 viral infection. Y/N 15. Do you agree that If non-urgent, TPE may be postponed until the patient is considered to be non-infective by local infectious disease consultations and country specific/WHO protocols? Y/N? Y: 14/14 (100%) Y: 14/14 (100%) 16. Do you agree it is important to maintain safety of staff, TPE patients and caregivers prior to, during and post TPE with pre-procedure screening of all patients? Y/N Y: 14/14 (100%) Y: 14/14 (100%) Abbreviations: ASFA, American Society For Apheresis; GBS, Guillain-Barre syndrome; IVIG, intravenous immunoglobulins; Jan, January; N, no; NID, neuroimmunological diseases; PCR, polymerase chain reaction; PPE, personal protective equipment; RTK, reverse transcriptase; TPE, therapeutic plasma exchange; Y, yes.

Question 1. Do you have Covid-19 cases at your hospital? Yes or No.

Question 2. Is your hospital a Covid-19 designated hospital/hybrid hospital? Yes or No.

78.5%, (11/14) of respondents during Phase 1 and 100% (14/14) of respondents during Phase 2 were either directly or indirectly involved in treating possible or confirmed Covid-19 patients with neurological disorders at their hospitals as a Covid-19 designated or hybrid Covid-19 hospital

Question 3. (Tables 1 and 3). Do you still refer neuroimmunological cases for TPE during the pandemic at your hospital? Y/N. Are these visits face to face visits or virtual visits for TPE counseling and decision making? If yes, do you do “in-house Neurology based TPE” or is it outsourced to the Hematology or Nephrology departments? What type of TPE is being used: Membrane filtration, centrifuge technologies, both or others? (Others: manual small volume TPE/limited plasma exchange).

(a) All respondents were still seeing patients with neuroimmunological diseases for possible TPE during Phases 1 and 2 albeit in reduced numbers due to general advice to minimize patient's exposure to possible Covid-19 infections by reducing elective non-urgent follow-ups. 14.2% and 28.5% of respondents during Phase 1 and 2, respectively, conducted virtual neurological visits for TPE counseling and planning via virtual platforms (telephone calls, whatsapp, face-time, emails, etc, eg, Malaysia) or modified tele-neurology visits (eg, Malaysia and Singapore) in the absence of established teleneurology portals in the former mainly in Phase 2.5

(b,c) TPE was conducted either as “In house Neurology based TPE” or outsourced to the Nephrology and Hematology departments. Types of TPE used included centrifuge (8/9, 89%), membrane filtration (8/9, 89%) or both technologies (7/9, 78%) using either dedicated centrifuge or membrane filtration machines or adapting a membrane column to a conventional renal replacement machine) (Table 1).2, 3 Two countries were utilizing alternative methods of TPE (2/9, 22.2%) such as small volume plasma exchange (SVPE) technology in addition to conventional TPE, that is, Myanmar and Bangladesh.

Question 4. If still doing TPE, how many cases per year in 2019 versus 2020, is there are drop or increase? Explain in terms of percentages/absolute number of cases or ranges. What were the commonest central and peripheral neuroimmunological conditions that required TPE? Explain.

In 2019, the total number of TPE cases reported by SEATPEC stake holders was 653 and in Phase 1 of 2020, there was a reduction of 30%, that is, 229 cases versus 325 cases in 2019, which rebounded in the second half of 2020 to January 2021 (286 vs 327 cases in 2019). Overall, compared with the previous year there was a reduction of 22%, with the majority reporting reductions from 0% to 50%. The four commonest neurological diseases treated were that of neuromyelitis optica spectrum disorders and related conditions, Guillain-Barré (Covid/Non-Covid related), myasthenia gravis, and autoimmune encephalitis (Table 3).

Question 5.

If Yes, still doing TPE, are you also doing TPE for Covid-19 patients with neurological complications? Y/N. Explain.

92.8% of the respondents surveyed (13/14) were still able to access and perform TPE either in house or outsourced to the hematology or nephrology units during early phase 1 of the Survey except for Malaysia, for non Covid-19 patients. In Malaysia, Neurology based TPE services was halted from March till May 2020 due to redistribution of beds and reassignment of health personnel including TPE staff to Covid-19 related activities. Regionally, all respondents continued TPE with gradually increasing numbers during the early Phase 2 of the Survey except for Malaysia in late Phase 2 again due to increasing number of Covid-19 infections locally.

In Phase 1, none of the respondents had performed TPE for Covid-19 related central or peripheral neurological conditions. In Phase 2, 87.5% of respondents were treating Covid-19 patients with neurological conditions such as cerebrovascular events, Guillain-Barré syndrome (GBS), encephalitis, and acute disseminated encephalomyelitis TPE (personal communication from Malaysia, Myanmar, Indonesia, Singapore9). 87.5% of respondents were performing TPE for active Covid-19 infections with neurological complications during Phase 2 and the remaining 12.5% were performing TPE only for convalescent Covid-19 patient's (beyond the 14th day of infection) with Covid-19 or non-Covid-19 associated neurological central and peripheral neuroimmunological conditions.

None of the neurologists interviewed had reservations about treating these patients with TPE as all felt it was a basic human right as long as the indication as per ASFA was present.18

Question 6.

If not performing TPE at the moment or reduced number of TPE's performed, why has this occurred during the pandemic? Explain the factors causing this.

All respondents agreed that, TPE patient loads had reduced during Phases 1 and 2 of the Covid-19 pandemic due to multiple factors as described below;

Patient-related factors.

Among the factors identified included the patient's fear of hospital exposure to Covid-19 and anxiety related to performing Covid-19 screening tests. Additionally, logistic issues due to movement control orders enforced by many countries also contributed to reduced TPE patient loads.

Shortage of TPE Staff, human resource related factors and staff concerns:

The main factor identified by all SEATPEC members (14/14, 100%) was the shortage of TPE staff consequent to the redistribution of TPE staff and doctors to help with the management of increasing Covid-19 wards and patients, clustering of cases among hospital staffs being exposed to positive patients/community spread, quarantine of staff in addition to logistic/transport issues due to movement control orders. Fifty percent of respondents also reported staff related fears of exposure to Covid-19 during the conduct of TPE but some felt this did not contribute to reduced patient loads.

Other factors: Stratification of indication for TPE: Emergency versus Elective cases.

Furthermore, reduction in TPE procedures/clinic attendance was done through careful stratification of TPE cases as either essential or non-urgent/electives which could be postponed or substituted with alternative therapies such as GBS, myasthenia gravis and neuromyelitis optica spectrum disorders (NMOSD) where other rescue treatment options exist such as intravenous immunoglobulins or steroids.

This allowed for better utilization of staff, time and resources. A minority of respondents (35.7% and 42.8% in Phases 1 and 2, respectively) also stratified the use of TPE mainly to include the young rather than the elderly with multiple co-morbidities to avoid the risk of viral exposure to the latter group.

Question 7.

Have there been any issues with supply of TPE consumables, biomarker testing, or replacement fluids?

Reassuringly, none of the countries expressed problems with supply of consumables (standard centrifuge/membrane filter sets or replacement fluids that is, 5% albumin/fresh frozen plasma [FFP]) for standard TPE during this period. The main issue was the shortage of manpower to run the service.

In house, biomarker testing for a very limited panel of neuroimmunological antibody tests was currently only available in 4/9 countries (Malaysia, Singapore, Thailand, and Philippines) prior to the pandemic with all countries only having a limited panel for testing. The remaining countries (5/9) had to outsource this to country specific private/overseas commercial/academic laboratories of which non-reported any interruptions during the pandemic. So although, there were no interruptions to access, nearly all countries, 8/9 reported challenges in being able to ask for comprehensive biomarker testing panels for both common and uncommon auto-antibody panels for central and peripheral neuroimmunological disorders due to local in-availability and needing to outsource the service.

Question 8. Do you think it is safe to perform TPE for neuroimmunological disorders during the Covid-19 pandemic? Do you feel TPE increases the risk of Covid-19 in patients? Yes or No? Explain. Have any of the patients with neuroimmunological disorders developed Covid-19 post TPE? What about the timing of TPE and vaccinations?

Safety of TPE and confidence to continue TPE.

All respondents felt that TPE was safe in patients with autoimmune neuroimmunological disorders in non-Covid-19/Covid-19 patients (during acute/post-convalescent period) in both phases of the Survey during the pandemic.

Risk of Covid-19 in planned TPE patients and vaccination.

From a real world observational perspective, majority felt that TPE would not increase the risk of patients developing Covid-19 infection which seemed to be more dependent on exposure risk and local country-specific epidemiology. However, all acknowledged the need for more longitudinal data on this observation. All felt there was insufficient current evidence that TPE would reduce the immune responsiveness and ability for immune surveillance during the pandemic.

Occurrence of Covid-19 in post-TPE patients.

Majority of the countries reported none of their post-TPE patient's developing Covid-19 during the last 11 months of the Survey except for Malaysia. In Malaysia, one patient with CRION with multiple co-morbidities including obesity, diabetes mellitus, and hypertension developed severe Covid-19 and died 2 weeks after TPE. However, in this patient the Covid-19 was deemed unrelated to the TPE but rather due to contact with community spread of Covid-19 and the multiple underlying co-morbidities. So 85% felt there was no data to suggest that TPE should be postponed during the pandemic for essential cases in the absence of other options. All respondents were unanimous, that TPE was an essential, vital service, lifesaving in some and did not increase the risk of developing Covid-19 post-procedure short term or long term.

Timing of vaccinations:

All felt elective TPE should be delayed/postponed prior to and following vaccination by a month unless urgent to allow time for post vaccination immune response. For ur

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