Long COVID Update

by Geraint Jones

Theauthor, a health-care worker at a hospital in Wales, became infected with COVID-19 in April 2020. This turned into a virulent example of Long COVID which was described in detail in an article featured in Issue 70 of IP last November. A huge number of patients, over 2 million in the UK alone, have been affected by Long COVID. In this followup article the author provides the latest research uncovering some of the debilitating and recurring symptoms that he and many other patients experience and suggesting better treatment options for both adults and children.

As we approach three years since the start of the COVID-19 pandemic, our knowledge continues to grow as we are now expected to ‘live with COVID’ – a stark contrast to the public health messaging that was broadcast in the first few months of 2020. There are worldwide collaborative efforts to try to help understand this novel virus, along with the immunity of those infected and the long-term effects of acute and continued infection. The rapid delivery of the vaccination programme has notably slowed the incidence of patients requiring admission to hospital with COVID-19; however, the risks of Long COVID still remain and many fear that the prolonged levels of disability related to the condition will become increasingly significant over the coming years. In a cross-sectional study, persistent symptoms were still present in 10.1% of infected individuals 12 months after SARSCoV-2 infection1

Given the high level of cumulative incidence of COVID-

19, the absolute prevalent number of people with persistent symptoms is a growing public health concern, and one which needs to be swiftly addressed2, including a conversation around the impact of ‘clean air’ in healthcare settings3. In November 2022, the Office of National Statistics (ONS) released an update on the number of individuals affected by Long COVID in the U.K., reporting that 2.1 million individuals were affected which equates to 3.3% of the entire population. The prevalence of Long COVID was seen to be greater in those aged between 35 and 59 years of age and 6% of respondents were employed within the social care sector, further emphasising employment as a risk-factor for being affected by Long COVID. 1.1 million people report being unwell for over a year, and 507,000 report having symptoms for two years or longer, showing the daily impact on those who contracted COVID-19 in the early stages of the pandemic. There were also 749,000 individuals reporting symptoms of Long COVID following the Omicron variant which could be argued was likely due to the huge numbers of those infected and combined with COVID restrictions being completely withdrawn throughout the U.K.4,5 These figures also coincide with the updated NICE Guidance ‘COVID19 rapid guideline: managing the long-term effects of COVID-19’6; a much more comprehensive document than the previous year. Sadly, there are individuals who have been gaslighted by clinicians, with some minimising their symptoms or incorrectly attributing them to a mental health diagnosis. Some of those have been so affected that they felt there was no other option but to end their life7,8,9, highlighting how debilitating and isolating the illness can be. There is continued research and mounting evidence that a multitude of post-acute COVID-19 syndromes can develop after SARS-CoV-2 infection and vaccination10; a series of thorough investigations, including imaging and monitoring should be undertaken, now that clinicians are more suitably equipped with a strong evidence base.

The UK Department of Work & Pensions (DWP) have recently reported a 25-fold increase in personal independence payment (PIP) claims relating to Long COVID, with one in five successful claimants receiving the enhanced rates of both components11. The total of both components of PIP allows a payment of £156.90 a week to

Source: https://www.nature.com/articles/s44161-022-00177-8/figures/2 the claimant, demonstrating the widespread scale of disability throughout the U.K. and the implication of this on the workforce and the economy.

As ever, the patient-support groups and communities on Twitter were instrumental in sharing guidance and providing support when there was little offered elsewhere, and it’s perhaps quite bittersweet that they remain, being a crutch for those who need that support. Facebook groups allowed strangers to share their experiences of Long COVID, and since growing to over 50,000 members, strangers have become friends, some turning into patient advocates for the condition. As a healthcare professional, I was quite sceptical of the level of support that peergroups could provide, hearing many ‘horror stories’ where other patients have provided quite dangerous advice, but having been personally affected, my opinion is now one of complete support. Members of the group began sharing personal experiences and financial support and quickly found themselves speaking in the media and national press, some even featuring and reviewing guidance on Long COVID, and others being accepted as Core Participants in the U.K. Public Inquiry12

It is now acknowledged that everyone, regardless of age, gender, COVID risk factors, vaccination status or comorbidities, can be affected by Long COVID13.

• World-famous popstar Billie Eilish contracted COVID-19 in

August 2021. She spoke about her illness in December 2021 and said she was unwell with the virus and that she was still experiencing undisclosed side effects14

• Swiss 800m runner Selina Rutz-Büchel tested positive in April 2021 and has not been able to return to her training routine and in November 2022 announced her retirement from the sport15 Canadian record holder and Olympic 200m champion Andre De Grasse also struggled after testing positive in June 202216 and was not able to fully regain his fitness for the World Athletics Championships in July and was forced to withdraw.

• In November 2022, Australian radio show host Jackie O revealed on air that she is ‘struggling with this fatigue’ and received medical advice to stop working. “Ever since picking up that virus, I’ve been to the doctor several times, and he said it’s because I’ve been pushing myself every day, after the show. All I’ve been doing is sleeping, and I’m not getting better” she added17

• In August 2021, Formula 1 driver Lewis Hamilton said he had been "fighting all year" with his health, after contracting COVID-19 in December 2020. Hamilton said he hadn’t spoken to anyone about it, but that his symptoms were ‘lingering’, also reporting that his training had been ‘different’, and that ‘the levels of fatigue are different and it's a real challenge’18

I’m pleased to say that since last writing for the International

Pharmaceutical Federation (FIP) in November 2021, I’ve made substantial progress with my Long COVID and hope to be nearing the end of an illness which has had a significant impact on my professional and personal life for 32 months. However, this has not been without its challenges having seen all my routine tests throughout this period return unremarkable results. Despite being frustrating, I was determined to understand why I was remaining visibly unwell with marked symptoms, both of which had a significant impact on my day-to-day life. Since the onset of my illness, I had maintained that my body had felt somewhat inflamed and swollen. The fluctuating and wide-ranging symptoms were things that I’d never experienced before; eczema-like rashes on my arms, extreme tiredness, feeling like I’d had memories completely erased and temperature dysregulation. Combined with my gastrointestinal symptoms, cognitive dysfunction and newly diagnosed inappropriate sinus tachycardia, I began wondering how long it would be before I would recover or how long would patients need to wait before there was a test to show what was happening inside our bodies – it is quite a scary thought when you’re going through it.

I read some reports in 2021 of patients in the United States paying to undergo cytokine panels, despite their extortionate costs, with most showing levels of prolonged inflammation which could be targeted by repurposing licensed medications which exist for other conditions. Thankfully there was a small cohort of patients who could undergo these tests in the U.K. for a small fee as IncellDx began to realise that they were on the cusp of creating the first diagnostic test designed for identifying patients with Long COVID19,20. In May 2022, I attended a private clinic to have my blood tested, and within four-weeks, my results had been analysed and returned (see Table 1). As well as the tests being validating, it also reaffirmed what I felt my body was telling me in the months prior –there was a significant level of inflammation within my body!

I was provided with a personalised treatment plan and given a thorough explanation of my results via a 30-minute video consultation with a U.S. clinician. As the clinician was not based within the U.K., he was unable to prescribe the medications required and I was advised to source them privately from a U.K. based clinician. Despite sharing my results with local clinicians, understandably, they did not feel comfortable to prescribe the medications based on the opinion of another clinician and on the back of an experimental clinical test. Despite there being vast opportunities to purchase medications from overseas (which is quite scary!), and the growing trend of ‘drug tourism’, I opted to investigate other methods of controlling the inflammation, leading me into antiinflammatory diets and further (legal) supplementation.

Since the very outset of becoming infected with COVID19, patients have described ‘brain fog’, mood changes, sleep disorders, along with the now common characteristic of infection, loss of taste and smell – it has been consistent throughout the pandemic that there is some level of neurological impact21. What remains uncertain, and quite

COVID LONG HAULER PANEL

LH CYTOKINE 14 PANEL

IL-29.4HIGHpg/mL<7.0

IL-4138.7HIGHpg/mL<6.2

IL-63.4HIGHpg/mL<3.0

IL-875.2HIGHpg/mL<21.0

IL-102.4HIGHpg/mL<1.0

IL-131.2NORMALpg/mL<6.1

GM-CSF6.4NORMALpg/mL<77.0

SCD40L76440.4HIGHpg/mL<9236.0

COL3 (MIP-1 ALPHA)2.4NORMALpg/mL<33.0

CCL4 (MIP-1 BETA)44.3NORMALpg/mL<93.0

CCL5 (RANTES)20000HIGHpg/mL<11800.0

TNF-ALPHA33.4HIGHpg/mL<11.0

IFN-GAMMA40.3HIGHpg/mL<3.5

VEGF359.6HIGHpg/mL<12.3

LONG HAULER INDEX1.1HIGHINDEX<0.70 concerning, is the impact of repeated COVID-1922. More than one-third of patients who have tested positive, have experienced central or peripheral nervous system involvement, while an approximately threefold higher incidence of neurological symptoms is recorded in observational studies including patient-reported data23

In July 2022, I was invited to be a participant in the Brain and Brainstem Basis of COVID-19 (BBB-COVID) study conducted by the University of Oxford, where the study used a 7 Tesla MRI scanner to look at the effects of COVID-19 on the brain, and how it may potentially predispose some people to future brain conditions. Studies have demonstrated the potential for the virus to reside at immunologically privileged sites throughout the body, which can lead to a protracted course of illness24 and inflammation which could possibly explain the ongoing, various symptoms that patients routinely exhibit. Perhaps NICE’s term of ‘post-COVID-19 syndrome’ is factually incorrect as patients may not be ‘post’ COVID after all.

Despite experiencing gastrointestinal symptoms for over two years, a decision was made to discharge me from Secondary Care, with ongoing symptoms to be managed under my GP. I’m extremely fortunate to have had a supportive GP who has been willing to learn and understand about my symptoms, also offering emotional and mental health support during the more troublesome periods of such an isolating illness. Having spoken in length, it was agreed that perhaps a short trial of Montelukast could be beneficial having recognised its potential role in helping to control mast cell activation syndrome (MCAS)25; a possible diagnosis given my symptoms and recent results. There has been significant interest into the role of amyloid fibrin microclots in Long COVID26,27, pioneered by South African researchers, Resia Pretorius and Jacobus Laubscher and U.K. researcher, Douglas Kell. Starting as a brief Twitter interaction between researchers and patients, it quickly became a collective effort to source many fluorescence microscopes to confirm Resia’s early findings, all in aid of finding a cure to help the millions affected by Long COVID. A hashtag, #TeamClots, formed and allowed patients to keep up-to-speed with the progress and research from all around the world. I eagerly followed the research (and having personally spoken with Douglas and Resia about their research), I discovered repeated mentions of Nattokinase28 and Serrapeptase29, proteolytic enzymes which have been studied and found to be beneficial in patients with chronic diseases . Having trialled

Source: https://pubmed.ncbi.nlm.nih.gov/35198136/ many different supplements over my period of illness, I wasn’t going to let another potential ‘cure’ pass me by.

The first few days of taking Nattokinase and Serrapeptase were awful, I felt like I had relapsed. The only reasonable way I can describe it was as if someone had removed a slowing battery from within me; gradually winding down and then shutting off completely. Around ten days later, and with a lot of perseverance, I started to feel a bit more energised –the physical and mental ‘fog’ was lifting, and I really began to hope that this was the beginning of my recovery.

Currently on a combination of Ivabradine, Montelukast, Famotidine, Fluoxetine, Nattokinase, Serrapeptase, Omega-3, Vitamin D and prebiotics, I’d like to say that I’m back to about 95% pre-COVID health (with some minor blips and minus my pre-COVID level of fitness). Despite my previous article (see IP 70) seeming one of despair, I feel that there is hope out there for those living with Long COVID and to keep the faith, even in the darkest days, as I know that there are many clinicians and researchers working tirelessly to help you.

I sincerely hope that the sufferers of myalgic encephalomyelitis and chronic fatigue syndrome (ME / CFS) will also benefit from such research, especially where there is further evidence and emergence of more previously unknown post-viral30 conditions such as postural tachycardia syndrome (PoTS)31, autonomic dysfunction32 and mast-cell activation syndrome (MCAS)33. The care, advocacy and support from curious, adventurous clinicians34 has played a critical role in many journeys of recovery, and I truly hope they are all remembered for their heroic and vital work.

References

1 Robineau O, Zins M, Touvier M, et al Long-lasting Symptoms After an Acute COVID-19 Infection and Factors Associated With Their Resolution. JAMA Netw Open 2022; 5(11): e2240985. https://doi:10.1001/ jamanetworkopen.2022.40985

2 Neville, S. and Cocco, F. (2022) The growing evidence that covid-19 is leaving people sicker, Financial Times. Available at: https://www.ft.com/content/26e0731f15c4-4f5a-b2dc-fd8591a02aec (Accessed: December 13, 2022).

3 Bowles, C. et al. (2022) “A rapid review of supplementary air filtration systems in health service settings. September 2022.” Available at: https://doi.org/ 10.1101/2022.10.25.22281493.

4 Wise, J. (2022) “Covid-19: Long Covid Risk is lower with Omicron than Delta, researchers find,” BMJ [Preprint]. Available at: https://doi.org/10.1136/bmj.o1500.

5 Staff, Z.O.E.E. (2022) Covid: Is Omicron less severe than Delta?, COVID: Is Omicron Less Severe Than Delta? ZOE. Available at: https://joinzoe.com/learn/ covid-omicron-less-severe (Accessed: December 13, 2022).

6 Overview: Covid-19 rapid guideline: Managing the long-term effects of covid-19: Guidance (2022) NICE Available at: https://www.nice.org.uk/guidance/NG188 (Accessed: December 13, 2022).

7 My wife had long covid and killed herself. we must help others who are suffering | Nick Güthe (2022) The Guardian. Guardian News and Media. Available at: https://www.theguardian. com/commentisfree/2022/jan/12/longcovid-wife-suicide-give-others-hope (Accessed: December 13, 2022).

8 Couple who both had long covid planned suicide as 'neglected' sufferers struggle (2022) The Independent. Independent Digital News and Media. Available at: https://www.independent. co.uk/news/health/long-coviddepression-suicide-treatmentb2104764.html (Accessed: December 13, 2022).

9 Coronavirus and suicide risk (no date) Samaritans. Available at: https://www.samaritans.org/wales/abou t-samaritans/researchpolicy/coronavirus-and-suicide/one-yearon-data-on-covid-19/what-do-we-knowabout-coronavirus-and-suicide-risk/ (Accessed: December 13, 2022).

10 Kwan, A.C., Ebinger, J.E., Wei, J. et al. Apparent risks of postural orthostatic tachycardia syndrome diagnoses after COVID-19 vaccination and SARS-Cov-2 Infection. Nat Cardiovasc Res (2022). https://doi.org/10.1038/s44161-02200177-8

11 Terry and May, C. (2022) 25 fold increase in Pip Long Covid Awards, one in five getting maximum amount, Benefits and Work. Available at: https://www.benefitsandwork.co.uk/ne ws/25-fold-increase-in-pip-long-covidawards,-one-in-five-getting-maximumamount (Accessed: December 13, 2022).

12 Representing the Long Covid community as Core Participants in the U.K. Covid19 Inquiry module 2 (2022) Long Covid Support. Available at: https://www.longcovid.org/impact/repre senting-the-long-covid-community-ascore-participants-in-the-u-k-covid19inquiry-module-2 (Accessed: December 13, 2022).

13 Leite, A., Ridge, D. and Alwan, N. (2022) What's it like being a young person with long covid? you might feel like a failure (but you're not), The Conversation. Available at: https://theconversation.com/whats-itlike-being-a-young-person-with-longcovid-you-might-feel-like-a-failure-butyoure-not-192060 (Accessed: December 13, 2022).

14 Billie Eilish: I would have died from covid-19 if I hadn't been vaccinated (2021) The Guardian. Guardian News and Media. Available at: https://www.theguardian.com/music/20 21/dec/14/billie-eilish-i-would-have-diedfrom-covid-19-if-i-hadnt-beenvaccinated (Accessed: December 13, 2022).

15 Dickinson, M. (2022) Two-time European 800m champion retires from running, citing long covid, Canadian Running Magazine. Available at: https://runningmagazine.ca/sections/run s-races/two-time-european-800mchampion-retires-from-running-citinglong-covid/?fbclid=IwAR1lOaYKC6Bomp Z_z_94xja-dk6dcrCNTRRfhMCf7OC9SYj3 PS28hGimYbI (Accessed: December 13, 2022).

16 Harrison, D. (2022) Andre de Grasse has Covid, won't compete this week at track and field nationals in B.C. | CBC sports, CBCnews. CBC/Radio Canada. Available at: https://www.cbc.ca/sports/ olympics/summer/trackandfield/damianwarner-withdrawal-canadianchampionship-knee-injury-1.6494866 (Accessed: December 13, 2022).

17 Cain, S. (2022) 'I'm not getting better': Jackie O steps away from radio show to recover from long covid, The Guardian. Guardian News and Media. Available at: https://www.theguardian. com/media/2022/nov/14/im-not-gettingbetter-jackie-o-steps-away-from-radioshow-to-recover-from-long-covid (Accessed: December 13, 2022).

18 Benson, A. (2021) Lewis Hamilton suspects he has long Covid after hungarian grand prix, BBC Sport. BBC. Available at: https://www.bbc.co.uk/sport/formula1/5 8050499 (Accessed: December 13, 2022).

19 INCELLDX receives CE-IVD marking for Incellkine Long Covid diagnostic test (2022) Medical Device Network. Available at: https://www.medical device-network.com/ news/incelldx-ceivd-incellkine-long-covid/ (Accessed: December 13, 2022).

20 Patterson, B.K., Tian, J. and Buxton, T. The Need for Precision Medicine in Active and Post COVID-19, incelldx.com. Available at: https://incelldx.com/incelldx-content/ uploads/The-need-for-precisionmedicine-.pdf (Accessed: December 13, 2022).

21 Venkataramani, V. and Winkler, F. (2022) “Cognitive deficits in long covid19,” New England Journal of Medicine, 387(19), pp. 1813–1815. Available at: https://doi.org/10.1056/nejmcibr2210069

22 Bowe, B., Xie, Y. & Al-Aly, Z. Acute and postacute sequelae associated with SARS-CoV-2 reinfection. Nat Med 28, 2398–2405 (2022). https://doi.org/ 10.1038/s41591-022-02051-3

23 Stefanou, M.-I. et al. (2022) “Neurological manifestations of longcovid syndrome: A narrative review,” Therapeutic Advances in Chronic Disease, 13, p. 204062232210768. Available at: https://doi.org/10.1177/ 20406223221076890

24 Baig, A.M. (2021) “Chronic long‐covid syndrome: A protracted COVID‐19 illness with neurological dysfunctions,” CNS Neuroscience & Therapeutics, 27(12), pp. 1433–1436. Available at: https://doi.org/10.1111/cns.13737

25 Long COVID low histamine diet: Allergy UK: National Charity (2021) Allergy UK | National Charity. Available at: https://www.allergyuk.org/resources/res ponse-to-long-covid-mcas-and-lowhistamine-diet/ (Accessed: December 13, 2022).

26 Kell, D.B., Laubscher, G.J. and Pretorius, E. (2022) “A central role for amyloid fibrin microclots in long COVID/PASC: Origins and therapeutic implications,” Biochemical Journal, 479(4), pp. 537–559. Available at: https://doi.org/10.1042/bcj20220016

27 Grobbelaar, L.M. et al. (2022) “Relative hypercoagulopathy of the SARS-COV-2 beta and delta variants when compared to the less severe omicron variants is related to TEG parameters, the extent of fibrin amyloid microclots, and the severity of clinical illness,” Seminars in Thrombosis and Hemostasis, 48(07), pp. 858–868. Available at: https://doi.org/10.1055/s-0042-1756306

28 Shah, N. (2021) “Effects of systemic enzyme supplements on symptoms and quality of life in patients with pulmonary fibrosis—a pilot study,” Medicines, 8(11), p. 68. Available at: https://doi.org/10.3390/medicines8110068

29 Tiwari, M. (2017) “The role of serratiopeptidase in the resolution of inflammation,” Asian Journal of Pharmaceutical Sciences, 12(3), pp. 209–215. Available at: https://doi.org/10.1016/j.ajps.2017.01.003

30 “Long covid: An opportunity to focus on post-acute infection syndromes” (2022) The Lancet Regional HealthEurope, 22, p. 100540. Available at: https://doi.org/10.1016/j.lanepe.2022.10 0540

31 GP Guide: Pots on a page (2021) PoTS UK. Available at: https://www.potsuk.org/pots-formedics/gp-guide/ (Accessed: December 13, 2022).

32 Larsen, N.W. et al. (2022)

“Characterization of autonomic symptom burden in long covid: A global survey of 2,314 adults,” Frontiers in Neurology, 13. Available at: https://doi.org/10.3389/fneur.2022.1012 668

33 Weinstock, L.B. et al. (2021) “Mast cell activation symptoms are prevalent in long-covid,” International Journal of Infectious Diseases, 112, pp. 217–226. Available at: https://doi.org/10.1016/j.ijid.2021.09.043

34 Bath expert joins scientists around the world calling for international consensus to fight covid-19 (2022) University of Bath. Available at: https://www.bath.ac.uk/announcements /bath-expert-joins-scientists-around-theworld-calling-for-internationalconsensus-to-fight-covid-19/ (Accessed: December 13, 2022).