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As grant applications open for research into long COVID, experts stress the importance of avoiding reinfections

Introduction by Croakey: A round of research grants opened today for four streams of research on long COVID – or, using the term preferred by the Department of Health and Aged Care, for PASC or Post-Acute Sequalae of COVID-19.

The Medical Research Future Fund grants, administered by NHMRC, have four streams:

  1. A large-scale multidisciplinary project in partnership with primary care researchers and consumers (including all age groups and priority populations), to identify how people experience PASC, including the impact on their physical and mental health and social and emotional wellbeing.
  2. A large-scale multidisciplinary project in partnership with consumers, health service providers and policy makers using primary data collection and/or informatics approaches such as modelling and linkage to generate knowledge of population-wide and health system impacts of PASC.
  3. Small scale developmental projects that: investigate the molecular mechanisms, pathways or biomarkers that are central to the cause and progression of PASC; and build knowledge of key factors that impact PASC prognosis, including but not limited to psychosocial, physical and behavioural contributors.
  4. Inception projects that build evidence and capability to demonstrate the feasibility of establishing a national adaptive platform trial that would allow for rapid assessment of pharmacological and non-pharmacological interventions of PASC.

The Government has committed $50 million in 2023-2024 under the MRFF for research on PASC or long COVID, and an expert advisory panel has developed a PASC research plan, with research expected to begin in 2024 and 2025.

Dr Masha Somi, CEO of the Health and Medical Research Office in the Department of Health and Aged Care, told a webinar conducted with the Consumers Health Forum today that the Department is using the term PASC because it is broader than long COVID.

However, some participants in the webinar commented that this was confusing, given that ‘long COVID’ is a better known term.

Somi described how consumers would be closely involved in all stages of the research, in line with the MRFF’s principles for consumer involvement in research.

According to her presentation (see a selection of slides here), most research outcomes are expected from 2029.

Somi said the PASC research plan was just one part of the national response to long COVID under development by the Department.

Aims of the research plan include: to improve consumer, community and health system outcomes; to improve care by building knowledge of the mechanisms and pathways leading to PASC; identify the best therapies for PASC (including pharmacological and non-pharmacological); and to ensure health systems meet the needs of people with PASC.

Meanwhile, Associate Professor Suman Majumdar and Professor Brendan Crabb from the Burnet Institute give an overview of recent research on long COVID below, highlighting the importance of preventing reinfections.

Their article was first published at The Conversation under the headline, ‘Long COVID symptoms can improve, but their resolution is slow and imperfect’.


Suman Majumdar and Brendan Crabb write:

Around 5–10 percent of people who get infected with SARS-CoV-2 will experience symptoms that persist way beyond the initial acute period, a clinical syndrome we are learning more about, known widely as long COVID.

Shortness of breath, brain fog, lethargy and tiredness, loss of smell or taste are common features of long COVID, as is the development of new conditions such as diabetes, heart disease, stroke, depression and dementia.

But how long is the “long”? If and when do symptoms resolve?

A recent study has examined this in detail, following people for two years after their infection. This and other recently published studies on long COVID show that while symptoms do resolve in many people, their resolution is slow and imperfect.

What did the study find?

The key work, led by Ziyad Al-Aly, examines the effect of SARS-CoV-2 two years after infection in a large group of US veterans. The researchers followed 139,000 people with COVID and almost six million uninfected controls for two years, tracking deaths, hospitalisations and 80 long-term impacts of COVID, categorised into ten organ systems.

They found that people who were initially hospitalised with COVID were 1.3 times more likely to die and 2.6 times more likely to be hospitalised again, compared to the control group (people without COVID), over the two years. After two years, this “hospitalised” group remained at increased risk of 50 conditions.

People who had milder COVID (who weren’t hospitalised with their initial COVID infection) had an increased risk of death for up to six months and increased risk of hospitalisation for up to 18 months. However, at two years, they remained at increased risk of 25 conditions.

So, while people who were initially hospitalised for COVID had worse outcomes over the two-year follow-up, there was still a substantial burden of illness in people who initially had milder COVID. This included a risk of clots and blood disorders, lung disease, fatigue, gut disorders, muscle and joint disorders and diabetes.

Other findings

A separate cohort study followed more than 208,000 veterans with COVID over two years. It showed that overall, 8.7 percent died compared with 4.1 percent in the uninfected control group. The risk of death was concentrated in the first six months after infection.

A third, not yet peer-reviewed and smaller cohort study of 341 people with long COVID from Spain, found only 7.6 percent of them recovered at two years.

Another significant (not yet peer-reviewed) study from the United Kingdom assessed diabetes risk after COVID by following 15 million people in England from 2020–21. It found a 30–50 percent elevated risk of new type 2 diabetes after COVID. This increased risk persisted up to two years. But the risk for type 1 diabetes risk did not persist.

An Australian (not yet peer-reviewed) study followed 31 people who developed long COVID and 31 matched controls who recovered from COVID for two years. It found that most of the concerning immunological dysfunction effects that had been present at eight months, had resolved by two years. While almost two-thirds of those with long COVID (62%) reported improved quality of life over the two years, one-third were still struggling in this regard two years after their infection.

Finally, a recent whole-body positron emission tomography (PET) imaging and biopsy study showed prolonged tissue level immune-activation and viral persistence in the gut for up to a remarkable two years after COVID.

Limitations

It’s important to note the observational studies have some inherent limitations.

The US veterans cohort studied by Al-Aly is nearly 90 percent men, with an average age of 61 years, which is different to groups most at risk of long COVID.

They acquired their initial infection in 2020, before Omicron, before vaccination and before therapies – all of which are protective against long COVID to a degree.

Having said that, long COVID still frequently occurs in vaccinated people infected with Omicron.

Treatment trials

Increasing understanding about underlying mechanisms of long COVID, such as those involving persistent virus and effects on mitochondria – the powerhouse of the cells – can lead to treatment options that need to be trialled.

In July 2023, the White House established the Office of Long COVID Research and Practice. Two randomised trials are testing whether the antiviral nirmatrelvir-ritonavir (Paxlovid) can treat long COVID are currently recruiting patients.

A separate randomised, placebo-controlled trial has shown that metformin, a commonly prescribed anti-diabetic medication, taken for two weeks (and taken within three days of testing positive for COVID) reduced the chance of developing long COVID by 41 percent. The mechanism may involve an effect on mitochondria or directly on the virus.

Prevention matters

Taken together, these studies on the longevity of long COVID add substantially to the case to fast-track the development of interventions and therapies to prevent and/or cure the condition.

In the meantime, it’s crucially important to prevent (re)infections in the first place to reduce the future burden of long COVID, already estimated to be greater than 65 million people globally.

Breathe clean air by ensuring indoor spaces are well-ventilated. In poorly ventilated or crowded spaces, wear a well-fitted and high-quality mask (a P2, KN95 or N95 mask), and/or use air filtration devices suitable for the space you are in.

Keep up to date with boosters. And get tested so you can get antiviral treatment if you’re eligible.

If you suspect you have long COVID, discuss this with your GP, who may refer you to specialised services or multidisciplinary care.

Author details and disclosures

Associate Professor Suman Majumdar is the Chief Health Officer – COVID and Health Emergencies, Deputy Program Director (Health Security and Pandemic Preparedness) and Principal Research Fellow at the Burnet Institute. An infectious diseases physician, public health practitioner and researcher, he has experience in global health and in clinical care and public health in Australia and the Asia-Pacific region. He has appointments at the Alfred Hospital, Epworth Health Care and Monash University and worked as a Deputy Chief Health Officer in the Victorian Department of Health during the COVID-19 pandemic. through the Burnet Institute, he receives grant funding from the Australian Governemnt via the National Health & Medical Research Council of Australia, the Medical Research Future Fund and DFAT’s Centre for Health Security.

Professor Brendan Crabb AC PhD FAA FAHMS is an infectious disease researcher with a special interest in viruses and protozoan parasites, especially malaria. His research group develops and exploits genetic approaches to better understand malaria parasite biology, principally to help prioritise vaccine and drug targets. Brendan Crabb and the Institute he leads receives research grant funding from the National Health & Medical Research Council of Australia, the Medical Research Future Fund, DFAT’s Centre for Health Security and other Australian federal and Victorian State Government bodies. He is the Chair of The Australian Global Health Alliance and the Pacific Friends of Global Health, both in an honorary capacity. And he serves on the Board of the Telethon Kids Institute, on advisory committees of mRNA Victoria, the Sanger Institute (UK), the Institute for Health Transformation (at Deakin University), The Brain Cancer Centre (Australia), the WHO Malaria Vaccine Advisory Committee; MALVAC, and is a member of OzSAGE and The John Snow Project, all honorary positions.