Long COVID symptoms, research, and effects on society: global expert agreement

The World Health Organisation (WHO) lists 'confirmed' cases of COVID-19 at 775 million [1]. This number is likely much greater due to the limitations of testing and very limited surveillance [2]. Following acute COVID-19, the risk of developing symptoms that last beyond the initial illness, is estimated to be 15% per individual per infection [2]. This ailment is often termed Long COVID, but has several names including post-COVID conditions (PCC), post-acute COVID-19 or post-acute sequelae of SARS-CoV-2 infection (PASC).

Defining, diagnosing, treating, and understanding Long COVID and its impact on society pose some of the most significant scientific and medical questions of our time. The true global prevalence of Long COVID is likely much higher than 100 million as risk is amplified by reinfection [3] similarly affecting all ethnicities, with most cases in 18- to 64-year-olds. Women are affected approximately twice as often as men [4]. SARS-CoV-2 can also cause organ damage in individuals both with and without symptoms [5, 6].

From July 2023 to February 2024, a global panel of experts of more than half physicians diagnosing and treating Long COVID, as well as researchers and those with lived experience, engaged in a modified Delphi consensus process [7, 8]. Topics included definition, diagnosis and clinical assessment, treatment, research, and socioeconomic factors related to Long COVID. The overarching goal was to provide recommendations to physicians, researchers and policy makers.

The strongest consensus areas were in diagnosis and clinical assessment (1 statement unanimous, 19 with A-level, 13 with B-level and 3 with C-level statements), general research (24 A-level statements, 13 B-level and 6 C-level), research on children and young people (15 A-level statements and 6 B-level), and funding, economic and societal issues (4 A-level statements, 3 B-level, and 1 C level). Organ or body damage (1 A-level, 8 B-level and 1 C-level statements) and Long COVID and vaccines (2 A-level, 7 B-level, and 1 C-level statements) require more research before we can reach a broad consensus. Not surprisingly, there less congruence on treatment (9 A-level, 13 B-level and 15 C-level statements) and evaluation of treatment (2 A-level, 5 B-level and 2 C-level statements) as clinicians around the world have adopted their own practices in the absence of clear guidelines or a strong evidence-base. This reinforces the need for translational research and trials.

Statements not reaching consensus are listed in Table S2 of the supporting information. Of these 34 statements, 8 deal with definition, 5 with diagnosis, 17 with treatment, 2 with evaluation of treatment, 1 statement on vaccination improving Long COVID and 1 statement nearly reaching consensus calling for routine cognitive impairment testing in critical professions (discussed below). It is not surprising that definition and treatment have the most statements not reaching consensus as they are the areas most in need of clarity in understanding Long COVID.

To-date, like diagnostic approaches, there are no evidence-based guidelines on the treatment of Long COVID and no specific validated procedures that are clinically available to treat this complex disorder. Consensus shows it requires an individual and tailored approach to each patient accounting for patient history and physical examination and that multidisciplinary team management is beneficial.

Treatment has focused predominantly on the demonstrable pathologies and manifestations of their many varied presentations and identified processes. Midodrine, ivabradine beta-blockers, and fludrocortisone can be used for POTS [25 –27], whereas a combination of 5-HT1 inhibitors and two antihistamines can be helpful for management of symptoms of MCAS [28]. Statins can be used for hyperlipidaemia and melatonin for sleep dysrhythmia and endothelial protection. There have been several randomised controlled studies but no single unifying therapy. Considerable gaps remain in treatment protocols including the use of anticoagulants, probiotics [29], and mitochondrial supplements. Larger trials of antivirals for both prevention and treatment of Long COVID are needed. A small RCT showed no benefit of 15 days of nirmatrelvir-ritonavir [30]. Whilst there is a vast array of therapies for specific issues, there are few well-performed RCTs for treatment efficacy in Long COVID.

A summary of significant treatment criteria from consensus is given in the Supporting Information (Table S3). Clearly there is agreement that multidisciplinary team tailored therapies are essential [31]. The management of POTS, sleep disturbance and MCAS were highly conserved across both Delphi rounds 2 and 3. Attention to clotting abnormalities, whilst considered important, the consensus suggests that this is best undertaken when biomarkers are available, and expertise is required for treatment oversight.

There was excellent consensus for the appropriate treatment of mood disorders and the conjunctive value of psychological therapies and support [32]. Formal neurocognitive evaluation both at presentation and at follow-up is strongly supported. The usual standard evaluation tools were considered inadequate and more comprehensive testing was strongly recommended. This is critical as COVID-19 can lead to long-term cognitive impairment [33].

There was considerable caution around exercise and pulmonary rehabilitation, particularly in the absence of an adequate clinical evaluation and exclusion of POTS and PEMS [34]. The value of non-invasive vagus nerve stimulation therapies (including stimulators, cold exposure breathwork, mindfulness, and trauma release) was supported, but not strongly. This may reflect local practices and experience as well as the lack of RCT's for external stimulators and the efficacy of non-conventional treatments. Tracking devices for assessment of heart rate, sleep quality and pacing for patients, whilst Level B, may have value for both clinicians and patients. Group data for prospective evaluation of therapeutics may be where this lies in the future.

The overarching consensus from this Delphi, with regards to research, is the need for a designed framework. This will allow for a structured approach to addressing Long COVID, outlining key focus areas of interest, concern, and need.

The consensus statements on research and particularly on organ damage, align closely with the existing literature, which increasingly supports a multi-system involvement in Long COVID [6, 35]. Research to date indicates a complex interplay of factors that may contribute to the persistence of symptoms, suggesting the need for a holistic approach in future studies. Ongoing research has shown that Long COVID impacts the immune system [36] and there is an increased risk of cardiovascular complications such as heart attacks, coronary heart disease, heart failure, and deep vein thrombosis among those infected [37 –39]. These cardiovascular issues are often precipitated by disruptions in endothelial cell function, which regulate the flow of substances into and out of tissues and are a focal point of the virus's deleterious effects [40]. The virus also poses significant neurological risks [41].

Consistent with the consensus agreement, persistent symptoms have been associated with metabolic and endocrine systems, potentially leading to diabetes through mechanisms involving pancreatic dysfunction and altered insulin responses [42]. Reproductive health issues in both males and females have been noted [43 –45]; with the virus affecting hormonal balances, potentially disrupting menstrual cycles, impairing fertility, and complicating pregnancies. Kidney damage from the virus can escalate to chronic kidney disease, and gastrointestinal symptoms, may persist or lead to chronic conditions, reflecting the virus's ability to infect intestinal cells and possibly alter the gut microbiome [46, 47]. This extensive involvement of diverse bodily systems illustrates the critical need for a multi-disciplinary approach in research and treatment strategies for COVID-19 and Long COVID, highlighting the virus's ability to cause systemic damage beyond the respiratory system.

The research directions highlighted in the consensus emphasise the importance of investigating the relationship between Long COVID and other health conditions, such as sleep disorders, dysbiosis, and PEM. This suggests a complex interplay between Long COVID and pre-existing vulnerabilities or concurrent health issues. As most of the COVID-19-induced pathophysiology is immune-mediated or even immunologically driven, interactions with any existing or future inflammatory conditions are likely to be important at an individual level. The emphasis on endothelial dysfunction, coagulopathy, and mitochondrial dysfunction points to a nuanced understanding of the disease's pathophysiology, indicating potential pathways for targeted treatments.

Global SARS-CoV2 vaccination programs have saved lives, and research shows on a population basis that COVID vaccines reduce the risk of long COVID [48, 49]. However less is known about the individual effects of vaccination on patients who have pre-existing immune mediated inflammation from Long Covid. A common question our long COVID clinicians are asked by patients is whether the vaccine will make their long covid symptoms better or worse. To our knowledge this has not been studied and our experts showed consensus agreement that this was an important area for further research so clinicians can give patients scientifically informed answers. There was not agreement with the statement, 'Long COVID can improve with vaccination.' The consensus and nonconsensus show that vaccination and Long COVID is an issue that is still not clear.

In parallel, the consensus points to the need to address factors that may lower the incidence of Long COVID, such as reducing SARS-CoV-2 transmission and improving indoor air quality, highlighting the intersection between public health measures and individual health outcomes. This underscores the complexity of Long COVID and the necessity for longitudinal studies to fully comprehend its long-term implications.

The growing number of reports and studies on Long COVID in children show that dedicated research into how the condition affects this vulnerable population is imperative. Consensus points from recent rounds highlight the importance of studying the effects on educational performance, mental health, and physiological development. These priorities resonate with recent findings which underscore the unique challenges faced by children with Long COVID [50], including the potential for significant developmental disruptions and the need for tailored clinical approaches.

Existing evidence on Long COVID in children is scarce, partly due to a lack of a standardised case definition, short follow up duration, and heterogenous study designs, resulting in wide variation of reported outcomes [51]. Stigmatisation of children, due to a lack of an understanding or ignorance about the disease in children has also been reported [45]. There has, however, been evidence for widespread endothelial damage in children with Long COVID [52, 53].

A pivotal area of concern is the interaction between Long COVID and the education system, highlighting the need to explore how the condition affects school attendance and performance. This extends to the potential cognitive repercussions, including impacts on the developing brain and resultant challenges in learning and development. Of note, meta-analysis identified five paediatric studies documenting abnormal brain imaging findings in children and young people with Long COVID [54]. Moreover, the physical health consequences of Long COVID in children, such as new onset diabetes and alterations in the immune system, underscore the critical need for studies tailored to the paediatric population. The investigation into the long-term physiological effects, including those as specific as thrombotic endotheliitis, presents a clear directive for future research endeavours. This is particularly relevant considering recent pilot studies documenting objective physiological abnormalities in young patients with Long COVID, including dysautonomia [55, 56], pathological cardiopulmonary exercise testing [57], immune dysregulation [58], and platelet activation [53].

It is important to note that the burden of post-acute sequelae of COVID-19 may go beyond what is currently referred to as Long COVID. For example, there may be sub-clinical impacts following a SARS-CoV-2 infection as well as symptoms that may not be considered related to Long COVID. Unrecognised sequelae include new onset health conditions [3, 59] or worsening of pre-existing health conditions [60] in adults and children. Diverse medical presentations may not be considered Long COVID due to a lack of awareness. An area of research agreed on by consensus is to develop biomarkers for Long COVID, and this can be extended to unrecognised conditions including the heart, brain, vasculature, and more.

The consensus reached through the modified Delphi process offers a nuanced view of the global response required to address the socioeconomic challenges of Long COVID. More effective strategies and interventions are needed, especially for more impacted groups, since disparities appear exacerbated by Long COVID. A mixed-methods study across five countries explored the economic and social impacts of COVID-19 revealing significant disparities based on age, education, household size, and income [61]. Also, the well-known COVIDENCE UK study highlights the economic vulnerability caused by COVID-19, showing increased short-term household income inadequacy and long-term sickness absence from work, indicating a cycle of impaired health and poor economic outcomes [62]. Additionally, Long COVID requires a reinforced epidemiological surveillance program or periodic reviews for the health personnel who fall ill with it, having been the ones who provided direct care to patients who suffered from COVID-19.

Studies have also quantified impacts of Long COVID on workforce participation, sick leave, disability, and economic activity. A UK cohort study quantified the health and economic burden of Long COVID, finding substantial impacts on health-related quality-of-life and emphasising the need for continued support and research for those affected [63]. Another population-based cohort study in Hong Kong evaluated the long-term spill-over effects of COVID-19 on people with non-communicable diseases, showing significant disruptions in health outcomes and healthcare costs, stressing the need for optimised care [64].

In synthesising the consensus points, it becomes evident that tackling Long COVID requires a concerted effort from all sectors of society. For example, Uwishema et al. (2022) highlight how COVID-19 disrupts healthcare access for neurological patients in Africa, a challenge likely magnified by Long COVID's chronic burden [65] and Uwishema and Boon emphasize addressing neurological care inequities, a priority echoed in Long COVID's global burden on underserved populations [66]. The insights gained from this modified Delphi study not only inform immediate policy and research priorities but also illustrate the broader societal shifts necessary to deal with the pandemic's long-term effects effectively. The consensus conclusions can be aggregated into the following overarching considerations: (1) an interdisciplinary approach is needed to address the issue of Long COVID; (2) educational adjustments and policy implications need to be discussed and implemented; and (3) corporate responsibility and public health funding are needed. Additionally, the near consensus calling for routine cognitive impairment testing in critical professions underscores the practical implications of Long COVID on workforce safety and productivity.

One of the strengths of this study is the broad scope covering the entire issue of Long COVID. Another strength is we minimized potential bias by generating a large, geographically and diverse panel from multiple sources where nominees from the working group were combined with a comprehensive literature search to identify Long COVID authors. These made up most of the panellists. Additionally, we implemented a modified Delphi methodology where we used experts identified by literature search to answer questions about the most important topics in Long COVID. This allowed the most unbiased approach possible to an understanding of this complex topic and development of subsequent statements. The large sampling of physicians working with LC patients, and researchers, gives this consensus credibility, especially in the areas of understanding what Long COVID looks like, how it is diagnosed and treated, as well as what should be researched. Finally, statements from the second round of Delphi process were made clearer for round three with the help of open-ended comments after each section of the survey.

The Delphi method has many advantages, but limitations also exist. One limitation is that the survey was voluntary and, hence, this self-selection might have omitted some experts. However, everyone who wanted to participate was able to do so. It is important to note that a small number of the panel experts (16%) were also on the extended committee. This number is small making it unlikely to be significant. Another limitation is that Long COVID is an evolving syndrome, and the science reviewed in this paper covers a time period from mid-2023 to mid-2024; the scientific evidence will have to be revisited later. A follow up survey might be useful when diagnosis and treatment are more refined. One consideration that is difficult to address is that there might be insufficient data due to lack of good healthcare protocols especially in lower-middle income countries and issues related to stigmatization with people not going to the hospital, missed data, lack of funding and people not able to afford medical visits and therefore not being assessed for Long COVID. Furthermore, differences in how long covid cases are managed in high-income vs low-middle income countries might lead to differences across panelists. This limitation should be addressed by the broad range of countries used in this survey.

An important concern can be raised that there is a lack of randomised controlled trials in the areas of diagnosis and treatment of Long COVID. These still need to be developed, but our consensus establishes the groundwork for implementation of clinical care for people with Long COVID.

This modified Delphi study is the first to provide international consensus regarding the clinical evaluation and medical investigation of Long COVID with expert consensus recommendations to physicians. Gaining consensus agreement from 179 experts around the globe we establish conditions for diagnosis of different subgroups within the Long COVID umbrella. Strong consensus was gained for assessment and treatment of Long COVID-associated conditions, including POTS, MCAS, insomnia, new onset dyslipidaemia, diabetes, and hypertension. Consensus was also achieved that cardio-metabolic disturbance should be ruled out before prescribing graded exercise therapy as treatment. Biomarkers, where available, may be useful when monitoring treatment response to Long COVID.

Our expert panel agreed that further research was urgently needed for Long COVID. It was recommended that an international task force should be developed to oversee research priorities and facilitate/encourage global collaborative efforts and data sharing. Instead of abandoning public health related to infectious diseases, governments need to reaffirm priorities. There are over 400 million people worldwide affected by Long COVID and it is not just for covid, but for all post viral syndromes, that this work needs to be done. Clear consensus was reached that the impacts of COVID-19 infection on children should be a research priority (e.g. prevention of transmission in schools, long-term impacts of infections, impacts on learning/development, etc.). Consensus was also reached on the need to determine the effects of Long COVID on societies and economies, and that governments need to prioritise investment in public health protections to prevent reinfections.

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