Understanding long COVID: A family physician’s perspective

Sio-pan Chan 陳少斌, Alfred KY Tang 鄧權恩

HK Pract 2024;46:40-44

Summary

摘要

Introduction

COVID-19 infection has been rampaging the world for more than three years. Despite all our efforts in mass vaccination, it seems to be running its own course. It continues to mutate and has caused waves after waves of infections. Fortunately, it seems to have evolved into milder variants which are much less virulent and lethal. In May 2023, the World Health Organization (WHO) chief declared “end to COVID-19 as a global health emergency” although he also said “Last week, COVID-19 claimed a life every three minutes and that’s just the deaths we know about”. Apparently the world has gone back to a new sort of “normalcy” which is actually a different cognitive perception of COVID-19 infection. Regardless, no country can be spared from facing another wave of pandemic, i.e. the tens of millions of people suffering from the so-called “long COVID”. The term “long COVID” was first coined in a social media chat group long before doctors were aware of this phenomenon. Long COVID is also described by many other names such as long-haul COVID, post- COVID-19 syndrome, post-COVID-19 condition, post-acute sequelae of COVID-19 (PASC), or chronic COVID syndrome (CCS).

Definitions

There is no universally agreed definition of long COVID, in this article, we prefer to stick to the original term of “long COVID”.

The WHO defines long COVID as:

Post-COVID-19 condition occurs in individuals with a history of probable or confirmed SARS-CoV-2 infection, usually three months from the onset, with symptoms that last for at least two months and cannot be explained by an alternative diagnosis. The more common symptoms (by no means exclusive) of long COVID include a mixture of the following:

Definition

More common general symptoms:

Heart and circulatory symptoms

Joint and muscle pain

Brain (neurological or cognitive) symptoms

Mental health effects

Respiratory symptoms

Stomach and digestive symptoms

Ear nose and throat symptoms

Skin and hair symptoms

Gynaecological symptoms

Sexual problem

In many ways, the presentation of long COVID is similar to Chroinic Fatigue Syndrome, Post Intensive care syndrome, Fibromyalgia or post-viral infection such as SARS-1 or MERS. Depending on the symptomatology, the management involves many specialists of different fields including immunologists, cardiac and respiratory physicians, rheumatologists, gastroenterologists, virologists and the list goes on and on. With such diversified and non-specific symptomatology, we believe family physicians, as the first contact of patients, should play an important role in managing and orchestrating the management of long COVID patients. Therefore, it is imperative that primary care physicians should keep themselves better informed on recent progress and development in managing long COVID patients. We have performed a research on the updated information on long COVID for discussion as follows.

Prevalence

Since there is no exact definition of long COVID, it is impossible to quantify the exact prevalence of long COVID. According to the information from the World Health Organization (WHO), approximately 10- 20% of people infected with COVID-19 may continue to experience mild and long-term effects of COVID-19, which are collectively known as “Post COVID-19 condition,” or “long COVID”.1 According to the United Kingdom (UK) Office for National Statistics, it is estimated 2.1 million people living in the UK (3.3% of the population) are suffering from various severity of self reported long COVID.² In general, long COVID is more prevalent in those who had more severe symptoms in the acute phase, such as hospitalised patients. People with more than one infection are more prone to long COVID. It seems that people in the middle-age group are more prone to develop long COVID even if they have mild symptoms during the acute phase. It is generally believed that vaccination can reduce the risks of long COVID.

In Hong Kong, according to press releases of surveys from The Chinese University of Hong Kong (CUHK) and The Hong Kong Polytechnic University (HKPU) surveys, as much as 2 million and 41.8 percent of recovered patients had long COVID symptoms within six months after infection respectively.

Omicron variant appears to cause less severe acute illness than previous variants, at least in vaccinated populations. Among omicron cases, 2501 (4.5%) of 56,003 people experienced long COVID compared with 4469 (10.8%) of 41,361 people during the delta wave. Omicron cases were less likely to experience long COVID for all vaccine timings, with an odds ratio ranging from 0.24 (0.20–0.32) to 0.50 (0.43–0.59).²

Pathogenesis

Long COVID has a most heterogeneous clinical presentation including all sorts of symptoms involving nearly all organs and systems. The presentation can be continuous or intermittent. It does not correlate exactly with the initial severity of the acute illness. Even mild initial COVID disease may develop into long COVID. We would like to present some published postulations to explain the pathogenesis of long COVID, which are by no means conclusive.³

1. Direct organ/tissue damage

This is easily understandable and proportional to the severity of the initial disease

2. Chronic autoimmune response

Some long COVID patients suffering from symptoms including fatigue and shortness of breath are showing signs of autoimmune diseases like rheumatoid arthritis and lupus, as suggested by a Canadian study.4 This study identified two specific abnormal autoantibodies, which are known to attack healthy tissues causing autoimmune disease, persisted in about 30 percent of patients for a year after they were infected.

3. Chronic and low-grade inflammation

In long COVID patients, researchers have uncovered evidence of sustained inflammation and activation of the immune response. Patients with long COVID had highly activated innate immune cells, lacking naive T and B cells and an elevated expression of interferon responses (ifn-β) and (ifn-λ1), which then remained persistently high eight months after infection.5 These findings serve to provide a framework through which we can define and diagnose long COVID more accurately.

4. Micro-coagulopathy

Impaired coagulation that contributes to ischemiareperfusion injury due to the formation of fibrinolysis-resistant fibrin, amyloid microclots, which may be a key mechanism responsible for development of long COVID.⁶

5. Mitochondrial dysfunction

Studies had strongly pointed to patients' inability to utilise fat as energy because of mitochondrial damage by oxidative stress during the acute phase of COVID infection.⁷ Mitochondrial dysfunction results in impaired synthesis of ATP for energy at cellular level.

6. Persistent Sars-COVID 2 viral antigen/ spike protein in tissue.⁸

This study had shown that about 67% of long COVID patients had one of the viral antigens present within their plasma at any point of time following recovery from acute infection. The spike antigen was detected in 60% of long COVID patients. It is postulated that long COVID symptoms may be related to spike-induced hyperinflammation resulting from altered activation of the T-cell receptor repertoire by superantigenlike spike motifs. Without causing a cytokine storm, this may lead to malfunction of the cells in vascular lining and blood-brain barrier.

7. Hypothalamic-pituitary adrenal axis dysfunction⁹

When comparing the clinical presentations of long COVID with chronic adrenal insufficiency, some overlapping between the conditions can be seen, suggesting that long COVID might be related to some form of adrenal dysfunction.

8. Mast Cell Activation Syndrome (MCAS)¹⁰

Long COVID may progress in association with the development of mast cell activation syndrome (MCAS). High D-dimer levels and blood urea nitrogen were observed to be risk factors associated with pulmonary dysfunction in COVID-19 survivors 3 months post-hospital discharge with the development of long COVID.

9. Gut microbiome dysfunction¹¹

A study funded by the Hong Kong Government has implicated the gut microbiome in the severity of COVID-19 disease. Given that the gut microbiome has a major role in immunity, a disordered immune response to COVID-19 infection, induced by resident microbes, may affect the recovery process too.

10. Viral reactivation hypothesis¹²

Viral reactivation has been proposed as a potential cause of long COVID. Studies have suggested that reactivation of viruses such as Epstein- Barr virus (EBV), cytomegalovirus (CMV), and herpes simplex virus (HSV) may contribute to the development of long COVID symptoms.

Management and treatment

Since so little is known about the pathophysiology of long COVID, there is in fact little we can offer to the patients apart from symptomatic and psychological support. The Royal College of General Practitioners' Rapid Guidelines and others have proposed some basic investigation.¹³

Explanations on the rationale of the proposed blood tests will follow:

1. Blood tests, which may include a full blood count, kidney and liver function, C reactive protein, ferritin, (D-dimer), troponin, NT-pro-BNP and thyroid function, Vitamin D, HbA1C.
2. CXR (low dose CT) by 12 weeks after acute COVID-19 if the person has persistent respiratory symptoms and has not had one already.
3. ECG, Echocardiogram, CT coronary angiogram if indicated.
4. Exercise tolerance test according to the condition of the patient.

Rationales for some of the blood tests: post COVID-19 infection may induce a chronic hyperimmune state, elevated ESR, C-reactive protein, ferritin are biomarkers for inflammation. D-dimer test is indicated in suspected micro-coagulation condition. Troponin is a marker of myocardial damage and NT-pro BNP is indicated for suspected heart failure. Vitamin D deficiency is very common and should be corrected for its important role in immune modulation. Liver function test may demonstrate liver enzyme elevation and renal function may show impaired renal function by a decrease in e-GFR.

Some of the better known empirical treatment includes:

Discussion

The world has been plagued by SARS-CoV-2 for more than 3 years. By now, most countries, including China and Hong Kong, have now taken a much more relaxed attitude towards this disease. However, the impact of SARS-CoV-2 is far from over. No country can be spared from the huge burden of the long COVID sequelae. At present, the exact pathophysiology of long COVID remains a mystery. Most treatments are merely supportive, symptomatic or empirical. The management of long COVID often involves a multidisciplinary approach. As such, family physicians are in an ideal position to play a key role in the long-term holistic care of long COVID patients. Guidelines of how primary care physicians can manage long COVID patients are readily available in some overseas centres.¹³ We hope to stimulate more awareness on long COVID by primary care workers. Hopefully more local studies will be carried out to reflect the real status of long COVID in our locality.

References

1. WHO News Room https://www.who.int/europe/news-room/fact-sheets/item/post-Covid-19-condition
2. Antonelli M, Pujol JC, Spector TD, et al. Risk of long COVID associated with delta versis omicron variants of SARS-CoV-2. Lancet. 2022 Jun 18;399(10343):2263-2264.
3. Castanares-Zapatero D et al. Pathophysiology and mechanism of long COVID: a comprehensive review, Ann Med. 2022 Dec.
4. Son K., Jamil R., Chowdhury A., et al. Circulating anti-nuclear autoantibodies in COVID-19 survivors predict long-COVID symptoms. European Respiratory Journal 2022; DOI: 10.1183/13993003.00970-2022
5. Phetsouphanh C., Darley D.R., Daniel B., et al. Immunological dysfunction persists for 8 months following initial mild-to-moderate SARS-CoV-2 infection Nature Immunology. Nature Immunology 23, 210–216 (2022).
6. Simone Turner S., Naidoo C., Usher T., et al. Increased Levels of Inflammatory Molecules In Blood Of Long COVID Patients Point To Thrombotic Endotheliitis. medRxiv 2022.10.13.22281055; https://doi.org/10.1101/2022.10.13.22281055
7. Guntur V.P., Vamsi P., Nemkov R., et al. Signatures of Mitochondrial Dysfunction and Impaired Fatty Acid Metabolism in Plasma of Patients with Post-Acute Sequelae of COVID-19 (PASC). Metabolites 2022, 12(11), 1026.
8. Swank Z., Senussi Y., Manickas-Hill Z. et al. Persistent Circulating Severe Acute Respiratory Syndrome Coronavirus Spike Is Associated With Postacute Coronavirus Disease 2019 Sequelae. Clinical Infectious Diseases. 2023 Feb 8;76(3):e487-e490.
9. Kanczkowski, W., Beuschlein, F. & Bornstein, S.R. Is there a role for the adrenal glands in long COVID?. Nat Rev Endocrinol 18, 451–452 (2022).
10. Batiha, G.ES., Al-kuraishy, H.M., Al-Gareeb, A.I. et al. Pathophysiology of Post-COVID syndromes: a new perspective. Virol J 19, 158 (2022).
11. Liu Q, Mak JWY, Su Q, et al. Gut microbiota dynamics in a prospective cohort of patients with post-acute COVID-19 syndrome. Gut 2022;71:544-552.
12. Naendrup JH, Borrega JG, Böll B, et al. Reactivation of EBV and CMV in Severe COVID-19 --Epiphenomena or Trigger of Hyperinflammation in Need of Treatment? A Large Case Series of Critically ill Patients. Crit Care Med. 2021;37(9):doi:10.1177/08850666211053990.
13. Managing the long term effects of COVID-19: summary of NICE, SIGN, and RCGP rapid guideline: BMJ 2022;376:o126.