Long Covid: The hidden iceberg of Covid-19

Summary

In the wake of new variants and the relentless spread of Covid-19, understanding the complex nature of Long Covid is crucial. In this article, I aim to present useful information on the risk factors, plausible pathophysiological mechanisms and treatment of Long Covid.

The obscure nature of Long Covid is a conundrum both for doctors and patients. To mitigate the burden of Long Covid, early identification of disease signs, appropriate treatment and timely access to rehabilitation care is vital. I believe that strengthening the 4 Rs (Reporting, Recognition, Rehabilitation and Research) through close collaboration between government organisations, pharmaceutical industries, patients and health care providers could reduce the impact of Long Covid.

Content

Long Covid, characterised by heterogeneous Covid-19 disease sequelae, affects multiple organ systems. On average, 1 in 10 Covid positive patients develop persistent symptoms beyond 12 weeks [1], adding to an alarming five million cases globally.

Despite Long Covid being a burgeoning health concern, the risk factors and pathophysiology remain obscure. The varied clinical presentation of Long Covid poses a diagnostic challenge to clinicians. In order to establish a framework for better clinical decision making, understanding the complex nature of Long Covid is essential.

WHO definition 

The World Health Organization (WHO) defines Long Covid as ‘Post Covid-19’, a condition that occurs in individuals with a history of probable or confirmed SARS-CoV-2 infection, usually beginning within three months of the initial onset of Covid-19.[2]

Some common symptoms are fatigue, shortness of breath and cognitive dysfunction, but there are many others. The symptoms may have new onset or persist from the time of initial infection, lasting for at least two months. They cannot be explained by an alternative diagnosis. 

Who is at high risk? 

The US Centers for Disease Control and Prevention noted that people with higher body mass index, those above 40 years of age and those with pre-existing medical conditions are at higher risk of developing Long Covid.[3] Women are at increased risk due to intense immune responses influenced by genetic and hormonal factors  [4], and certain ethnic groups are more prone to develop Long Covid than others.

Recent reports show both hospitalised and non-hospitalised Covid patients experience Long Covid.[5] However, patients with severe disease and those who have more than five symptoms during their first week of illness are at greater risk.[6]

What causes Long Covid? 

The precise mechanisms causing Long Covid are unknown, and are likely to be multifactorial. Plausible mechanisms that could differ or co-exist among individuals, are: 

• virus-specific pathophysiological changes like endothelial damage, and micro-vascular injury. 
• maladaptation of Angiotensin Converting Enzyme 2 (ACE2) pathway leading to abnormal autonomic, endocrine, metabolic and neurological functions. 
• autoantibodies provoking chronic inflammation and long term Covid-19 sequelae. 
• expected sequelae of post-critical illness such as new or worsening abnormalities in physical, cognitive and psychiatric domains.[7]

In addition, alterations in host microbiome [8], and presence of persistent SARS-CoV-2 reservoirs in tissues [9] like gut, liver, gall bladder and lymph nodes could trigger long-term morbidity. 

How to treat Long Covid? 

Long Covid has no specific clinical presentation and the symptoms often fluctuate and vary between individuals. Hence, a holistic and multidisciplinary approach is essential for the treatment of Long Covid.[7]

The first step is careful evaluation of the symptoms and comprehensive clinical assessment of the patient’s history. Based on the initial evaluation, investigations like chest X-ray, blood tests, electrocardiogram (ECG) and exercise tolerance tests should be performed to distinguish from other possible diagnoses. 

In the next step, depending on the severity of the symptoms, individualised treatment plans should be devised. Symptoms including cough, fever, generalised body pain and fatigue are treated symptomatically. On the other hand, critically ill patients with signs of severe lung disease, cardiac chest pain, coagulation issues or psychiatric symptoms require close monitoring with intensive treatment. In general, patients affected by Long Covid need psychological support as well as physical rehabilitation care.

How do vaccines prevent Long Covid? 

There is evidence that vaccination plays an important role in alleviating the impact of Long Covid. According to some studies, vaccinated individuals are around 50% less likely to develop long Covid [10] than unvaccinated individuals. Recent studies show that priming the immune system with Covid-19 vaccines enhances immunity towards SARS-CoV-2 virus [11], thereby eliminating the viral reservoirs. Vaccines also help prevent persistent dysregulated immune response, limiting the chronicity of the disease.

Ways forward in preventing and treating Long Covid

The impact of Long Covid is unparalleled, and the condition remains enigmatic. To mitigate the effects of Long Covid, understanding the pathogenesis, risk factors and clinical presentation is important. Preventive measures like vaccination, social distancing and consistent use of masks should be diligently followed. Lastly, reinforcing the 4 R’s – Reporting, Recognition, Rehabilitation and Research – could reduce the burden of Long Covid.

Related reading

The mythology of Long Covid - 9 common misconceptions (20 December 2021)
Long Covid: Information gaps and the safety implications (7 June 2021)
Long Covid podcast: Claire Hastie - founder of Long Covid Support, & advocate (10 November 2021)

References

1 D Altmann, R Boynton. Decoding the unknowns in long covid. BMJ. 2021;372:n132
2 A clinical case definition of post COVID-19 condition by a Delphi consensus. World Health Organization. 6 October 2021
3 K Yomogida, S Zhu, F Rubino et al. Post-Acute Sequelae of SARS-CoV-2 Infection Among Adults Aged ≥18 Years — Long Beach, California, April 1–December 10, 2020. MMWR Morb Mortal Wkly Rep 2021;70:1274–1277
4 E Ortona, D Buonsenso, A Carfi et al. Long COVID: an estrogen-associated autoimmune disease?. Cell Death Discov. 2021;7:77
5 A Mohamed-Hussein, M Amin, H Maklouf et al. Non-hospitalised COVID-19 patients have more frequent long COVID-19 symptoms. International Journal of Tuberculosis and Lung Disease. 2021;25:9:732-737
6 C Sudre, B Murray, T Varsavsky et al. Attributes and predictors of long COVID. Nat Med. 2021;27;626–631
7 H Crook, S Raza, J Nowell et al. Long covid—mechanisms, risk factors, and management. BMJ. 2021;374:n1648
8 Y Kit Yeoh, T Zuo, G Chung-Yan Lui et al. Gut microbiota composition reflects disease severity and dysfunctional immune responses in patients with COVID-19. Gut. 2021;70:698-706 
9 V Marx. Scientists set out to connect the dots on long COVID. Nat Methods. 2021;18:449–453
10 V Tran, E Perrodeau, J Saldanha et al. Efficacy of COVID-19 Vaccination on the Symptoms of Patients With Long COVID: A Target Trial Emulation Using Data From the ComPaRe e-Cohort in France. Preprint available at SSRN: https://ssrn.com/abstract=3932953
11 H Ledford. Do vaccines protect against long COVID? What the data say. Nature, 23 November 2021

About the Author

Dr. Shruthi K V is a doctor specialising in clinical pharmacology. She has an interest in applied research with an emphasis on patient safety and is an Associate Medical Safety Director at IQVIA in Stockholm, Sweden.