Long-term Effects of COVID-19
(Long Covid)

Welcome to our Long Covid resource centre. As with our COVID-19 communications, we have compiled ongoing evidence-based research and information regarding the condition.

If you are aware of helpful research or literature in this field we would be very grateful for your input at longcovid@otandp.com.

 

About Long Covid

As we continue to learn more about COVID-19, we are just beginning to understand the long-term effects of the infection.

Long Covid is a multisystem, inflammatory condition where COVID-19 symptoms continue to linger months beyond the initial illness, or new systems develop weeks or months after the acute infection has subsided[1].

Symptoms may include debilitating fatigue, brain fog, shortness of breath, heart palpitations, and exercise intolerance, among many others[2]. The World Health Organisation estimates that there have been more than 200 symptoms reported in patients[3].

Although the understanding of Long Covid is still in its infancy, the research suggests that the condition is widespread[4]. The UK Office of National Statistics (ONS) found that 13.7% of Covid positive people reported at least one symptom after twelve weeks based on a cohort of 20’000[5].

A small study of 30 discharged patients in Hong Kong led by City University suggested that 80% of patients had at least one persistent symptom at six months after infection and one-third of patients had more than three symptoms at six months[4].

 

Long Covid Classifications

According to the National Institute for Health and Care Excellence (NICE), to effectively diagnose, treat and manage a condition, it needs to be defined and distinguished from other conditions[6].

The following classification system has been developed in the UK, with a similar model put in place by the NIH in the US:

  • 4 Weeks
  • 4-12 Weeks
  • 12+ Weeks
  • Long Covid

Acute COVID-19

Symptoms of COVID‑19 for up to 4 weeks.

Ongoing COVID-19

Symptoms of COVID‑19 from 4 weeks up to 12 weeks.

Post Covid / Post Acute Covid Syndrome (US)

Symptoms of COVID-19 last 12+ weeks while the possibility of an alternative underlying disease is also being assessed.

Long Covid

Symptoms that continue or develop after acute, ongoing and post COVID-19, and can’t be explained by an alternative diagnosis.

Who is More Likely to Get Long Covid?

Unlike acute infection survival rates, Long Covid affects people of all ages, including children and young people[7].

Research so far suggests that Long Covid disproportionately affects women, consistent with autoimmune conditions like chronic Lyme disease [8].

 

Current Long Covid Theories

Post-viral illnesses aren’t a new phenomenon, there have been links between viral infection and some form of post-viral fatigue, for example, SARS in 2003. In Hong Kong, a study amongst SARS survivors found that over 40% of respondents reported a chronic fatigue problem 40 months after infection[9]. Similarly, in the Middle-Eastern Respiratory Syndrome Coronavirus (MERS-CoV) outbreak, prolonged symptoms and fatigue were reported up to 18 months after acute infection[10].

There are broadly three different theories, which are not mutually exclusive, for the prevalence of Long Covid:

  1. The persistence of Sars-Cov-2 viral infection or viral debris
  2. Autoimmune reactions to the primary viral trigger
  3. Ongoing inflammatory reaction

Unfortunately, the lack of a single specific test makes the diagnosis of Long Covid challenging. Current treatment globally is based on managing the specific symptoms individual patients are experiencing.

 

patient getting information on Long Covid

 

Post-acute COVID-19 Sequelae and Diagnostic Tools

Cognitive Function / Neurological Symptoms

Reported Cognitive and Neurological Symptoms:

  • Headaches
  • Exhaustion
  • Brain fog
  • “Alzheimers-like” memory problems
  • Persistent impairment in sustained attention
  • Loss of smell
  • Tingling sensations
  • Inability to speak
  • Strokes
  • Seizures
  • Changes in mood
  • Sleep disturbance

There is increasing evidence to suggest that in the long term, a COVID-19 infection may cause some level of brain damage and cognitive impairment.

One British study points to brain damage directly by encephalitis (brain inflammation)[11]. Other research data also suggests Covid infection is a risk factor for strokes and dementia, affecting even younger patients[12]. Covid infections have also been linked to brain damage through a lack of oxygen.

Diagnostic Tests for COVID-19 Neurological Complications:

As there is no specific test for Long Covid, diagnosing the condition revolves around ruling out the possibility of alternative diseases. When patients present with neurological symptoms, the following battery of tests can be run:


  • Blood sample to look at the prevalence of antibodies
  • CAT scan
  • MRI
  • fMRI
  • S100b blood test (more typically used to ascertain the extent of concussion damage in concussion patients)

Current Research on Neurological Long Covid Symptoms:

  • (July 2020) Involvement of the central nervous system. Italian researchers detected viral particles in the endothelial cells lining the blood vessels of the brain in a post-mortem examination[13].
Cardiovascular Symptoms
Reported Cardiovascular Symptoms:
  • Heart beating rapidly
  • Heart palpitations
  • Chest tightness or pain
  • Chest discomfort
  • Feeling lightheaded or dizzy
  • Shortness of breath
  • Myocardial hypertrophy
  • Coronary artery atherosclerosis
  • Focal myocardial fibrosis
  • Acute myocardial infarction
  • Cardiac hypertrophy

One of the most commonly reported symptoms after a COVID-19 infection is heart palpitations and tightness of the chest, illustrating that the virus can affect the heart.

A study published in the British Medical Journal cited that cardiopulmonary symptoms, especially difficulty breathing (dyspnoea) were the most commonly reported. 35.7% felt symptoms 3-months post covid, and 22.1% continue to feel symptoms 6-months post covid[14]

Diagnostic Tests for COVID-19 Cardiovascular Conditions:

As there is no specific test for Long Covid, diagnosing the condition revolves around ruling out the possibility of alternative diseases. The following tests can be run to understand cardiovascular health:

  • Cardiac scan/Cardiac MRI
  • Measuring levels of circulating endothelial cells (CECs)
  • Endothelial activation markers
  • Electrocardiogram
  • Echocardiogram
Gastrointestinal Symptoms
Reported Gastrointestinal Symptoms:
  • Loss of appetite
  • Nausea
  • Acid reflux
  • Diarrhoea
  • Vomiting
  • Abdominal pain
  • Bloody stools

A Lancet study on Gastrointestinal sequelae post-covid infection found that loss of appetite, nausea, acid reflux and diarrhoea are common in patients 3 months discharge from hospitalisation due to COVID-19[15].

There are also a few studies linking gastrointestinal symptoms in children. One Spanish study found that ​​70% of children around 80.5 months old had reported abdominal pain linked to COVID-19 and multisystem inflammatory syndrome (MIS-C)[16]. Another study also similarly cites that MIS-C in children with COVID-19 most commonly reported fevers and gastrointestinal symptoms[17].

Diagnostic Tests for GI Conditions:

The following tests can be run to understand the GI symptoms:

  • MRI
  • CT scan
  • Faecal occult blood test
  • Stool culture
  • Ultrasound
  • Colonoscopy
  • Esophageal manometry

Current Research on GI Symptoms:
  • (July 2021) Gastrointestinal and liver diseases associated with COVID-19. Researchers went through 590 articles to find that GI manifestations are common in COVID-19 patients[18].
Psychological Symptoms
Reported Psychological Symptoms:
  • Chronic fatigue
  • Anxiety
  • Depression
  • Headaches
  • Sleep disorders
  • Memory loss
  • Impaired quality of life
  • Phobias
  • Avoidance behaviours
  • Loss of concentration
  • PTSD

While most research focuses on the short-term effects of COVID-19 on mental health, there is evidence to suggest that long-term mental health effects are anticipated to be intensified. One paper even suggests that failure to address the mental health issues stemming from the pandemic is likely to prolong its impact.

The psychological impact of diseases is not a new phenomenon. Both SARS and MERS were also found to be associated with psychiatric and neuropsychiatric symptoms, the most common ones included confusion, depressed mood, anxiety, panic attacks, psychotic symptoms and delirium [19]. During the post-illness stage, depression, anxiety, irritability, memory impairment, fatigue, insomnia and post-traumatic stress disorder were frequently reported [19], much like we are seeing with many post-covid patients.

Diagnostic Tests for Psychological Conditions:

The following tests can be run to understand the psychological impact:

  • Brain imaging
  • Anxiety screening
  • Depression screening
  • PTSD screening
Respiratory Symptoms
Reported Respiratory Symptoms:
  • Shortness of breath or difficulty breathing
  • Persistent cough
  • Chest tightness
  • Chest pain
  • Decreased exercise tolerance, having to stop to “catch” your breath
  • Tiredness or fatigue
  • Decreased peak exercise performance in elite athletes

The obvious place to check for long-term damage is in the lungs because COVID-19 begins as a respiratory infection. Many studies have published consistent findings that lower lobes of the lungs are the most frequently damaged, and the majority of the abnormalities observed by computed tomography were ground-glass opacities. These indicate inflammation, that might make it difficult to breathe during sustained exercise.

Diagnostic Tests for COVID-19 Respiratory Conditions:

As there is no specific test for Long Covid, diagnosing the condition revolves around ruling out the possibility of alternative diseases. The following tests can be run to rule out other causes and evaluate the full impact on the respiratory system.

  • Pulse oximetry
  • Spirometry
  • Sputum sampling
  • Arterial blood gas
  • Blood test for thrombo-embolism
  • Pulmonary function test
  • Chest XR
  • CT Thorax
  • High-Resolution CT Thorax
  • Pulmonary angiogram
  • Cancer markers
  • Bronchoscopy

Current Research on Respiratory Symptoms:

Post-COVID-19 survivors discharge care is recognised as essential and of high priority in the research field. Management of the respiratory sequelae is still evolving. Pulse oximetry has been suggested as a useful tool in monitoring those survivors with persistent respiratory symptoms though still waiting for evidence. Serial pulmonary function tests and half-yearly high-resolution computed tomography of the chest have also been proposed.[20][21][22]

Renal Symptoms
Reported Renal Symptoms:
  • Decreased urine output
  • Blood in urine
  • Frothy urine (bubbles in urine)
  • Swelling in the ankles, legs and around the eyes
  • Tiredness
  • Shortness of Breath
  • Confusion
  • Nausea
  • Seizures

While the full extent of the health implications in Long Covid cases is unknown, the incidence of Acute Kidney Injury, where kidneys suddenly stop working properly estimate from 2.1 up to 29%. Research on the exact mechanism is underway. The current proposal is that sepsis may lead to cytokine storm syndrome or that direct cellular injury may occur due to the virus invasion leading to acute tubular necrosis or tubulointerstitial nephritis. Hospitalized patients, even those with mild symptoms are likely to experience lingering kidney damage, and end-stage kidney disease (ESKD). Clinical guidance of how to care for this group of people is currently a top priority.

Diagnostic Tests for COVID-19 Renal Conditions:

As there is no specific test for Long Covid, diagnosing the condition revolves around ruling out the possibility of alternative diseases. The following tests can be run to rule out other causes and evaluate the full impact on the renal system.

  • Renal function test for urea, creatinine and electrolytes including sodium, potassium, calcium, magnesium, phosphate, bicarbonate
  • Glomerular Filtration Rate
  • Blood for antibodies that may attack the kidneys
  • Hepatitis panel to rule out other causes of kidney injury
  • Urine Protein
  • Renal Ultrasound
  • CT Kidneys
  • MRI Kidneys
  • MR angiography of the kidneys

Current Research on Renal Symptoms:

Renal physicians are currently researching the long-term impacts that this pandemic will cause, bracing for a surge in the population of patients battling lasting illnesses and disabilities.

  • (Sept 2021) Kidney Outcomes in Long Covid. Journal of the American Society of Nephrology[23].

Long Covid Knowledge Centre

Below we include the academic references to papers discussed in this document, in addition to external resources and support groups.

General Long Covid Research and Summary Papers

1. Centers for Disease Control and Prevention. (2021). ‘Post-COVID Conditions.’ CDC. 12 July 2021. Available at: <https://www.cdc.gov/coronavirus/2019-ncov/long-term-effects.html> [Accessed 10 September 2021].

2. National Health Service. (2021). ‘Long-term effects of coronavirus (long COVID)’ NHS. 2 September 2021. Available at: <https://www.nhs.uk/conditions/coronavirus-covid-19/long-term-effects-of-coronavirus-long-covid/> [Accessed 10 September 2021].

3. The World Health Organization. (2021). ‘Episode #47 - Post COVID-19 condition.’ WHO. 30 July 2021. Available at: <https://www.who.int/emergencies/diseases/novel-coronavirus-2019/media-resources/science-in-5/episode-47---post-covid-19-condition> [Accessed 10 September 2021].

6. National Institute for Health and Care Excellence. (2020). ‘COVID-19 rapid guideline: managing the long-term effects of COVID-19’. NICE. 18 December 2020. Available at: <https://www.nice.org.uk/guidance/ng188/chapter/Context> [Accessed 10 September 2021].

8. Kent J. Nielsen, Jesper Medom Vestergaard., et al. (2021). ‘Day by day symptoms following positive and negative PCR tests for SARS-CoV-2 in non-hospitalised health-care workers: a 90-day follow-up study’. International Journal of Infectious Diseases. March 03, 2021. Available at: <https://www.medrxiv.org/node/310296.external-links.html> [Accessed 10 September 2021].

20. Huang, Chaolin et al. (2021). ‘6-month consequences of COVID-19 in patients discharged from hospital: a cohort study’. The Lancet, Volume 397, Issue 10270, 220 - 232. 8 January 2021. Available at: <https://doi.org/10.1016/S0140-6736(20)32656-8> [Accessed 10 September 2021].

Investigations for Long Covid
4. CUHK Faculty of Medicine. (2021). ‘CU Medicine Finds New Evidence for Link between Gut Microbiome and COVID-19 Severity Microbiome Imbalance Might Influence “Long COVID” Risk’. CUHK. 18 January 2021. Available at: <https://www.med.cuhk.edu.hk/press-releases/cu-medicine-finds-new-evidence-for-link-between-gut-microbiome-and-covid-19-severity-microbiome-imbalance-might-influence-long-covid-risk> [Accessed 10 September 2021].
Clinical Manifestations of Long Covid

5. Office for National Statistics. (2021). ‘Prevalence of ongoing symptoms following coronavirus (COVID-19) infection in the UK: 1 April 2021’. ONS. 1 April 2021. Available at: <https://www.ons.gov.uk/> [Accessed 10 September 2021].

9. Lam MH, Wing Y, Yu MW, et al. (2009). ‘Mental Morbidities and Chronic Fatigue in Severe Acute Respiratory Syndrome Survivors: Long-term Follow-up’. Arch Intern Med. 2009;169(22):2142–2147. 14 December 2009. Available at: <doi:10.1001/archinternmed.2009.384> [Accessed 10 September 2021].

10. Lee SH, Shin HS, Park HY, et al. (2019). ‘Depression as a Mediator of Chronic Fatigue and Post-Traumatic Stress Symptoms in Middle East Respiratory Syndrome Survivors'. Psychiatry Investig. 2019;16(1):59-64. 7 January 2019. Available at: <doi:10.30773/pi.2018.10.22.3> [Accessed 10 September 2021].

11. Paterson RW, Brown RL, Benjamin L, et al. (2020). ‘The emerging spectrum of COVID-19 neurology: clinical, radiological and laboratory findings’. Brain. 2020;143(10):3104-3120. 1 October 2020. Available at: <doi:10.1093/brain/awaa240> [Accessed 10 September 2021].

12. Fridman S, Bres Bullrich M, Jimenez-Ruiz A, et al. (2020). ‘Stroke risk, phenotypes, and death in COVID-19: Systematic review and newly reported cases. Neurology’. 2020;95(24):e3373-e3385. 15 September 2020. Available at: <doi:10.1212/WNL.0000000000010851> [Accessed 10 September 2021].

13. Paniz-Mondolfi A, Bryce C, Grimes Z, et al. (2020). ‘Central nervous system involvement by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2)’. J Med Virol. 2020;92(7):699-702. July 2020. Available at: <doi:10.1002/jmv.25915> [Accessed 10 September 2021].

14. Shoucri SM, Purpura L, DeLaurentis C, et al. (2021). ‘Characterising the long-term clinical outcomes of 1190 hospitalised patients with COVID-19 in New York City: a retrospective case series’. BMJ Open 2021;11:e049488. 1 June 2021. Available at: <doi: 10.1136/bmjopen-2021-049488> [Accessed 10 September 2021].

15. Weng, Jingrong et al. (2021). ‘Gastrointestinal sequelae 90 days after discharge for COVID-19’. The Lancet Gastroenterology & Hepatology, Volume 6, Issue 5, 344 - 346. 9 March 2021. Available at: <https://doi.org/10.1016/S2468-1253(21)00076-5> [Accessed 10 September 2021].

18. Sweed, D., Abdelsameea, E., Khalifa, E.A. et al. (2021). ‘SARS-CoV-2-associated gastrointestinal and liver diseases: what is known and what is needed to explore’. Egypt Liver Journal 11, 64. 31 July 2021. Available at: <https://doi.org/10.1186/s43066-021-00123-6> [Accessed 10 September 2021].

19. Klaus W. Lange. (2021). ‘Coronavirus disease 2019 (COVID-19) and global mental health’. Global Health Journal. 13 February 2021. Available at: <https://doi.org/10.1016/j.glohj.2021.02.004.> [Accessed 10 September 2021].

21. Zhao YM, Shang YM, Song WB, et al. (2020). ‘Follow-up study of the pulmonary function and related physiological characteristics of COVID-19 survivors three months after recovery’. EClinicalMedicine. 2020;25:100463. 25 August 2020. Available at: <doi:10.1016/j.eclinm.2020.100463> [Accessed 10 September 2021].

22. Shah AS, Wong AW, Hague CJ, et al. (2020). ‘A prospective study of 12-week respiratory outcomes in COVID-19-related hospitalisations’. Thorax 2021;76:402-404. 3 December 2020. Available at: <https://thorax.bmj.com/content/76/4/402> [Accessed 10 September 2021].

23. Benjamin Bowe, Yan Xie, Evan Xu, Ziyad Al-Aly. (2021). ‘Kidney Outcomes in Long COVID’. American Society of Nephrology. 1 September 2021. Available at: <https://doi.org/10.1681/ASN.2021060734> [Accessed 10 September 2021].

Long Covid in Children

7. Buonsenso, D., Munblit, D., De Rose, C., Sinatti, D., Ricchiuto, A., Carfi, A. and Valentini, P. (2021). ‘Preliminary evidence on long COVID in children’. Acta Paediatrica, 110: 2208-2211. 09 April 2021. Available at: <https://onlinelibrary.wiley.com/doi/10.1111/apa.15870> [Accessed 10 September 2021].

16. Öcal Demir et al. (2021). ‘SARS-CoV-2 associated multisystem inflammatory syndrome in children (MIS-C). A single center's experience’. Minerva Pediatrics. 23 April 2021. Available at: <https://pesquisa.bvsalud.org/global-literature-on-novel-coronavirus-2019-ncov/resource/pt/covidwho-1200473> [Accessed 10 September 2021].

17. Rubens J H, Akindele N P, Tschudy M M, Sick-Samuels A C. (2021). ‘Acute covid-19 and multisystem inflammatory syndrome in children’. BMJ 2021; 372 :n385. 1 March 2021. Available at: <doi:10.1136/bmj.n385> [Accessed 10 September 2021].

If you are aware of helpful research or literature in this field we would be very grateful for your suggestions at longcovid@otandp.com.

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