Long Covid - 2022

Long COVID

A full day's conference run by Biolab and led by Dr Rachel Nicoll in March 2022, on the emerging condition of Long Covid. Report by Michelle Berriedale-Johnson.

In April this year, under the wonderfully knowledgeable guidance of Dr Rachel Nicoll, Biolab ran a day’s medical conference on Long Covid. What follows is a laymans’ overview of the day so I hope that Dr Nicoll will excuse the fact that it will exclude much of the more technical information.

Is there any agreement of what Long Covid actually is?

Both NICE and NHS England define Long COVID as ‘signs and symptoms that develop during or following an infection consistent with COVID-19 which continue for more than 12 weeks and are not explained by an alternative diagnosis’. Which does not tell you a lot.

Substantial sums of money have already been spent on – and are being allocated to – further research into Long Covid but because it is such a new condition there are no studies that stretch back for more than a year. And what studies there are lack uniformity: differing lengths of follow up; some relying on blood tests and scan results, others only taking account of symptoms; test results are notoriously unreliable; study designs are different and there are no control groups.

The one positive outcome is that Long Covid is definitely recognised as a medical condition, even if not much is known about it – in stark contrast to the years in which neither ME or CFS were recognised as medical conditions.

How long does Long Covid last?

As yet, no one knows. However, it appears that if you still have symptoms 6 months after having COVID you have a much poorer chance of making a full recovery and a higher chance of relapse.

Different surveys have noted that among those who still had symptoms at 12 weeks, 42% still had symptoms at 1 year; among patients who reported symptoms lasting for longer than 6 months 86% experienced relapses with exercise, physical or mental activity and stress reported as common triggers.

It should also be noted that rehospitalisation and death can occur during Long COVID. A January 2021 UK survey of hospitalised patients reported that 29% of recovered patients were readmitted to hospital and 12% died within 5 months.

Symptoms

The symptoms recognised by the NHS include:

extreme tiredness (fatigue)
shortness of breath (dyspnoea)
pain or tightness
memory and concentration impairment (brain fog)
difficulty sleeping (insomnia)
heart palpitations
dizziness
pins and needles
joint/muscle pain
depression and anxiety
tinnitus, earaches
feeling sick, diarrhoea, stomach aches, loss of appetite
a high temperature
cough,sore throat
changes to sense of smell or taste
rashes

However, there have been a number of other symptoms reported including damage to vital organs such as the lungs, heart, kidneys and liver, persistent fever, circulatory problems, PTSD, neuro cognitive disorders, visual impairment and ear pain and new onset allergies and anaphylaxis.

New onset diagnosis

Long covid patients have also been diagnosed with new conditions, the most common being:

psychiatric conditions – anxiety disorders, insomnia and dementia
cognitive dysfunctions which increased over all age groups over the first 3 months. (Those with a psychiatric diagnosis in the previous year were reported to be at a 65% greater risk of being diagnosed with COVID-19, suggesting that mental ill health could be both a risk factor and a complication of COVID-19.)
Both Type 1 & Type 2 diabetes

Implications of suffering from Long COVID

An international survey found that 45% of Long COVID sufferers had reduced their workload and 22% were still unable to work. This has implications for labour force productivity and the cost of long-term sickness absence.
The latest ONS Survey found that Long COVID symptoms adversely affected the day-to-day activities of 63% of those with self-reported long COVID, with 18% reporting that their ability to undertake their day-to-day activities had been ‘limited a lot’.

Diagnosing Long COVID

There are no GP tests to diagnose Long COVID; instead the GP must run usual blood tests based upon signs and symptoms. However that may not reveal anything as in a recent survey of Long COVID patients two-thirds of those who had undergone GP blood testing reported normal results.
But the essential thing is that as long as sufferers have at least one symptom on the NHS recognised Long COVID list (above) and no other cause, the GP should diagnose them with Long COVID, i.e. the patient should be believed.

Prevalence of Long COVID

Self reporting ONS surveys differ between 1.5% and 10% of the population being symptomatic after 12 weeks with fatigue being the most common symptom reported followed by shortness of breath.

Risk factors for Long COVID

There seems to be very little evidence on risk factors there being no clear consensus on the effect of:

age
ethnicity
other COVID 19 risk factors
severity of initial COVID 19 symptoms
test result on hospital admission or discharge

However some studies found those with a pre-existing diagnosis of depression, anxiety or any psychiatric disorder had a higher prevalence of Long COVID while a SAGE report showed that those with pre-pandemic poor physical and mental health are more likely to suffer both severe COVID-19 infection and Long COVID.

Vaccinations and medications

The majority of studies looking at the effects of vaccination against Long COVID or post-COVID symptoms suggest that vaccinated people (1 or 2 doses) were less likely to develop symptoms of long COVID following infection.
There is no clear consensus on which medications could be risk factors for Long COVID patients, but if any are it would probably be steroids.

Children/Adolescents and Long COVID

A comprehensive review of 14 studies (published Aug 2021) found that although the risk of severe COVID-19 is low, there may be a greater risk for Long COVID. But the quality of the studies was poor and the authors commented that long COVID symptoms are difficult to distinguish from pandemic-associated symptoms resulting from school closures, not seeing friends and being unable to do sports and hobbies.

Which organs and systems can be affected by Long COVID?

Breathing problems / pulmonary symptoms

Several studies show that patients are still suffering from breathlessness, fatigue and reduced exercised capacity 3 moths after hospital discharge. This can be caused by:

Pulmonary fibrosis or lung scarring which reduces lung capacity, leaving patients breathless.
Ground glass opacity. This is a hazy gray area that can be observed in CT scans or X-rays of the lungs. They indicate increased density inside the lungs, usually caused by infection or inflammation.
Hypoxia with need for supplemental oxygen.

Cardiovascular disease (CVD)

COVID 19 can both cause CVD and exacerbate pre-existing CVD although symptoms show no relationship to original COVID-19 severity. There is an increased risk of major cardovascular events (heart failure, myocardial infarction, stroke, venous or pulmonary thromboembolism) up to at least 5 months after infection. Risk of death is high within the first month.
This risk was evident even among individuals who were not hospitalised during the acute phase of the infection but risk increased with the degree of severity of the infection.

Persisting gut symptoms and prevalence

Among patients hospitalised for COVID-19, up to 44% reported gastrointestinal symptoms 3 months after discharge: loss of appetite, nausea, acid reflux and diarrhoea were the most commonly reported with some lasting up to 6 months.
A Chinese study investigated the microbiome content in hospitalised patients and found a COVID-19 specific composition of gut microbiota.

Kidney injury

Acute kidney injury is a common complication of acute COVID-19 disease, affecting up to 37% of hospitalised patients; this was significantly associated with risk of death.

Liver and pancreatic injury

Some relatively minor liver abnormalities were seen in a small number of patients.

Skin manifestations

An international registry for COVID-19 dermatological manifestations has reported a range of different skin conditions, most of which occurred after the acute COVID-19 symptoms.

Musculoskeletal symptoms

Muscle and joint pain are common complaints in Long COVID. Loss of muscle mass and function through prolonged hospital stay is also common.

Neurological /nerve pain related conditions

PET scans of the brains of Long Covid sufferers up to 3 weeks after initial infection showed evidence of memory and cognitive impairment and autonomic dysfunction. At 3 months post-discharge, 55% still complained of neurological symptoms.
Long-lasting pain is emerging as a frequent and important complication of COVID 19 in patients with severe illness but also in non-hospitalised patients with mild- to moderate illness.
It remains unclear what exactly is causing the pain or whether SARS-COV-2 infection exacerbates pre-existing neuropathies or nerve related pains.
Chronic pain often results leads to a decline in quality of life and sedentary life-styles in previously active people.
The extent of the pain is not associated with severity of the acute disease.

The immune system and autoimmune conditions

In patients who did not go on to suffer Long COVID their immune systems appear to have reacted vigorously to the virus; in these patients, the immune and inflammatory response quickly subsided.
In Long COVID patients, the immune response was far less vigorous.
Infectious diseases have long been considered as one of the triggers for autoimmune and autoinflammatory diseases and there appears to be a connection between COVID 19 and a range of autoimmune conditions including Guillain-Barré syndrome, Systemic lupus, Type I diabetes, psoriasis, Graves’ disease and inflammatory arthritis.
Two months after having COVID 19, 7% of Long COVID patients had persisting lymphopaenia – abnormally low level of blood lymphocytes, i.e. immune suppression.

Inflammatory conditions connected with Long COVID

There seem to be a number of inflammatory conditons implicated in Long COVID, some of which have not been seen before:

Multisystem inflammatory syndrome in children (MIS-C) also knowns as Paediatric inflammatory multisystem syndrome (PIMS)
Multisystem inflammatory syndrome in adults (MIS-A)
Cytokine release syndrome (CRS) – systemic inflammation and multiorgan dysfunction that can lead to multiorgan failure.
Systemic inflammatory response syndrome (SIRS) – an exaggerated defence response of the body to infection which can cause a massive inflammatory cascade leading to organ malfunction and even death.
Compensatory anti-inflammatory response syndrome (CARS) – an overwhelming and prolonged counterbalancing response to SIRS.

Mental Health symptoms

A study of more than 230,000 mostly American patients shows that 34% of COVID-19 survivors were diagnosed with a neurological or psychiatric disorder within six months; 12.8% reported that this was their first such diagnosis.
An earlier US study found that 20% of COVID-19 survivors were diagnosed with apsychiatric disorder within three months. Anxiety (17%) and mood disorders (14%) were the most common and were not related to severity of the COVID-19 infection.
Two studies found the prevalence of PTSD to be around 30% among hospitalised patients.
BUT….. A 2020 meta-analysis concluded that the prevalence of anxiety and depression in the background population (with unknown COVID-19 status) during the pandemic was also up to 30%.
This suggests that the increased incidence of depression/anxiety could be caused by indirect effects of the pandemic.
A systematic review found that risk factors for mental health issues were disease severity, duration of symptoms, and being female.
Generally, anxiety and depressive symptoms were reported to improve with time.
Because of the increased level of depression and anxiety in the general population due to lockdown, school closures and other pandemic measures it is hard to pin mental health issues amongst Long Covid patients specifically of the virus.

However, even if one discounts the mental health issues there is still ample evidence that Long COVID does exist even if the mechanisms are not yet understood. Just because a condition is not understood, it should not be dismissed or ridiculed.

Other syndromes that could be involved in the causation of Long COVID

Post-viral syndrome Profound muscular fatigue, muscle pain, headache, unexplained skin sensations, dizziness, urinary frequency, cold extremities, bouts of sweating and fainting attacks, poor memory, brain fog, sleep disturbance, senstivity to sounds and emotional instability – with no clinical abnormalities.
Post-intensive care syndrome Chronically damaged lung function, neuromuscular weakness, long-term psychological impact and reduced quality of life. Common among people who have spent long periods on ventilators.
Multisystem inflammatory syndrome – children (MIS-C)
Multisystem inflammatory syndrome – adults (MIS-A)
Systemic inflammatory response syndrome (SIRS) An exaggerated defence response of the body to infection which can cause a massive inflammatory cascade leading to organ malfunction and even death.
Chronic Inflammatory Response Syndrome (CIRS) Progressive, multi-system, multi-symptom illness characterized by exposure to biotoxins (toxins coming from funghi, plants or animals). The ongoing inflammation can affect virtually any organ system of the body and if left untreated becomes debilitating.
Central sensitisation syndrome A group of conditions including chronic headache, irritable bowel syndrome and fibromyalgia which are believed to share physiological processes with brain inflammation but rarely show any abnormaities in laboratory tests.
Mast Cell Activation Syndrome (MCAS) A multisystem, inflammatory disease caused by mast cell (the cells which precipitate allergic reactions) hyperactivity. The mast cells may be normal in number, but release excessive amounts of the chemicals such as histamine that trigger allergic reactions.
Chronic fatigue syndrome (CFS) Wide ranging symptoms which overlap closely with those of Long COVID. A 2019 review suggested that the most common causes were: Infections (64%); stressful incidents (34%) and exposure to environmental toxins (20%).
Postural orthostatic tachycardia syndrome (POTS) Many POTS symptoms are thought to be related to inadequate control of blood flow, causing dizziness when moving to an upright position, as well as brain fog, palpitations, tachycardia and chronic fatigue, among other symptoms.
Macrophage activation syndrome An acute and severe inflammatory syndrome, primary or secondary to infection, rheumatic disease, malignancy or drugs. It is frequently confused with sepsis.

Is SARS-Cov-2/COVID 19 a novel virus?

It would appear not. Long COVID shares mutiple symptoms with, among others:

H1N1 and H1N9 Bird flu
MERS (Middle East Respiratory Syndrome)
SARS-CoV-1 (responsible for the 2002–2004 SARS outbreak)
Spanish flu
Epstein-Barr virus
Ebola
West Nile virus (leading cause of mosquito-borne disease in US)
Dengue virus (mosquito-borne tropical viral infection)
Legionnaires’ disease (lung infection)
Acute viral hepatitis (involving inflammation of the liver)
Rubella (German measles)
Mumps

In all these conditions some symptoms are reported to have persisted for up to 10 years.

Mechanisms of Long COVID – the medical hypotheses

1. Effect of SARS-CoV-2 itself

The virus is still harboured in a reservoir organ (brain, lung, heart, gut, lymph nodes, spleen and central nervous system) which is sheltered from the immune system. If the immune system is dysfunctional or distracted, the infection in viral reservoirs is reactivated.
SARS-CoV-2 is a superantigen which, in Long COVID patients, overstimulates anti-viral immune responses inducing a negative feedback loop that allows the virus to persist.
Delayed viral clearance due to immune exhaustion and the slower generation of antibodies.
Persistent viral fragments, though not infectious, may still be triggering inflammation.
Antibody dependent enhancement (ADE) when antibodies target a virus without neutralising it. Instead this can generate viral replication, immune activation and massive inflammatory responses.

2. Direct after-effects of SARS-CoV-2

Tissue and organ (heart, kidney, lung, liver and others) damage from acute COVID-19.
Persistent excess inflammation which can be a result of an over-active immune system or an exhausted immune system.
Overactivation of the renin-angiotensin system (RAS). The RAS plays a key role in maintaining the physiological balance of the body.
Endothelial dysfunction (non-obstructive coronary artery disease), vascular injury (to large or small blood vessels) and hypercoagulation (excess bood clotting).

3. Indirect effects of SARS-CoV-2

Induction of autoimmune conditions through molecular mimicry or cross reactivity with other condtions/symptoms.
Mitochondrial damage in COVID-19 patients impairs their ability to produce energy.
Reactivation of other dormant viruses.
Microbiome alteration which, in one study pf Long COVID patients, was still not restored 6 months post-COVID-19.
Demyelination (damage to the myelin sheaths that protect nerves) in the brain and nervous system

4. Contributory factors

Genetics although there is a yet little research into this.
Diet and malnutrition. These might contribute to Long COVID, as well as inhibiting recovery. Malnutrition from being unwell and living alone or following a prolonged hospital stay can contribute to long-COVID symptoms. This can be exacerbated by alterations in taste and smell which can result in low appetite. As a result, Long COVID patients may not get the nutritients essential to a normal function of body including immune system. Impaired mental health can result in poor diet and malnutrition.
Lack of exercise and physical deconditioning due to immobility while ill.
Poor methylation/high homocysteine resulting in poor regulation of body processes.

Conclusions

There are many potential mechanisms underlying Long COVID. There is no one mechanism involved and there may be several mechanisms in operation at the same time.
A likely, but relatively unexplored, candidate is reactivation of viruses (SARS-CoV-2 and others) from viral reservoirs. This would explain the initiation or continuation of viral symptoms, as well as the remitting and relapsing nature of Long COVID. It would also explain why Long COVID patients test PCR negative for SARS-CoV-2, unless the viral reservoir is in the upper respiratory tract.
In common with some other ‘retrovirus-associated viruses’, SARS-CoV-2 can (probably) insert itself in the human genome, is immunosuppressive, and can disable tetherin (crucial in responding to/combatting viruses) – all of which enable viral spread.
Immunosuppression and the disabling of tetherin prevent an appropriate interferon response to the virus. (Interferon is the protein released by animal cells which prevents the virus replicating itself.) The interferon response may be the determining factor in whether a COVID-19 patient develops Long COVID or not.
Various natural substances, particularly vitamin D, can boost interferon production.