Late sequelae of COVID-19: Breathless!

December 5, 2020 0 By S Harachand

Sidharth Loke, a 33-year-old architect from Mumbai has been complaining of memory loss, difficulty in focusing, confusion, dizziness etc for several days. At times he cannot even recall the names of familiar household items like a toothbrush. He just sits and stares, unable to function; or wanders around, like a zombie. These problems are wreaking havoc on his professional life. Loke had no pre-existing ailments when he was infected with SARS-CoV-2 via his wife, a bank employee, a month ago. Loke’s was a brief illness, punctuated by fever and throat pain, which lasted only for a couple of days.

And he’s not alone. Thousands of people are suffering from what is vaguely termed ‘COVID brain fog’ and other debilitating ailments after successfully fighting off a SARS-CoV-2 infection.

These fluctuating symptoms continue to haunt COVID-19 survivors for months, often severely impairing their ability to return to their normal lives.

Usually, a negative test result means the pathogen is officially gone from one’s system, but in the case of COVID-19, there is increasing evidence that it may not be so. Persistent symptoms, such as heaviness in chest, breathlessness, muscle pains and fatigue have been haunting survivors for months.

Differing symptoms

COVID-19, which affected over 60 million people worldwide as of 25th Nov 2020, is a mild infection that lasts for a few days in most cases.

For the unlucky minority, what has followed the initial acute phase has been relentless and devastating.

These people don’t seem to recover completely even several months after the infection. The fatigue and the depression simply don’t go away, and hang around like unwelcome guests upsetting their lives’ rhythms.

Variously described as the “post-COVID syndrome”, “chronic COVID-19” and “long COVID”, researchers are yet to reach a consensus on the appropriate terminology for the disparate set of symptoms.

What is more puzzling about ‘long COVID’ or ‘chronic COVID-19’ is its absolute unpredictability. Clinicians and researchers may be able to say who is at an increased risk of dying from COVID-19. But they have no idea who is likely to experience prolonged ill health following the infection.

Because the disease is so new, the post-recovery symptoms are not yet clearly defined nor are there any listed documents to guide the clinician how to diagnose and manage them. What is even more confounding is that no two people come up with similar sets of symptoms.

As ‘long-COVID’ exhibits widely differing manifestations from patient to patient, advocacy groups argue that the patient’s voice must be put at the centre of the process of defining the illness. They are equally vehement that the definition of ‘recovery’ must include the duration, severity and fluctuation of symptoms as well as the functionality and quality of life.

Global agencies seem to be open to this view. WHO director-general Tedros Adhanom Ghebreyesus told COVID patient groups in August: “We have received your SOS. We have heard loud and clear that long COVID needs recognition, guidelines, research and ongoing patient input and narratives to shape the WHO response from here on.”

Clinicians find that other than the afore-mentioned debilitating physical fatigue and persistent mental depression, patients present with a plethora of symptoms affecting everything from breathing, the brain, the heart and the cardiovascular system to the kidneys, the gut, the eyes, the ability to smell and taste, the liver and the skin, utterly destroying people’s quality of life.

Fatigued in a fuzzy world

As the name suggests, SARS-CoV-2 primarily targets the lungs. The type of pneumonia often associated with COVID-19 can cause long-standing damage to the alveoli in the lungs. The resulting scar tissue can lead to long-term breathing problems. In addition, COVID-19 infects alveolar type 2 (AT2) cells, kills them and floods the alveolus. There is evidence for microthrombosis, which may block the vascular side.

COVID researchers, so far, have been focusing their attention on acute respiratory complications, especially in critically ill patients. But a large number of case reports now suggest the damage is not limited to the lungs. COVID-19 affects all major organs of the body, including prominently the cardiovascular system.

Nearly one-third of patients show cardiovascular symptoms during the acute phase of COVID-19, say experts. The heart, as an organ, is particularly susceptible to inflammation resulting from an immune system overdrive. Even though the damage to the heart is one of the short-term consequences, it can linger for a long time in some patients. COVID-19 also exacerbates heart failure in patients with pre-existing cardiac conditions.

A small study involving cardiovascular magnetic resonance (CMR) imaging of recovered patients with ongoing cardiac symptoms, published in JAMA Cardiology, found cardiac involvement in 58% of the patients, consisting of myocardial oedema and scar by late gadolinium enhancement (LGE).

Cardiomyopathy is one such symptom. It affects the heart’s ability to pump blood. Some patients also have pulmonary thrombosis. As the virus infects the endothelial lining of the blood vessels, it also injures the wider circulatory system.

COVID-19 can make blood cells more likely to clump up and form clots. While large clots can cause heart attacks and strokes, much of the heart damage caused by COVID-19 is believed to stem from very small clots that block capillaries in the heart muscle.

Other parts of the body affected by blood clots include the lungs, legs, liver and kidneys. COVID-19 can also weaken blood vessels and cause them to leak, leading to potentially long-lasting problems with the liver and kidneys.

Studies show that people who have had pneumonia have an elevated risk of cardiovascular disease 10 years later.

WHO also warns that widespread inflammation caused by the coronavirus could lead to people having heart problems at a much younger age.

Similarly, patients with severe COVID-19 experience neurological complications, including delirium. Evidence shows that cognitive difficulties, such as confusion and memory loss, persist for some time after the acute symptoms have cleared.

A study, which appeared in August, on 120 COVID-19 patients who had been hospitalized in a French hospital found that 34 percent had memory loss and 27 percent had problems with concentration months later.

Treating clinicians find neurological symptoms in COVID-19 patients scarier, even as the list of after-effects continues to get longer with the addition of new symptoms such as hemorrhage and encephalitis.

Even young people without conventional risk factors are having strokes. Patients are showing acute changes in mental status that are not otherwise explained, say neurologists.

Encephalitis can sometimes escalate to a severe form called acute disseminated encephalomyelitis, involving both the brain and spinal cord. In this case, the patients may show symptoms akin to multiple sclerosis.

What percentage of COVID-19 patients suffer from neurological disabilities is not yet clear. Some studies indicate that the prevalence of neurological symptoms in intensive care patients can be as high as 50%.

Data from other coronaviruses show that symptoms affecting the central nervous system occurred in at least 0.04% of people with severe acute respiratory syndrome (SARS) and in 0.2% of those with the Middle East respiratory syndrome (MERS).

Researchers have gathered evidence suggesting that SARS-CoV-2 can infect neurons, but they are uncertain about what leads to these untoward neurological manifestations. Many clinical experts believe that it may be due to persistent immune activation after the initial infection subsided.

Besides complications of the respiratory, circulatory and central nervous systems, COVID-19 can lead to fibrosis and inflammation in multiple organs, including kidneys, liver, adrenal glands and the gastrointestinal tract.

A Kidney International study found that over a third of the COVID-19 patients in a New York medical facility developed acute kidney injury, and nearly 15% required dialysis.

Chronic fatigue is the common long-term effect of COVID-19. Every day, an increasing number of people report crippling exhaustion and malaise after getting infected with the SARS-CoV-2. This insidious fatigue makes the lives of the sufferers deeply miserable. They struggle to get out of bed or to work for more than a few minutes or hours at a time. A study conducted on 143 people with COVID-19 discharged from a hospital in Rome found that 53% had reported fatigue and 43% had shortness of breath at an average of 2 months after their symptoms started. Another study in Chinese patients showed that 25% had abnormal lung function after 3 months and that 16% were still fatigued.

Not unique to COVID-19 patients, chronic fatigue is a common symptom after initial recovery from many viral infections. Some symptoms such as cough can also last for months. However, with SARS-CoV-2 infection, it looks more long-lasting. The number of people getting affected also appears to be far greater.

Watch out for mental health

Yet another long-lasting consequence of COVID-19 is on mental health. A longer stay in ICUs and ventilators can result in several mental conditions, including anxiety, depression, post-traumatic stress disorder and sleep disturbance.

“Mental health [issues] associated with COVID-19 certainly need a lot more attention,” says Dr Aashish Contractor. currently Director of Rehabilitation and Sports Medicine at the Sir HN Reliance Foundation Hospital, Mumbai.

According to him, COVID-19 has taken a huge toll on mental health across the world. Besides the physical burden of the disease, the associated stigma and social isolation has led to a large number of survivors grappling with issues such as anxiety and depression, he adds.

As for the chances of some of these mental health issues connected to COVID-19 proving to be really long-lasting, psychologists believe obsessive-compulsive disorder (OCD) could be one of the likely candidates.

Alongside OCD, which is itself a manifestation of anxiety, general anxiety is also another important mental health issue to watch out for in the long term. Chronic loneliness brought on by social isolation or “a lack of meaning” in life during the pandemic is another major concern, experts point out.

People with a history of mental illness are at a risk of relapse during this time.

Currently, there is no available datasets quantifying the proportion of patients suffering from such long-haul symptoms. One published study indicates that about 50% of hospitalized patients are suffering from symptoms such as fatigue, shortness of breath and joint pains two months after hospital discharge.

A 750 person study conducted in Bergamo, Italy, once the world’s coronavirus epicentre, found that around 30 percent still have lung scarring and breathing trouble. Another 30 percent reported problems linked to inflammation and clotting, such as heart abnormalities and artery blockages. A few are at risk of organ failure.

Another study conducted in Rome found that 87% of the 143 people studied reported at least one symptom more than two months later. Yet another research conducted in the UK in about 4 million people using the COVID-19 tracker app showed that 12% of the people had at least one symptom after 30 days and 2% had long COVID symptoms after 90 days.

Because it’s difficult to predict long-term outcomes of COVID-19, scientists are looking at the long-term effects seen in related viruses, such as the one that causes SARS.

Meanwhile, follow-up research on COVID patients after discharge from the hospital has only just started.

Overactive immune system to blame?

As the research community pours over the causative mechanisms behind the long-standing symptoms of SARS-CoV-2 infection, medical experts say that these symptoms may have different origins, such as permanent damage to the vital organs such as the lungs and heart, post-intensive-care syndrome, post-viral fatigue syndrome or continuing COVID-19 symptoms.

Many hypotheses are going around, claiming to explain the strange phenomena of long-lasting COVID symptoms. Some theories propose that the wide distribution of angiotensin-converting enzyme 2 (ACE-2), the cellular receptor that SARS-CoV-2 uses to enter the host, is partly responsible for the extent of the damage.

However, most recent research squarely blames a hyperactive immune system triggered by the coronavirus for the devastating effects. Studies have observed very high levels of inflammatory cytokines (cytokine storm) in the blood of hospitalized patients with severe COVID-19. Excessive inflammation can lead to collateral damage and worsen pre-existing conditions.

Others think that the symptoms result from post-viral autoimmunity and the consequences of thrombotic complications. Besides causing abnormal clotting, COVID-19 damages the microvasculature systems too.

Researchers at Yale suggest three possible reasons for the long-term effects of COVID-19. Patients with long-term symptoms might still harbour the
infectious virus in some reservoir organ, not identified by nasal swabs. The second possibility is that persistent fragments of viral genes, though not infectious, may be triggering an exuberant immune reaction. Thirdly, even after clearing the virus from the body, the immune system may continue to be in an overactive or perturbed state, similar to the one observed after glandular fever.

At times, the virus can cause parts of the immune system to become overactive and trigger harmful inflammation throughout the body. This is well documented in the acute phase of the illness. This mechanism is also implicated in some of the short-term impacts of the infection. Immune overreaction can also happen in adults with severe COVID-19.

The side effects of intensive treatments such as intubation may also be behind some of the damage. Patients experience injury to muscles or the nerves that supply them. But what is interesting is that the long-term symptoms are not limited to people who stay in intensive care with severe illness, but are also found in those with relatively mild infections.

Researchers are grappling with each and every theory and hypothesis to unravel the mysteries of the strange virus.

Currently, many large medical centers are opening specialized clinics to provide care for people who have persistent symptoms or related illnesses after they have recovered from COVID-19.