Observational studies and clinical trials need to determine how long the changes in people with Covid persist and come up with ways to treat and prevent long-Covid. By Pharmacy Magazine clinical editor Mark Greener

By early November some 1.2 million people across the UK had tested positive for SARSCoV- 2. What is becoming clear is there is no guarantee of a quick recovery, even in young people and those with mild acute infections.

An Italian study of 143 patients reported that only 13 per cent were symptom-free a mean of 60.3 days after the onset of Covid-19. None of the patients still had fever or other acute symptoms but 32 per cent had one or two symptoms and 55 per cent experienced at least three symptoms, most commonly fatigue (53 per cent), dyspnoea (43 per cent), joint pain (27 per cent) and chest pain (22 per cent).¹

Persistent symptoms

A study from China that assessed 55 patients three months after discharge from hospital following acute Covid-19 found that 64 per cent had persistent symptoms, including gastrointestinal problems (31 per cent), headache (18 per cent), fatigue (16 per cent), exertional dyspnoea (15 per cent), and cough and sputum (2 per cent).²

Covid-related skin changes can also persist. A multinational study presented at this year’s virtual European Academy of Dermatology and Venereology congress reported that Covid-related skin symptoms last, on average, for 12 days but the duration varies. Urticaria lasts for a median of five days. Outbreaks of scaly papules and plaques typically persist for 20 days. Chilblain-like changes – so-called ‘Covid toe’ – last a median of 15 days but can persist for 130-150 days.

Symptoms don’t just persist in people that the coronavirus left severely ill. American researchers telephoned a random sample of 292 outpatients who tested positive for SARS-CoV-2. Of these, 94 per cent experienced at least one symptom when tested. A median of 16 days later, 35 per cent of the symptomatic people had not returned to their usual health state. The proportion rose from 26 per cent in those aged 18-34 years to 32 per cent in those aged 35-49 years, and 47 per cent in those aged 50 years and older.

Among those who experienced cough, fatigue or shortness of breath at testing, 43, 35 and 29 per cent respectively still reported these symptoms at follow-up. “These findings indicate that Covid-19 can result in prolonged illness even among persons with milder outpatient illness, including young adults,” the authors concluded.³

Guidelines needed

The increasing recognition of chronic symptoms led to NHS England and the chief medical officer of the Scottish Government asking NICE and SIGN to develop a guideline on long-Covid. The RCGP is also collaborating on the guideline development, which is due for publication by the end of the year. There is currently, however, no agreed definition of post-acute Covid-19 syndromes.⁴

Obviously, recovering from an infection can take time, so the guidelines will assume that the post-Covid syndrome applies to signs and symptoms that develop during or after acute Covid-19, continue for more than 12 weeks and for which there is no alternative diagnosis. They will need a broad perspective.

Imaging studies show, for example, that objective changes linger. The study from China reported that 71 per cent of patients showed radiological abnormalities on high resolution computed tomography three months after discharge. Despite generally not having respiratory symptoms, 25 per cent still showed impaired lung function.² In a study of 100 patients who recovered from Covid-19, magnetic resonance imaging revealed persistent cardiac involvement in 78 per cent and ongoing myocardial inflammation in 60 per cent.

The extent and severity of cardiac inflammation was similar to that among hospitalised patients.⁵ Cardiologists are concerned that the heart damage could increase the risk of long-term cardiovascular complications, such as atrial fibrillation and other arrhythmias, coronary artery disease and death.⁵

Neurologists are also concerned. In about 36 per cent of patients, Covid-19 causes neurological symptoms, such as dizziness, headache, impaired consciousness and seizures. At discharge, about a third of people show cognitive impairment or motor deficits.⁶ High levels of pro-inflammatory cytokines triggered by Covid-19 could, in theory at least, increase the risk of neurological conditions, particularly Alzheimer’s disease.⁶

In addition, the consequences of an intensive care stay often linger even without the additional burden imposed by Covid-19. A US study followed 43 survivors admitted to intensive care units with a variety of conditions. Of these, 47 per cent needed mechanical ventilation. A median of eight months after discharge, 84 per cent had post-intensive care syndrome: new or worsening impairment in cognition, mental health, or physical function after critical illness. For instance, 58 per cent reported symptoms of anxiety, depression or post-traumatic stress disorder, 56 per cent reported physical impairment and 56 per cent had memory problems or difficulty thinking clearly or solving problems.⁷

Further studies need to uncover the causes of these persistent symptoms but there are several clues. The symptoms could follow direct tissue invasion by SARS-CoV-2, possibly by binding to the now notorious angiotensin-converting enzyme 2 receptor. Infection can trigger marked inflammation, including cytokine storms, so the long-term symptoms could reflect damage from an ‘overactive’ immune response.⁴

Hypercoagulability and increased thrombotic risk are common among people critically ill with Covid-19: 25 to 42 per cent of Covid-19 patients develop thrombotic complications.⁸ A hypercoagulable state could contribute to chronic symptoms.⁴ Of course, more than one mechanism is probably responsible.

Virus-associated long-Covid should not have come as much of a surprise. After all, Ebola, Dengue and West Nile fever can all cause chronic symptoms.⁹

During the SARS outbreak, doctors identified a constellation of chronic symptoms, including persistent fatigue, diffuse muscle pain, weakness and depression.¹⁰ Many of these signs and symptoms are reminiscent of chronic fatigue syndrome (myalgic encephalomyelitis [ME]) and fibromyalgia.¹⁰ Viruses, bacteria or parasites can trigger ME: 50-80 per cent of ME patients report that the symptoms started with a flu-like illness.¹¹

Perhaps a better understanding of long-Covid could also throw new light on these enigmatic diseases.

References

1. JAMA 2020; 324:603-605
2. EClinicalMedicine 2020; 25: DOI:10.1016/j.eclinm.2020.100463
3. Morbidity and Mortality Weekly Report 2020; 69:993-998
4. JAMA 2020; 324:1723-1724
5. Heart Rhythm 2020; 17:1984-1990
6. Alzheimer’s Research & Therapy 2020; 12: DOI: 10.1186/ s13195-020-00640-3
7. Annals of the American Thoracic Society 2016; 13:1351-1360
8. Anesthesia & Analgesia DOI:10.1213/ane.0000000000005292
9. Immunology Letters 2020; 228:35-37
10. BMC Neurology 2011; 11:37
11. Reviews on Environmental Health 2015; 30:223