Systematic review with meta-analysis of the current evidence regarding the incidence of long COVID symptomatology

The coronavirus disease 2019 (COVID-19) pandemic has affected over 500 million people worldwide, at the very least, in just over two years. While most of these have been asymptomatic or mild infections, resolving rapidly and spontaneously, many survivors have reported chronic symptoms related to the condition, lasting for many weeks or months from the date of recovery. This has been termed long COVID or post-acute sequelae of COVID-19 (PASC).

A new paper compiles the current knowledge of long COVID incidence, which may help plot the future course of healthcare for these patients. Long COVID is associated with long-term, often disabling, symptoms, even in those with prior asymptomatic infection, and may sometimes resemble other medical conditions. This suggests that it may pose a formidable challenge regarding the financial burden, health toll, and cost to society.

Introduction

The researchers searched several databases looking for observational studies on the incidence of long COVID symptoms and signs by organ system, based on the World Health Organization (WHO) criteria. Such symptoms include breathlessness, anxiety, alopecia, depression, severe tiredness, chest pain, loss of appetite, and weakness.

The lack of unified definitions and terminology for this syndrome has affected the comparison between studies. Even the name varies from Long COVID, Long-haul COVID, PASC, and post-acute COVID-19 syndrome, or even just chronic COVID-19. The period of follow-up has also been widely different between studies. The WHO criteria published in October 2021 are used in this study, posted as a preprint on Preprints with The Lancet*.

This definition of long Covid runs as follows, “a condition that occurs in individuals with a history of probable or confirmed SARS-CoV-2 infection, usually 3 months from the onset of COVID-19 with symptoms that last for at least 2 months and cannot be explained by an alternative diagnosis.”

What did the study show?

The researchers found that of almost 121,000 participants, with an average age of 52 years, equally divided between males and females, almost 60% reported one or more features of long Covid during a median follow-up period of six months.

The most frequent symptoms of long Covid were general, reported by almost one in three participants, while gut-related features were less frequent. Almost one in three expressed fatigue, making it the most common general feature.

In particular, females were more likely to have any or general features of long COVID and were also at higher risk for neurological or cardiovascular features. Neurological features ranged from brain fog, affecting one in seven cases, to seizures, seen in less than 1%. About one in ten complained of headaches, disorders of taste and/or smell, dizziness and cramps, along with cognitive issues.

One in five had mental health symptoms, such as anxiety, depression, post-traumatic stress disorder (PTSD), and sleep disorders, each of which occurred in over a tenth of individuals. Heart-related symptoms were present in over a tenth, mostly palpitations.

Conversely, older people were more likely to have psychiatric, respiratory, general, gut-related, or cutaneous symptoms or signs. Overall, one in four had respiratory symptoms, almost always breathlessness.

Mobility was impaired in almost one in seven, mostly due to poor exercise tolerance. This was more common in adults and studies with a follow-up period of over six months.

Also, the continent being assessed made a difference in the incidence of long COVID symptoms. The patient age and the duration of follow-up also affected the incidence of such symptoms.

Two out of three studies from Oceania, for instance, reported any long COVID symptoms compared to less than half of European studies. This was true of neurological long COVID as well, which was almost twice as likely in the former set of studies than the latter, and higher in adults compared to children.

Studies with three months follow-ups were more likely to report neurological long Covid than those with longer periods. Adults also were at higher risk for cardiovascular and general symptoms.

Asians were less likely to have psychiatric conditions compared to Africans, and people older than 60 years had a four-fold higher incidence than younger people in their teens or children. European studies tended to show a higher incidence of respiratory symptoms. African studies showed a higher frequency of general and cardiovascular symptoms.

What are the implications?

The findings of this study indicate the high prevalence of long COVID, making it a potentially significant risk to human health in the long term and thus a major factor to be integrated into the future public and national healthcare policies. Almost half of these participants reported one or more symptoms consistent with the above definition of long COVID, even if a study period of at least three months was adopted as a criterion for inclusion.

Almost one in four patients with a history of COVID-19 reported breathlessness, fatigue, and similar general or respiratory symptoms even if it was asymptomatic. This persistence of symptoms after clinical resolution of the initial acute infection with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been seen with both the earlier pathogenic coronaviruses SARS-CoV and MERS (Middle East Respiratory Syndrome)-CoV.

With the latter two, respiratory function was affected, but also wasting and tiredness appeared to be very common, being reported by most patients with long-term sequelae at up to a year following acute infection. Almost 30-40% of these patients have been shown to have such features, as well as mental ill-health and impaired exercise tolerance.

Though severe COVID-19 affected more males than females, long COVID seems to show the reverse trend. Older age also acts as a risk factor for this condition. It is thought-provoking that neuropsychiatric, general, respiratory, and pulmonary features appeared to be present for two years when patients were followed up for this long a period, warning that “for the COVID-19 we should expect similar long-term consequences.”

The findings also indicate that females and older people should be followed up more vigilantly and that follow-up should occur irrespective of the initial severity of the illness. Genetic and environmental factors also play a role, as is clear from the disparity in the incidence of various symptoms in studies from different continents.

Further research will be required to evaluate the potential preventive and therapeutic approaches to this condition which can be debilitating. The introduction of large-scale vaccination and newer or novel treatment strategies may perhaps avert or reduce the risk of such long-term symptoms, but this remains to be established. The role of particular variants of the virus also remains unknown.

*Important notice

Preprints with The Lancet publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.

Written by

Dr. Liji Thomas

Dr. Liji Thomas is an OB-GYN, who graduated from the Government Medical College, University of Calicut, Kerala, in 2001. Liji practiced as a full-time consultant in obstetrics/gynecology in a private hospital for a few years following her graduation. She has counseled hundreds of patients facing issues from pregnancy-related problems and infertility, and has been in charge of over 2,000 deliveries, striving always to achieve a normal delivery rather than operative.