eClinicalMedicine: Long-term Symptom Profiles after COVID-19 vs Other Acute Respiratory Infections

#17,709

Prior to the COVID pandemic there were estimated be as many as 2.5 million Americans suffering from Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS); a chronic and debilitating illness similar in many respects to Long COVID. 

While the exact cause of ME/CFS remains unknown, many doctors suspect it is triggered by a viral illness (see The viral origin of myalgic encephalomyelitis/chronic fatigue syndrome).

For many years, CFS patients were marginalized or ignored by the medical community. The lack of a definitive diagnostic criteria, and the complexity of their illness, led many doctors to assume these were psychological - not medical - conditions.

From the CDC Long COVID Website:

People with Long COVID may develop or continue to have symptoms that are hard to explain and manage. Clinical evaluations and results of routine blood tests, chest X-rays, and electrocardiograms may be normal.

The symptoms are similar to those reported by people with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and other poorly understood chronic illnesses that may occur after other infections. People with these unexplained symptoms may be misunderstood by their healthcare providers, which can result in a delay in diagnosis and receiving the appropriate care or treatment.

Today, with tens of millions of people experiencing extended Post-COVID sequelae, ME/CFS is much harder to dismiss.  ME/CFS, however, isn't the only example of prolonged post-viral illness. 

A century ago the world experienced a mysterious neurological epidemic in the decade following the 1918 influenza pandemic; a devastating condition called Encephalitis Lethargica (EL)

An estimated 5 million people were afflicted with EL between 1917 and 1927 -  and while roughly 1/3rd died during the acute phase of the illness - many of the survivors would go on to develop Parkinsonian features and other profound neurological sequelae, often years later. 

Initially, many scientists suspected this disease to be a rare sequelae of the 1918 pandemic virus, but a 2012 study presented a case for the EL epidemic having been caused by an enterovirus (see Evidence for an enterovirus as the cause of encephalitis lethargica). 

Still, the exact cause remains unknown.

Throughout history, there have been reports of similar outbreaks, resulting in severe neurological disease, including febris comatosa which sparked a severe epidemic in London between 1673 and 1675, and in 1890 in Italy, in the wake of the 1889–1890 influenza pandemic, a severe wave of somnolent illnesses (nicknamed the "Nona") appeared.

Among those who survived, Parkinsonism and other neurological sequelae was common.

Over the years we've looked at number of studies which have found evidence that viral infections can have long-term, debilitating health impacts, including.  

mBio: Contemporary EV-D68 Strains Have Acquired The Ability To Infect Human Neuronal Cells

JNeurosci: Another Study On The Neurocognitive Impact Of Influenza Infection

Nature Comms: Revisiting The Influenza-Parkinson's Link. 

Ten months ago, in  Neuron: Virus Exposure and Neurodegenerative Disease Risk Across National Biobanks, a study published in Cell Neuron found statistical linkage between viral illnesses and developing neurodegenerative diseases later in life.  

While falling short of proving causation, it adds to the preponderance of evidence.

Today we've an analysis - based on data gathered from the COVIDENCE UK study - that compares the persistence of post-viral symptoms following both COVID and Non-COVID respiratory illness. 

This study is subject to a number of limitations, including a relatively small number (n=472) of non-COVID ARI cases in the cohort, and a focus on symptoms for each individual at a single time. 

Comparing the relative severity and duration of non-COVID post viral symptoms against Long COVID will require additional longitudinal analysis.  Even so, this study did find memory problems linked more strongly to COVID than non-COVID ARIs. 

Due to its length, I've only posted some excerpts from this open access study, so follow the link to read it in its entirety. 

Long-term symptom profiles after COVID-19 vs other acute respiratory infections: an analysis of data from the COVIDENCE UK study
Giulia Vivaldi, Paul E. Pfeffer, Mohammad Talaei, Tariro Jayson Basera, Seif O. Shaheen, Adrian R. Martineau

Open Access Published:October 06, 2023 DOI:https://doi.org/10.1016/j.eclinm.2023.102251

Summary

Background

Long COVID is a well recognised, if heterogeneous, entity. Acute respiratory infections (ARIs) due to other pathogens may cause long-term symptoms, but few studies compare post-acute sequelae between SARS-CoV-2 and other ARIs. We aimed to compare symptom profiles between people with previous SARS-CoV-2 infection, people with previous non-COVID-19 ARIs, and contemporaneous controls, and to identify clusters of long-term symptoms.

Methods

COVIDENCE UK is a prospective, population-based UK study of ARIs in adults. We analysed data for 16 potential long COVID symptoms and health-related quality of life (HRQoL), reported between January 21 and February 15, 2021, by participants unvaccinated against SARS-CoV-2. We classified par (SNIP)ticipants as having previous SARS-CoV-2 infection or previous non-COVID-19 ARI (≥4 weeks prior) or no reported ARI. We compared symptoms by infection status using logistic and fractional regression, and identified symptom clusters using latent class analysis (LCA). This study is registered with ClinicalTrials.gov, NCT04330599.

Findings

We included 10,171 participants (1311 [12.9%] with SARS-CoV-2 infection, 472 [4.6%] with non-COVID-19 ARI). Both types of infection were associated with increased prevalence/severity of most symptoms and decreased HRQoL compared with no infection. Participants with SARS-CoV-2 infection had increased odds of problems with taste/smell (odds ratio 19.74, 95% CI 10.53–37.00) and lightheadedness or dizziness (1.74, 1.18–2.56) compared with participants with non-COVID-19 ARIs. Separate LCA models identified three symptom severity groups for each infection type. In the most severe groups (representing 22% of participants for both SARS-CoV-2 and non-COVID-19 ARI), SARS-CoV-2 infection presented with a higher probability of problems with taste/smell (probability 0.41 vs 0.04), hair loss (0.25 vs 0.16), unusual sweating (0.38 vs 0.25), unusual racing of the heart (0.43 vs 0.33), and memory problems (0.70 vs 0.55) than non-COVID-19 ARI.

Interpretation

Both SARS-CoV-2 and non-COVID-19 ARIs are associated with a wide range of symptoms more than 4 weeks after the acute infection. Research on post-acute sequelae of ARIs should extend from SARS-CoV-2 to include other pathogens.

         (SNIP)

Discussion

In this large, observational study, we found that previous SARS-CoV-2 infection was associated with increased prevalence and severity of a wide range of symptoms—covering gastrointestinal, neurological, musculoskeletal, and cardiopulmonary problems—as well as lower HRQoL, and that this increased symptom burden persisted more than 12 weeks after the acute infection. Participants with SARS-CoV-2 infection were more likely to report problems with taste or smell and lightheadedness or dizziness than those with non-COVID-19 ARI, but we observed little difference in other symptoms or HRQoL measures. The lower burden of coughing, problems with taste or smell, and dyspnoea among participants who had been infected with SARS-CoV-2 more than 12 weeks prior compared with those with more recent infections suggests these symptoms may be the first to show improvement; however, other symptoms considered showed little difference between remote and more recent infections. A severe initial SARS-CoV-2 infection—either requiring bedrest or hospitalisation—was found to be associated with a greater prevalence of ongoing symptoms, and reduction in HRQoL. Finally, as ongoing symptom severity increased, participants were more likely to report having long COVID, with nearly half of participants with severe symptoms reporting suspected long COVID.

The scale and fast spread of the COVID-19 pandemic, alongside a lower case–fatality ratio than previous coronavirus pandemics,31 has resulted in hundreds of millions of survivors globally over just a few years, focusing attention on their post-COVID-19 experience. While post-acute sequelae of other viral respiratory infections have been observed,32 they have not been as well characterised. 

Similar to our findings for previous SARS-CoV-2 infection, we observed increased burden of many symptoms among participants with previous non-COVID-19 ARI when compared with no infection. However, long-term symptom profiles differed slightly between SARS-CoV-2 infection and non-COVID-19 ARI, with the former showing greater increases in problems with taste or smell and lightheadedness or dizzinesss.

Our findings suggest that there may be long-lasting health impacts from other respiratory infections that are going unrecognised, although we do not yet have evidence that these symptoms have a similar duration to long COVID. 

Our cohort of community infections will not represent those worst affected by long COVID, and so the elevated symptom burden seen for both SARS-CoV-2 infections and non-COVID-19 ARIs is likely to represent a milder phenotype of post-acute sequelae. Indeed, retrospective cohort studies have generally found worse post-acute outcomes among patients with SARS-CoV-2 compared with influenza 33, 34 and other viral infections 35; these studies have largely been restricted to hospitalised patients or electronic health record data, thus representing people with either a severe acute infection or sufficiently severe post-acute symptoms to seek medical help. Given our findings of post-acute sequelae in people with milder disease, longitudinal studies are needed to investigate the distinct pathogens responsible and trajectories of recovery.

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