Thursday, June 24, 2021

Two Preprints on `Long COVID' To Ponder

Slide From June 17th CDC COCA Call on `Post-COVID' Syndrome


Viral epidemics and pandemics have a long history of leaving behind a legacy of under-recognized and  poorly understood `post-pandemic' illness, often leaving victims with life-long disabilities.  The most famous of these was the decade-long global epidemic of Encephalitis Lethargica of the 1920s following the 1918 pandemic (The Lancet: COVID-19: Can We Learn From Encephalitis Lethargica?).
Among those who survived, Parkinsonism and other neurological sequelae was common.

ME/CFS is another apparent post-viral syndrome, for years scoffed at by many doctors, that is now taken very seriously by the National Institute of Health. Even non-viral infections, like Lyme Disease, can leave lingering and debilitating sequelae. 

We've seen cases of non-polio paralysis - particularly in children and adolescents - following outbreaks of enteroviruses, including EV-71 and more recently, EV-D68 (see CDC MMWR/Vital Signs: Acute Flaccid Myelitis (2020 Edition)).

And over the past year we've seen increasing reports of recovered COVID patients enduring a wide spectrum of chronic, and often debilitating symptoms - such as fatigue, recurrent fevers, `brain fog', myalgias, etc. - that are highly reminiscent of ME/CFS.

Last week the CDC held a COCA call on Evaluating and Caring for Patients with Post-COVID Conditions which focused on a wide range of issues (see graphic below).

While there seems little doubt that Post-COVID or `Long-COVID' is very real, there is much we don't know, including its root cause, and how widespread it is. 

Yesterday two Pre-prints on `Long COVID' were released, which attempt to answer some of these questions. 

The first - from Imperial College London - examines self-reported symptom data from over half a million people included in three REACT-2 rounds, from 15 September to 8 February. The report finds a substantial number of people experiencing persistent symptoms for 12 weeks or more after COVID infection. 

Persistent symptoms following SARS-CoV-2 infection in a random community sample of 508,707 people

Authors: Whitaker, M    Elliott, J  Chadeau-Hyam, M   Riley, S   Darzi, A  Cooke, G  Ward, H  Elliott, P

Item Type: Working Paper

Abstract: Introduction Long COVID, describing the long-term sequelae after SARS-CoV-2 infection, remains a poorly defined syndrome. There is uncertainty about its predisposing factors and the extent of the resultant public health burden, with estimates of prevalence and duration varying widely. 

Methods Within rounds 3–5 of the REACT-2 study, 508,707 people in the community in England were asked about a prior history of COVID-19 and the presence and duration of 29 different symptoms. We used uni- and multivariable models to identify predictors of persistence of symptoms (12 weeks or more). We estimated the prevalence of symptom persistence at 12 weeks, and used unsupervised learning to cluster individuals by symptoms experienced. 

Results Among the 508,707 participants, the weighted prevalence of self-reported COVID-19 was 19.2% (95% CI: 19.1,19.3). 37.7% of 76,155 symptomatic people post COVID-19 experienced at least one symptom, while 14.8% experienced three or more symptoms, lasting 12 weeks or more. This gives a weighted population prevalence of persistent symptoms of 5.75% (5.68, 5.81) for one and 2.22% (2.1, 2.26) for three or more symptoms.

Almost a third of people 8,771/28,713 (30.5%) with at least one symptom lasting 12 weeks or more reported having had severe COVID-19 symptoms (“significant effect on my daily life”) at the time of their illness, giving a weighted prevalence overall for this group of 1.72% (1.69,1.76). The prevalence of persistent symptoms was higher in women than men (OR: 1.51 [1.46,1.55]) and, conditional on reporting symptoms, risk of persistent symptoms increased linearly with age by 3.5 percentage points per decade of life.

Obesity, smoking or vaping, hospitalisation , and deprivation were also associated with a higher probability of persistent symptoms, while Asian ethnicity was associated with a lower probability. Two stable clusters were identified based on symptoms that persisted for 12 weeks or more: in the largest cluster, tiredness predominated, while in the second there was a high prevalence of respiratory and related symptoms. 

Interpretation A substantial proportion of people with symptomatic COVID-19 go on to have persistent symptoms for 12 weeks or more, which is age-dependent. Clinicians need to be aware of the differing manifestations of Long COVID which may require tailored therapeutic approaches. Managing the long-term sequelae of SARS-CoV-2 infection in the population will remain a major challenge for health services in the next stage of the pandemic.

Issue Date: 24-Jun-2021

A second report, published in Nature Medicine, reports on a relatively small cohort (n=312) in a single geographic location (Bergen, Norway), but finds a high incidence of `Long COVID' symptoms, even among younger individuals who had mild illness. 

Bjørn BlombergKristin Greve-Isdahl MohnKarl Albert BrokstadFan ZhouDagrun Waag LinchausenBent-Are HansenSarah LarteyTherese Bredholt OnyangoKanika KuwelkerMarianne SævikHauke BartschCamilla TøndelBård Reiakvam Kittang,
Bergen COVID-19 Research GroupRebecca Jane CoxNina Langeland

Nature Medicine (2021)Cite this article


Long-term complications after coronavirus disease 2019 (COVID-19) are common in hospitalized patients, but the spectrum of symptoms in milder cases needs further investigation. We conducted a long-term follow-up in a prospective cohort study of 312 patients—247 home-isolated and 65 hospitalized—comprising 82% of total cases in Bergen during the first pandemic wave in Norway.

At 6 months, 61% (189/312) of all patients had persistent symptoms, which were independently associated with severity of initial illness, increased convalescent antibody titers and pre-existing chronic lung disease. We found that 52% (32/61) of home-isolated young adults, aged 16–30 years, had symptoms at 6 months, including loss of taste and/or smell (28%, 17/61), fatigue (21%, 13/61), dyspnea (13%, 8/61), impaired concentration (13%, 8/61) and memory problems (11%, 7/61). 

Our findings that young, home-isolated adults with mild COVID-19 are at risk of long-lasting dyspnea and cognitive symptoms highlight the importance of infection control measures, such as vaccination.

          (Continue . . . )

Both of these papers have some weaknesses, such as self-reporting of symptoms, a lack of a  control group - and in the case of the Bergen study - a relatively small data sample.  But we continue to see compelling, and remarkably consistent reporting on the lingering sequelae of COVID infection, suggesting these are legitimate illnesses. 

A bigger unknown is what slower, and more insidious, manifestations of Post-COVID might still arise.  It has been suggested by Cardiologists and Neurologists that we may see a wave of serious post-COVID sequelae 5 or even 10 years down the road. 

Emily A. Troyer, Jordan N. Kohn, and Suzi Hong

Similarly, what appears to be minor heart damage today may, over time, progress into something more problematic. 

Coronavirus Disease 2019 (COVID-19) and the Heart—Is Heart Failure the Next Chapter?

Clyde W. Yancy, MD, MSc1,2; Gregg C. Fonarow, MD3,4
JAMA Cardiol. Published online July 27, 2020. doi:10.1001/jamacardio.2020.3575

And, similar to what was seen in the 1920's with Encephalitis Lethargica, there are concerns over a rise in Parkinson's disease in aftermath of COVID (see  Review Article: Parkinsonism as a Third Wave of the COVID-19 Pandemic?).

Many people dismiss COVID infection as mostly mild, and point to the high survival rate - even among those hospitalized - as if that tells the whole story. 

But there are millions of people who have survived their initial COVID infection, and have found that what doesn't kill you, doesn't always make you stronger.