key: cord-0744416-jbfpjgaa
authors: Darley, David Ross; Dore, Gregory John; Byrne, Anthony Luke; Plit, Marshall Lawrence; Brew, Bruce James; Kelleher, Anthony; Matthews, Gail Veronica
title: Limited recovery from post-acute sequelae of SARS-CoV-2 (PASC) at eight months in a prospective cohort
date: 2021-10-08
journal: ERJ Open Res
DOI: 10.1183/23120541.00384-2021
sha: a294a0af03b6be7bfb67e46626ad1b04892c98c4
doc_id: 744416
cord_uid: jbfpjgaa

Global attention is gradually turning to focus on the problem of prolonged illness following acute coronavirus disease 2019 (COVID-19), commonly termed ‘Long COVID’ or Post-Acute Sequelae of SARS-CoV-2 infection (PASC). Whilst an increasing number of reports now recognise this condition, accurate characterisation of its prevalence, clinical features and natural history is complicated by choice of denominator population, lack of case definition and marked self-selection bias. Nevertheless, a picture is emerging of a syndrome characterised predominantly by fatigue, dyspnoea, chest tightness, and ‘brain fog’ present in around 10–30% of individuals at 2–3 months post-acute infection and affecting both those with initial severe illness and those in whom acute infection was mild [1–3].

Global attention is gradually turning to focus on the problem of prolonged illness following acute coronavirus disease 2019 (COVID-19), commonly termed 'Long COVID' or Post-Acute Sequelae of SARS-CoV-2 infection (PASC). Whilst an increasing number of reports now recognise this condition, accurate characterisation of its prevalence, clinical features and natural history is complicated by choice of denominator population, lack of case definition and marked self-selection bias.

Nevertheless, a picture is emerging of a syndrome characterised predominantly by fatigue, dyspnoea, chest tightness, and 'brain fog' present in around 10-30% of individuals at 2-3 months post-acute infection and affecting both those with initial severe illness and those in whom acute infection was mild (1-3).

In April 2020 we commenced a prospective observational cohort study (ADAPT) following all patients with a positive SARS-CoV-2 RNA test through our hospital testing centres. At a median of 79 days post infection, 40% reported persistent symptoms including a high proportion of those managed in the community for initial infection (4) . We now report further 8-month post-infection follow-up to characterise persistence of symptoms, measures of health-related quality of life (HRQOL) and recovery, and assess within-individual changes in measures of psychologic and somatic dysfunction.

The ADAPT study is a prospective cohort at St Vincent's Hospital Sydney, with nasopharyngeal swabconfirmed SARS-CoV-2 infection, being followed for up to 24 months (4) . Data from the 4-and 8month assessments for patients with initial positive PCR from 09-Mar-2020 until 28-Apr-2020 were analysed. This cohort includes both patients who were diagnosed at St Vincent's Hospital testing clinics (internal) and self-referred patients (external). Standardised case report forms were used to collect specific symptoms at 4 and 8-months after infection. Patients were classified as 'Long COVID'

if ≥ 1 of the following persistent symptoms were reported; fatigue, dyspnoea, or chest pain. The Somatic and Psychologic Health Report-34 item SPHERE-34 is a self-report questionnaire containing depression, somatic distress, and persistent fatigue are scored to produce total and somatic and psychological subscale scores. Key somatic symptoms such as muscle pain or tiredness after activity, needing to sleep longer or poor sleep, and prolonged tiredness after activity. A visual analogue scale for fatigue (VAS-F) and the Medical Research Council (MRC) dyspnoea scale, to compare breathlessness pre-COVID and at 8-months, were performed (7, 8) . Functional recovery was interrogated on a 5-point Likert scale. Data distribution was tested using the Shapiro-Wilk test. 

A total of 99 patients underwent 8-month assessment at a median 240 (IQR 227-256) days after positive SARS-CoV-2 PCR. Of these, 66 patients were diagnosed at St Vincent's Hospital testing clinics and 33 patients were self-referred following external diagnosis. Fifteen patients originally enrolled in ADAPT did not attend (n=6), were lost to follow-up (n=7), or withdrew consent (n=2). The majority (87%) of patients were managed in the community. Median age was 47 (IQR 35-58) with 61% males.

To minimise self-selection bias, prevalence of symptoms at 8 months is reported for patients To understand the evolving nature of these symptoms over time, we further evaluated changes in measurements between 4 and 8 months.

Complete paired SPHERE-34 at both timepoints, were available in 88 patients. For each patient, the within-individual change in SPHERE-34 was calculated as the 8-month value minus the 4-month value. The median intersession change in SPHERE-34 total score was 0.0 (IQR -3.8-2.0). There were no significant differences in the median total SPHERE-34 scores between 4-months (4.5, IQR 1.0-12.0) and 8-months (4.0, IQR 0.0-10.0) (p=0.19). There were no significant differences in the mean SOMA scores between 4-and 8-months, nor in the proportion of patients with abnormal SOMA scores. There was a significant difference in the mean PSYCH score between 4-months (1.7, SD 2.4) and 8-months (1.0, SD 1.9) (p=0.03). There was a trend to decreasing proportions of abnormal PSYCH between 4-and 8-months.

Ninety-eight patients underwent assessment for functional recovery at 8 months. 28/98 (29%) patients reported an increase in dyspnoea, as measured by the MRC dyspnoea scale from pre-COVID levels. The median fatigue visual analogue scale score was 2.0 (IQR 0.38-5.0). In regard to COVID-19 recovery 78/98 (80%) agreed they had fully recovered, 88/98 (90%) agreed they felt confident returning to pre-COVID work, 89/98 (91%) agreed they had returned to usual activities of daily living, while 76/98 (78%) agreed they had returned to normal exercise level (Table 3 ). In all measures, recovery was significantly lower among patients with Long COVID, with only 54% agreeing that they had recovered from COVID-19.

The spectrum of long-term recovery following SARS-CoV-2 infection remains uncertain. Our study documents the longitudinal nature and prevalence of persistent symptoms and the effect on HRQOL, and delivers potentially concerning findings. At a median of 8 months after infection, even when self-referred patients were excluded, a third had persistent symptoms. A fifth of patients could be classified as having 'Long COVID' and there appears to be minimal improvement between 4-and 8months after infection, including no significant differences in the total scores or somatic sub-scales of SPHERE-34. In the total cohort, we observed a significant difference in SPHERE-34 mean psychologic sub-scales scores indicating some improvement in psychologic symptoms. Concerningly, a considerable proportion of (around 20%) the total cohort did not feel confident returning to pre-COVID work, had not returned to usual activities of daily living or had not returned to normal exercise level.

The aetiology of persisting symptoms following SARS-COV2 infection is likely to be multifactorial and encompassing both prolonged recovery from persisting cardiothoracic damage as has been demonstrated by us and others (4, 9, 10) , and a more ill-defined syndrome with some features akin to Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (11) . This latter illness, commonly characterised by intense fatigue and cognitive dysfunction ('brain fog') has been variably reported following other viral infections (12) .

Female gender and hospitalisation during initial infection were both independently associated with an increased risk of Long COVID in our cohort. Recovery from illness causing severe pneumonia and/or intensive care stay is often prolonged and well documented to last many months (13, 14) .

The relationship with female gender is less well explained although confirmed in other cohorts including a large app-based study of > 4,000 individuals (1). Whether this relates to a higher risk of viral-induced immune dysregulation and auto-immunity, differences in health care utilisation, or some other mechanism is unclear. Further research is required to understand physiologic correlates of functional recovery and the role of rehabilitation intervention to assist patients with exercise capacity and dyspnoea (15) .

A key strength of our study is the longitudinal assessment of symptoms, HRQOL and functional recovery performed across the spectrum of study participants at 4-and 8-months. The high rate of ongoing symptoms highlights the long-lasting and persistent nature of post-viral quality of life impact and somatic symptoms that may occur after COVID-19. Our study has several limitations. Our definition for Long COVID is conservative and based on the presence of one or more of three major symptoms of fatigue, shortness of breath or chest tightness. It does not include the full spectrum of symptoms after initial infection and is thus a probable underestimate of the true burden of ill health in this population. A third of patients were referred into the study, the reasons for which varied. In many cases this was due to concern over ongoing symptoms. To address this potential selection bias, we excluded the externally referred patients from the description of symptom prevalence and included them only for outcome analysis where we had longitudinal follow-up to compare withinindividual change.

In summary, a considerable proportion of patients experience persistent symptoms after SARS-CoV-2 infection and a fifth of patient met our definition for Long COVID at 8 months. Persistent symptoms impact HRQoL and there appears to be little change between 4-and 8-months. A significant proportion of patients experience abnormal functional recovery at 8-months. The longterm significance of these findings is unknown.

Attributes and predictors of long COVID

Persistent fatigue following SARS-CoV-2 infection is common and independent of severity of initial infection

Persistent Symptoms in Patients After Acute COVID-19

High rate of persistent symptoms up to 4 months after community and hospital-managed SARS-CoV-2 infection

Development of a simple screening tool for common mental disorders in general practice

Validation and psychometric properties of the Somatic and Psychological HEalth REport (SPHERE) in a young Australian-based population sample using non-parametric item response theory

Standardised questionnaire on respiratory symptoms : a statement prepared and approved by the MRC Committee on the Aetiology of Chronic Bronchitis (MRC breathlessness score)

Validity and reliability of a scale to assess fatigue

lung function and CT findings three months after hospital admission for COVID-19

Cardiopulmonary recovery after COVID-19 -an observational prospective multi-center trial

Potential causal factors of CFS/ME: a concise and systematic scoping review of factors researched

Chronic viral infections in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS)

Improving long-term outcomes after discharge from intensive care unit: report from a stakeholders' conference

Long-term cognitive impairment and functional disability among survivors of severe sepsis

COVID-19 rehabilitation delivered via a telehealth pulmonary rehabilitation model: a case series

The authors thank the research staff at the St Vincent's Institute for Applied Medical Research.We appreciate grant support from the St Vincent's Clinic Foundation and the Curran Foundation.