key: cord-0707154-i46vi0yl
authors: Gautam, Nandan; Madathil, Shyam; Tahani, Natascia; Bolton, Shaun; Parekh, Dhruv; Stockley, James; Goyal, Shraddha; Qureshi, Hannah; Yasmin, Sadhika; Cooper, Brendan G; Short, Jennifer; Geberhiwot, Tarekegn
title: Medium-term outcome of severe to critically ill patients with SARS-CoV-2 infection
date: 2021-04-24
journal: Clin Infect Dis
DOI: 10.1093/cid/ciab341
sha: 7d2412975eb9a0d963d7fddaf4a00ee9b185ea63
doc_id: 707154
cord_uid: i46vi0yl

BACKGROUND: The medium and long-term effects of severe SARS-CoV-2 infection on survivors are unknown. Here we studied the medium term effects of COVID-19 on survivors of severe disease. METHODS: This is a retrospective, case series of 200 patients hospitalised across three large Birmingham hospitals with severe-to-critical COVID-19 infection 4-7 months from disease-onset. Patients underwent comprehensive clinical, laboratory, imaging, lung function test, quality of life and cognitive assessments. RESULTS: At 4-7 months from disease-onset, 63.2% of patients experienced persistent breathlessness, 53.5% complained of significant fatigue, 37.5% reduced mobility and 36.8% pain. Serum markers of inflammation and organ injuries that persisted at hospital discharge had normalised on follow-up indicating no sustained immune response causing chronic maladaptive inflammation. Chest radiographs showed a complete resolution in 82.8%; and significantly improved or no change in 17.2%. Lung function test (LFT) revealed gas transfer abnormalities in 80.0% and spirometry in 37.6% patients. Patients with breathlessness had significantly high incidence of comorbidities, abnormal residual chest X-ray and LFT (p<0.01 to all). In all parameters assessed and persisting symptoms there was no statically significant difference between patients managed on hospital wards and on ITU groups. All patients reported a significantly reduced quality of life in all domains of the EQ-5D-5L quality of life measures. CONCLUSIONS AND RELEVANCE: A significant proportion of COVID-19 with severe illness experience ongoing symptoms of breathlessness, fatigue, pain, reduced mobility, depression and reduced quality of life at 4-7 months from disease-onset. Symptomatic patients tend to have more residual CXR and LFT abnormalities.

The Coronavirus Disease 2019 (COVID 19) caused by the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is a new illness with a global distribution and highly variable case fatality rate. At the time of writing the world health organisation estimates that approximately 137million people have been infected worldwide and there have been 2.9 million deaths 1 . Little is yet known about the medium and long-term sequelae of severely ill COVID 19 survivors. Even individuals not admitted to hospital are reporting a prolonged and debilitating set of symptoms after their acute episode, sometimes labelled as 'long Covid' 2 . Patients hospitalised with COVID-19 most commonly suffer pneumonitis and in many cases multiorgan involvement, requiring supplemental oxygen, invasive ventilation and organ support 3 . Whilst most survivors will have a full recovery, some may develop chronic physical, mental health and social issues. Data from previous coronavirus (severe acute respiratory syndrome coronavirus [SARS-CoV] and Middle East respiratory syndrome coronavirus [MERS-CoV] ) outbreaks indicate that between 20% and 40% of survivors experience medium and long-term complications 4, 5 . In a recent report of 143 COVID-19 patients at a mean follow-up of 2 months, a high proportion of individuals still reported fatigue (53.5%), dyspnoea (43.4%), joint pain (27.3%) and chest pain (21.7%) 6 . There are other short-term studies that have confirmed this observation 7 .

The recovery trajectories are likely to be heterogeneous and may be influenced by different factors such as severity of the acute COVID-19 illness, duration of hospitalisation, preexisting co-morbidities, individual's age, gender and ethnicity. There is an urgent need to carefully follow these patients to better understand the natural course of the disease, to recognise and manage the sequelae, support patients and care providers and understand the driving mechanisms. Here, we report a 4-7 months post disease onset follow-up details of severe to critically ill patients seen in our multidisciplinary COVID-19 follow-up clinic.

A c c e p t e d M a n u s c r i p t

Two hundred severe to critically ill patients with laboratory-confirmed SARS-CoV-2 infection admitted for treatment at three large Birmingham hospitals of the University Hospitals Birmingham National Health Service Foundation Trust, Birmingham, UK, between 2 nd March -30 th May 2020 were invited for follow-up clinic. Details of the multidisciplinary and multiprofessional clinic, inclusion and exclusion criteria were published elsewhere 8 . In brief, inclusion criteria included hospital admission for more than 3 days, with fraction of inspired oxygen of greater than 40% for more than 6 hours, new stroke, pulmonary embolism, deep venous thrombosis, delirium, elevated high-sensitivity troponin levels, residual acute kidney injury, or tachycardia of more than 100 beats per minute at discharge.

Patients with mild to moderate disease who did not meet any of the above disease severity criteria, frailty score 6 or above on admission or discharged to residential/nursing home were excluded. The Clinical Frailty Scale (CFS) was adopted by the United Kingdom's National Institutes of Clinical Excellence (NICE) in response to COVID-19 outbreak to assess risk of outcome and rationalise the limited Intensive Treatment Unit (ITU) capability 10. This study was carried out as part of contemporaneous clinical service evaluation and registered with the local audit authority.

Demographic and clinical information was obtained from patient records and included: dates and spectrum of COVID-19 symptoms, inpatient treatment modalities and whether treated on a ward or ITU and any COVID-19 related complications. Furthermore, participant's frailty was assessed using the CFS (range 1-7) and compared to their scores on admission. In order to assess subjective recovery from COVID-19 illness, participants were also asked a binary question regarding their perception of having returned to state of health prior to their illness.

A c c e p t e d M a n u s c r i p t Using a Visual Analogue Scale (VAS), patients were asked to grade their overall recovery compared to pre-COVID state of health on scale ranging from 0 to 100%.

Additionally, the EQ-5D-5L was used to assess mobility, personal care, usual activities, pain and anxiety/depression. The Medical Research Council (MRC) dyspnoea scale was used to assess the extent of breathlessness and The Montreal Cognitive Assessment (MoCA) was used to screen for cognitive impairments. 

Continuous variables were described using mean and standard deviation (SD) for parametric data and median with interquartile range (IQR) for non-parametric data. Categorical variables were reported as frequency and percentages. Mean differences between two groups were evaluated using Student's t-tests. Distributions of non-parametric data were compared through Mann-Whitney U-tests for comparisons between two groups and Kruskal-Wallis test for comparisons between three groups. Associations between two groups were compared using the Chi-square test or Fisher's exact test as appropriate. Statistical analyses were performed using SPSS version 27 (IBM, New York, USA). Statistical significance was set at p<0.05. Table 1 . The mean age was 56.5 years ± 13.2 and 62.5% were men. 52% belongs to Black, Asian and other Minority Ethnic groups.

Comorbidities were present in nearly half of all patients, with obesity being the most common (47.1%), followed by hypertension (45.3%), diabetes (38.2%) and asthma (22.4%).

During hospitalisation, the mean length of hospital stay was 22.7 ± SD 18.4 days. On A c c e p t e d M a n u s c r i p t admission, more than three-quarters of patients presented with dyspnoea (78.3%) and cough (75.8%). Other common symptoms were fever (67.5%), tiredness (28.7%), myalgia (24.2%), headache (15.3%), diarrhoea (14.6%), loss of taste (10.8%) and loss of smell (10.8%). 23.5% of patients developed ITU-related delirium and a further 13% developed stage III acute kidney injury during hospitalisation.

At 4-7 months from disease onset, none of the patients had residual fever or any signs or symptoms of acute illness. More than half of the patients still experienced some breathlessness (63.2%) and fatigue (53.5%); other common symptoms were reduced mobility (37.5%) and pain (36.8%). A transient cough was still present in 17.4% of patients. More than 20% of patients complained of anxiety or low mood, sometimes associated with intrusive thoughts or flashbacks. Moreover, those with prior psychological problems before contracting COVID-19 (12.4%) showed a worsening of their symptoms during hospitalisation and after discharge. In 12.5% of patients, some cognitive impairment was noted. These were mainly in concentration and short-term recall ( Table 2 ). On admission, 98% of patients scored between 1 (very fit) and 4 (mildly vulnerable), on the CFS and 68% of patients scored very fit or well (score 1 and 2). On the contrary, only 26.5 % of patients scored 1 or 2 on follow-up. Furthermore, 12.2 % of patients became frail (5 or more). There was no significant difference between patients with or without mechanical ventilatory support A c c e p t e d M a n u s c r i p t

A high proportion of patients reported a significantly reduced quality of life (EQ-5D in all five domains) (Figure 1b) . However, no significant differences were found in all domains between patients who had been managed in ITU or ward ( Figure 1b) .

As shown in Figure 1c , the VAS grading of overall recovery by patients showed that the recovery towards usual state of health was low with only 17% of patients returned back to their pre-COVID state of health. In addition, more than half of patients reported a score less than 70%.

At follow-up (Table 2) A c c e p t e d M a n u s c r i p t

Persistent breathlessness is one of the key finding of our cohort and hence we performed sub analysis. Seventy-six (38.2%) experienced new onset symptoms of significant breathlessness (MRC dyspnoea score ≥2). Comparisons of clinical characteristics, LFT and chest radiography in patients with and without shortness of breath are shown in Table 3 . Patients with breathlessness tend to have higher rate of comorbidities, abnormal LFT and chest radiography (p<0.01). In addition, out of the 13 symptomatic patients who underwent highresolution chest CT, 12 (92%) had a patchy reticulation seen within the lungs indicating mild focal fibrosis at follow-up. We found no significant difference in blood markers for inflammation or organ injury nor the state of their acute illness between the two groups (eTable 4). Persistent cardiac dysfunction was considered in all symptomatic patients and their 12 lead resting ECG and BNP showed no significant difference between the two groups.

The medium and long-term sequelae of COVID-19 remain largely unknown. We found that just over half of patients who survived severe COVID-19 illness had persistent symptoms that interfered with activities of daily living and quality of life 4-7 months after their critical illness. Of those who were symptomatic, biochemical, haematological and immunological findings had normalised during the follow-up periods. Chest X-ray and pulmonary function tests were near normal to normal in most patients. However, patients with significant breathlessness tended to have high rate of comorbidities, residual chest radiographic abnormalities and abnormal LFT.

As previously reported, breathlessness (63.2%) and fatigue (53.5%) were the most common reported symptom by participants. However, the rate of significant breathlessness (38.2%) in our severely ill patients followed up to 7 months is lower than that reported in an earlier study A c c e p t e d M a n u s c r i p t (45-53%) 2-3 month after disease onset 6, 7 , which suggests that dyspnoea caused by COVID-19 may improve over time. On the other hand, recent study by Huang et al. describe the clinical follow-up of a cohort of 1733 adult with COVID-19, 6 months after illness onset, 76% of the patients reported at least one symptom that persisted 11 .It is noteworthy that patents with persistent breathlessness tended to have a significantly higher residual abnormality of Chest X-ray and an abnormal LFT. In addition, there is an early indication of focal fibrosis on chest CT. Respiratory compromise in survivors of other coronavirus (SARS) was one of the key persisting symptoms at 6 months 12 . Similarly, the impairment is mainly restrictive in nature, with predominance of abnormalities in TLCO, VC, and VA, compared with FEV1, thereby supporting the parenchymal infiltrative damage during acute insult that might lead to pulmonary fibrosis. Furthermore, the absence of an inflammatory signature associated with persistent breathlessness is a striking positive finding suggesting there is no enduring evidence of active disease. Our study has excluded cardiac cause as a cause for shortness of breath.

Post-viral fatigue is well recognised 13 and fatigue has been reported in 40% of individuals with SARS-Cov1 one year after initial infection 14 . Consistent with this, we observed a high proportion of our patients up to 7 months follow-up still complaining of fatigue. Fatigue is a complex symptom, which overlaps with physical, mental and social wellbeing leading to a significant impact on daily function of an individual. We observed an increased tendency of fatigue in patients who also experienced pain symptoms and had pre-existing anxiety/depression. Longitudinal studies will be needed to assess the trajectory and persistence of fatigue as a form of chronic post viral fatigue syndrome. The other common persistent symptoms are myalgia and arthralgia. These are more notable in patients who were proned during ITU admissions. In line with the previous reports 15 , we have observed a high-A c c e p t e d M a n u s c r i p t level of self-reported symptoms of anxiety, low mood and depression among survivors. This is amplified in survivors with pre-existing chronic disease or previous anxiety state.

The semi quantitative CFS is a simple tool to assess patients' frailty (diminished physiologic reserve) and has been shown to correlate with morbidity and mortality 16 M a n u s c r i p t A c c e p t e d M a n u s c r i p t A c c e p t e d M a n u s c r i p t (Fig 1a) assessed at follow up in 58 intubated and 77 notintubated patients. Quality of Life Questionnaire (Fig 1b) evaluated at follow-up in 75 intubated and 77 not-intubated patients. In Quality of Life Questionnaire, each domain is scored on a 5-point scale: 1-no problem, 2-slight problem, 3-moderate problem, 4-severe problem, and 5-unable to do. Visual Analogue Scale (Fig 1c) evaluated at follow-up in 68 intubated and 76 not-intubated patients. No significant differences were found in the CFS, QoL and VAS between the two study groups. A c c e p t e d M a n u s c r i p t 

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