Quality of Life and Physical Performance After Novel Coronavirus Infection (COVID-19);

Currently, the U.S. National Library of Medicine (April 2nd) reports 282 studies registered investigating the COVID-19 infection. According to the present knowledge the COVID-19, also known as novel type Coronavirus or SARS-CoV-2 (severe acute respiratory syndrome-Coronavirus-2), belongs to a large family of viruses consist-ing of hundreds of variations and subtypes of this virus (World Health Organisation (WHO)/emergencies, April 2nd 2020). These types of virus' can cause respiratory and gastrointestinal symptoms ranging from a mild cold to pneumonia. The clinical manifestation of this novel type of Coronavirus - COVID-19 - was found to cause more severe pneumonia or severe acute respiratory syndrome such as the acute respiratory distress syndrome (ARDS). According to the data of Arabi and colleagues (2020) average age in Chinese affected individuals were 60, 40% had comorbid conditions, 42% required invasive mechanical ventilation and the mortality rate was at 62%. Epidemiological information from other countries is not yet published. According to the WHO in the Europe Region, 503730 cases and 33617 deaths were reported since January 25th 2020. In the 8,5 million populated countries of Switzerland, the number of confirmed cases raised to 23'574 and 756 deaths (Bundesamt für Gesundheit) Situationsbericht, April 9th). According to this report, the incidence of infection and hospitalization is highest in individuals aged 50 and older with a higher presence registered in men. Nevertheless, a certain number of affected individuals is between 20 and 50 years which is in accordance with the number presented from large studies in China (50.7%-55.1%). Among the 23'674 positive tested 2730 are currently hospitalized. Among these 280 individuals require mechanically assisted ventilation, meaning health care at an intensive care unit (status April 2nd).

In this acute situation of the pandemic, there is an enormous urge to finding a vaccine or medications to release or prevent severe symptoms and complications due to the new virus. Therefore, in the listed studies keen interest is on drug interventions to stop the expansion of this virus. However, knowledge on long-term consequences of physical condition and psychological state is unknown. Although, taking into account the clinical manifestation observed in the severe cases negative long-term consequences have to be expected as described in the following paragraph.

Up to date knowledge exist on the clinical manifestation which varies from asymptomatic to severe disease with approximately 80% of the cases found to present an asymptomatic carrier.

Thus, about 13.8% to 35% is suffering a severe course including dyspnoea, respiratory frequency ≥30/minute, desaturation of blood oxygen (≤93%) and or lung infiltrates >50% of the lung within 24-48 hours. Further signs of hospitalized individuals are fever, cough, myalgia, fatigue and sputum production. In literature, the clinical picture is described as bilateral pneumonia or acute respiratory distress syndrome which leads to a severe organ failure of the lung. These patients require oxygen therapy with invasive (17%) or non-invasive (14%) mechanically assisted ventilation. And the higher probability of preloaded organ dysfunctions due to co-morbidities most often high blood pressure (13%), diabetes (4-6%) and COPD (1-5%) has to be taken into account.

According to the WHO report and Lai et al (2020) between 6.1% to 28%, respectively, were found to be in a critical stage. Acute respiratory failure, septic shock and/ or multiple organ failure defined this stage. According to a retrospective analysis from a large population in Wuhan, these patients require intensive care with most of them presenting (multi) organ failure with acute respiratory distress (ARDS, 67%), acute kidney injury (29%), cardiac injury (23%), and liver dysfunction (29%). These patients require invasive or non-invasive mechanical ventilation. The mortality rate for critically ill COVID-19 patients varies from 1-4% to 4.3% according to large studies reported by Lai et al. (2020).

According to these statistics, about 4.3% of the 280 patients requiring intensive care in Switzerland (n=12) would not survive. Taking the current number of 2730 hospitalised patients reported above, these statistics result in about 2718 individuals surviving severe illness in Switzerland. A critical point is the high risk of the length of stay on the ward as explained in the following paragraph.

Patients in the severe and critical state are likely to suffer prolonged length of stay in the hospital according to Lia et al. (2020) and Wang et al. (2020) (±21 days). Studies on ARDS and critically ill patients led to strong evidence that prolonged length of stay, particularly with prolonged mechanical ventilation, leads to a significant negative impact on lung function, physical activity and emotional state. For example, from 109 patients suffered an ARDS (age interquartile from 35 to 57) the 5 years follow up showed a relevant reduction on physical condition (76% of the distance in the 6 Minute Walk Test (6MWT)) when compared to age and sex-matched norm values. Interestingly, these deficits were found despite normal to "near"-normal pulmonary function. A recent post-hoc analysis on 116 patients mechanically ventilated for at least >24h showed that a longer duration of mechanical ventilation and exposure to norepinephrine were associated with intensive-care-unit acquired weakness (ICU-AW; defined as <48/100 on the Medical Research Council Score). Hatch et al. (2018) for example found in their multicenter follow-up study, that 46% of the survivors of critical illness suffered from anxiety, 40% from depression and 22% from post-traumatic stress disorder (PTSD). In the specific population of ARDS survivors (n=74) numbers are slightly lower ranging from moderate to severe depression in 16% and 23%, respectively and for anxiety 24% and 23% at 1 and 2 years, respectively. These findings on survivors of ARDS and critical illness underline the assumption that survivors of a COVID-19 induced hospitalized will suffer from physical and psychological long-term consequences.

In research on critical illness post-ICU, only moderate evidence and large risk of bias exist on the effect of follow-up rehabilitation post-ICU. However, some qualitative studies support the thought that patients might need additional care after discharge home. King et al. (2019) investigated in their scoping review of qualitative studies the needs of critical illness survivors and found that after discharge home patients had continuing information needs on understanding their critical illness and coping with the long-term sequelae and stress.

These qualitative findings were underlined and supported by quantitative studies investigating long-term effects in this population. In patients who suffered an acute respiratory failure greatest change in physical function was found two months after discharge. And in ICU survivors requiring one or more weeks of mechanical ventilation the degree of disability one week after ICU discharge was predictive for physical and mental recovery and mortality in the one-year follow up.

In contrast to the findings on critical illness aftercare programs were found having a positive impact in a population with pulmonary disease. In survivors of ARDS due to severe influenza, A pneumonitis an 8-week pulmonary rehabilitation program improved significantly exercise capacity and quality of life improved significantly. And in patients with chronic obstructive pulmonary disease (COPD), the American Thoracic Society recommends respiratory rehabilitation early after discharge. Furthermore, according to the NICE guidelines "Rehabilitation after critical illness in adults" patients with rehabilitation needs should be seen two to three months after hospital discharge and should be reassessed to establish health and social care needs.

Additionally, based on an expert consensus following questions are still unanswered and considered as being relevant for the rehabilitation of these patients. Some examples are listed below:

• "What proportion of COVID-19 survivors have (extra-pulmonary) physical, functional, emotional and sociable treatable traits, justifying rehabilitation…?"
• "What types of patients will exist post-COVID-19 (e.g. good recovery, frailty, persistent respiratory impairment) and in what proportion?"
• "What is the impact of a COVID-19-related prolonged ward stay on physical and emotional functioning?
• What are the opportunities to intervene early, immediately post-acute hospital discharge?
• For how long after hospital discharge are COVID-19 survivors contagious? The latter two questions are cardinal to provide safe and feasible rehabilitation post-acute hospital discharge. To present the feasibility and safety of the aftercare program developed and conducted on the study site a short excurse on literature is provided.

Recent knowledge (published February 28 and 1st of April) from high impact journals give following solid time frames on viral shedding according to the traceability of Covid-19 RNA. Reverse transcription-polymerase chain reaction (RT-PCR) of virus RNA was used to measure the quantity of virus RNA in both studies.

Wölfel and colleagues isolated the virus daily from sputum, pharyngeal swabs, and stool since the first day of symptom onset. The samples were taken from individuals with mild to moderate symptoms (e.g. symptoms of lung affection). Maximal viral load was found before 5 days in these participants with the mild course being highest in stool and sputum. Based on their findings authors state that being 10 days beyond symptoms and less than 100,000 viral RNA copies per ml of sputum do have a little residual risk of infectivity, based on cell culture. Ling et al., isolated viral RNA from 66 participants post-Covid-19 infection as well from the stool, urine, and blood specimens during the convalescence. These samples were obtained from patients who survived a severe course of infection. The longest duration from onset of symptoms to first negative RT-PCR results for oropharyngeal swabs of convalescent patients was 22 days.

Zhou et al. (2020) studied as well the viral shedding with the daily analysis using PCR of Covid-19 throat swab specimens from 191 patients. For survivors, the duration of viral shedding showed an interquartile range of 17 to 22 days in patients with severe disease status (survivors). In summary, current knowledge shows the duration of viral traceability and thus the risk of infection from 10 to 22 days in patients with mild and severe illness, respectively. The average time to incubation found ranged from 5.2 to 12.5 days (Zhou et al., 2020) and average hospital duration ranged from 7 to 15 days in the 425 patients from Wuhan.

Therefore, subtracting lowest period of incubation (5 days) from the maximal duration of viral shedding (22 days) resulting in 17 days after first confirmed diagnose to be safe for hospital on-site testing. Based on this data and adding the criteria 4 days without specific COVID-19 symptoms (described in chapter 6.2.1), the committee developing the specific aftercare program - from which data will be taken for this study - considered as safe and feasible inviting patients post-acute hospital discharge when 14 days post diagnose and the mentioned four days (total ≥18 days).

In summary, there is a lack of knowledge on long term consequences of physical, emotional and quality of life outcomes. The similarity of clinical manifestation of the COVID-19 infection with ARDS or/and critical illness leads to the consideration of evidence found in this patient population. This evidence points out the high risk of long-term deficits on the above-mentioned outcomes and the relevance of patient-tailored rehabilitation programs.

Therefore, we consider it as essential to gather and analyse data on short and long-term quality of life and physical performance of patients after hospitalization due to COVID-19 infection.