What are the long‐term holistic health consequences of COVID‐19 among survivors? An umbrella systematic review

Abstract Many people who have survived COVID‐19 have experienced negative persistent impacts on health. Impacts on health have included persistent respiratory symptoms, decreased quality of life, fatigue, impaired functional capacity, memory deficits, psychological impacts, and difficulties in returning to paid employment. Evidence is yet to be pooled to inform future directions in research and practice, to determine the physical, psychological, social, and spiritual impacts of the illness which extend beyond the acute phase of COVID‐19 survivors. This umbrella review (review of systematic reviews) critically synthesized physical (including abnormal laboratory parameters), psychological, social, and spiritual impacts which extended beyond the acute phase of COVID‐19 survivors. The search strategy was based on the sample, phenomena of interest, design, evaluation, research model and all publications were double screened independently by four review authors for the eligibility criteria. Data extraction and quality assessment were conducted in parallel independently. Eighteen systematic reviews were included, which represented a total of 493 publications. Sample sizes ranged from n = 15 to n = 44 799 with a total of n = 295 455 participants. There was incomplete reporting of several significant data points including the description of the severe acute respiratory syndrome coronavirus 2 variant, COVID‐19 treatments, and key clinical and demographic data. A number of physical, psychological, and social impacts were identified for individuals grappling with post‐COVID condition. The long term sequalae of acute COVID‐19 and size of the problem is only beginning to emerge. Further investigation is needed to ensure that those affected by post‐COVID condition have their informational, spiritual, psychological, social, and physical needs met in the future.


| INTRODUCTION
Severe acute respiratory syndrome (SARS) coronavirus 1 is a strain of coronavirus that causes the SARS, the respiratory illness responsible for the 2002-2004 SARS outbreak. The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was detected in China in December 2019. 1 Since this time there have been 465 million confirmed cases and 6 million deaths from SARS-CoV-2. 2 During this pandemic, humanity has observed an unprecedented effort from health and scientific communities to diagnose, treat and prevent COVID-19, however, the long-term physical and psychological sequelae of this disease among survivors are yet to be fully understood. 3 Within the published literature, defining the post-COVID condition is problematic because of a range of different terms, which are not standardized or consistent. Terms such as long COVID- 19,4 postacute COVID-19 syndrome, 3 long-term effects of COVID-19, 5 longhaulers, 6 and persistent COVID-19 symptoms 7 have all been used to describe persistent signs and symptoms, or physiological measurements which have not returned to normal levels. 8 Further complicating these definitions, the "timeframe" employed to describe residual signs and symptoms is highly variable and the spectrum of long-term consequences is broad, encompassing the physical, psychological, social, and spiritual dimensions of health 9 among COVID-19 survivors. The timeframes specified to define persistent side-effects of COVID-19 include: (a) an illness in which individuals who have recovered from COVID-19 continue to experience unusual symptoms longer than expected 10 ; (b) persistent symptoms 2 weeks following COVID-19 recovery 5 ; and (c) symptoms that have continued for more than 3 months post COVID- 19. 11 Moreover, the National Institute for Health and Care Excellence (NICE) distinguishes between ongoing symptomatic COVID-19 which lasts between 4 and 12 weeks, and post COVID-19 syndrome which is sustained beyond 12 weeks. 12 Therefore, given the heterogeneity within the existing literature, this review of post-COVID conditions will use an inclusive classification of all changes in physical, psychological, social, and spiritual domains of health irrespective of the duration following the initial acute disease episode of COVID-19, which is inclusive of the first 4 weeks. 12 This holistic approach to defining the subsequent impacts of COVID-19 on health could guide the future provision and design of multidisciplinary services for those affected following acute COVID-19.
Developing personalized services by understanding an individual's informational, spiritual, psychological, social, and physical needs during follow-up phases would improve the survivor experience. It would also include issues of health promotion and prevention and COVID-19 individualized rehabilitation. 13 Numerous systematic reviews have been conducted to understand the longer-term impact of COVID-19 on health and well-being among survivors. 5,11,[14][15][16][17][18][19] This evidence reveals that globally many people who have survived COVID-19 have experienced negative persistent impacts on health, including financial implications, 11 however, the exact numbers of those affected remain unknown. 18 Impacts on health have included persistent respiratory symptoms, decreased quality of life, fatigue, impaired functional capacity, memory deficits, psychological impacts and difficulties in returning to paid employment. 11 Despite the many systematic reviews conducted on the topic, the evidence is yet to be pooled for the purpose of informing future clinical trials, clinical guidelines, and policy for future multidisciplinary team clinical service design to address the holistic person-centered needs of COVID-19 survivors.
Therefore, the aim of this study is to present an umbrella systematic review (a review of reviews) to summarize the evidence, appraise its quality, and combine relevant data to provide clinical decision makers with the evidence they need for targeted interventions to improve holistic health outcomes for people affected by COVID-19. Umbrella systematic reviews enable a systematic approach to appraise the evidence on an entire topic in relation to addressing the following research question: • Among COVID- 19

| Types of reviews
All qualitative, quantitative, and mixed methods reviews (systematic review, meta-analysis, narrative review, descriptive review, scoping review, qualitative review, realist review, critical review, literature review, mixed methods reviews, qualitative evidence synthesis, rapid review, review of reviews) were included irrespective of review design. Reviews were excluded if they did not describe the search strategy, inclusion criteria, and quality assessment methods. All reviews where the primary aim/research question for the review did not describe the physical, psychological, social, and spiritual impacts of COVID-19 beyond the acute phase were excluded. Reviews in languages other than English were counted but not read or evaluated. Reviews not based on primary empirical studies were also excluded.

| Phenomena of interest/outcomes
The main phenomenon of interest was the experience of physical, psychological, social, and spiritual impacts extending beyond the acute phase of COVID-19 among survivors.

| Context setting
The context included diverse geographical locations, a wide range of cultural factors, and different health care settings (acute, primary, and community health care), including wider clinical and demographic profiles of COVID-19 survivors.

| Search strategy
The search strategy was based on the sample, phenomena of interest, design, evaluation, research (SPIDER) model. 22 The SPIDER model is a tool developed for research questions and consists of five domains of interest, namely:  •Design (D): All qualitative, quantitative, and mixed methods reviews.  Table 1 for a full record of database searches. All records were managed using Endnote X20 and uploaded to Covidence systematic review software for deduplication of records and the study selection process. A preselection eligibility criterion was applied to all records.

| Systematic review selection
All publications (titles and abstracts) were double screened independently by four review authors to promote consistency and reliability in the application of the eligibility criteria. Articles that met the inclusion criteria were retrieved in full text and double screened with any disagreements resolved by discussion.

| Critical appraisal systematic reviews and research synthesis
Systematic reviews that were eligible for inclusion were assessed for methodological quality (critical appraisal) using the JBI tool 23 performed by two reviewers and cross-checked together. Each criterion was scored as being "met," "not met" "unclear" or "not applicable," see Table 1.

| Data extraction
Data extraction was cross-referenced by two reviewers using templates guided by JBI. 20

| Data synthesis
A metalevel narrative synthesis 20,23 of the findings across the included reviews was structured around (1) the type of reviews T A B L E 1 Critical appraisal checklist for systematic reviews and research syntheses Is the review question clearly and explicitly stated?
Were the inclusion criteria appropriate for the review question?
Was the search strategy appropriate?
Were the sources and resources used to search for studies adequate?
Were the criteria for appraising studies appropriate? Was critical appraisal conducted by two or more reviewers independently?
Were the methods used to combine studies appropriate?
Was the likelihood of publication bias assessed?
Were recommendations for policy and/or practice supported by the reported data?
Were the specific directives for new research appropriate?
There were a range of countries represented within the systematic reviews ( Figure 2), but the geographical location of included studies was not reported in four systematic reviews. [24][25][26][27] There is a lack of research with non-WEIRD (Westernised, Educated, Industrialized, Rich, Democratic) 28  F I G U R E 1 Preferred reporting items for systematic reviews and meta-analyses diagram 21 treatments, requirement for supplemental oxygen, ventilation, and so forth, (3) lack of healthy age-matched controls, (4) absent control for change over time, (5) racial differences, (6) gender, (7) pregnancy, (8) frequency, severity, and burden of symptoms at the time of disease onset, (9) influence of biological factors (such as immune, inflammatory, genetic and metabolic function, black and white fungus), and (10) geographical differences, and (11) influence of pre-existing mental health disorders, all of which may contribute directly to the experience and reporting of long-COVID sequalae.
These are important shortcomings in the interpretation of the existing evidence across the suite of included systematic reviews (Table 2). Overall, the methodological quality of the included systematic reviews was of medium to high quality (Table 3).

| Holistic health impacts of post-COVID condition
The existing evidence base is largely skewed in favor of a biomedical evaluation of health outcomes in individuals affected by post-COVID condition, and predominately focused on physical outcomes (

| Physical impacts
There were a range of clinically important findings largely related to the experience of symptomatology in patients living with post-COVID condition. Fifteen of the 18 included systematic reviews that provided information on the physical impacts. There was significant heterogeneity in the measurements used and time points of assessment which made performing a meta-analysis problematic.
Other important considerations are that the data concerning physical impacts of post-COVID condition are limited to the frequency/ prevalence of symptoms only. Symptoms are among the most common reasons that patients seek health care support but are also inter-related with symptom intensity and bother/distress. Of the evidence which is available in relation to the physical impacts of post-COVID condition, the most frequently reported symptoms included: fatigue, dyspnea (shortness of breath), myalgia (muscle pain), joint ache, headache, cough, chest pain, altered smell, altered taste, and diarrhea. 5,11,18,24,27,[29][30][31][32][33] Less commonly reported symptoms included a runny nose, sneezing, hoarseness, and ear pain. 24 However, it is unclear what the symptom intensity and bother/ distress experiences were for these symptoms among the participants. One systematic review reported that a total of 63.2% of the sample exhibited one or more post-COVID- 19  One systematic review 34 focussed specifically on the overall prevalence of joint pain which was observed to be 7.7% at onset/ hospital admission and 33.2%, 4.6%, 12.0%, 12.1%, at 30, 60, 90, and ≥180 days after onset/hospitalization, respectively. Of the available data, there was no significant differences between hospitalized and nonhospitalized patients. 34 A further systematic review 35  Two reviews explored factors which predicted the experience of post-COVID condition physical symptoms. One systematic review identified that hospitalization, and age between 40 and 49 years, were the two most significant predictors of post-COVID condition. 30 However other factors including the initial presentation symptoms (fever, dyspnea, anosmia, ageusia, and chest pain), gender or the number of comorbidities, did not predict post-COVID condition. 30 In contrast, a different systematic review reported that comorbidities, increasing age, being female, a loss of taste, and minority ethnicity were associated with post-COVID condition. 18 Therefore, the evidence about physical and demographic predictors of post-COVID condition is conflicting at this stage.

| Psychological impacts
Ten systematic reviews 5,18,24,26,[31][32][33][36][37][38] identified the psychological impacts of post-COVID condition which included anxiety, depression, posttraumatic stress disorder, somatization, fear, attention deficit disorder, and hair loss. Hair loss was thought to be more psychosocial in nature rather than caused by physical consequences of COVID-19 31 due to emotional distress which lasted up-to 3 months postacute COVID-19. 5 Participants also reported thoughts of self-harm and suicidal tendencies. 24 The most commonly experienced psychological impacts included depression 45% (n = 4028, 95% CI: 37%-54%), anxiety 47% (n = 3315, 95% CI: 37%-57%) and sleep disturbances 34% (n = 1795, 95% CI: 19%-50%) but these were not associated with gender or age. 36 Another review reported that severity of the infection was associated with different levels of anxiety, depression and posttraumatic stress, somatization, and fear. 37 Some participants expressed concerns that physical and psychological recovery was not possible and this caused them distress. 33 Other participants described a change in their identity when they reflected on how they perceived themselves before being diagnosed with COVID-19. 33 One systematic review reported an increased incidence of 5.8% of newly diagnosed psychiatric diseases 14-90 days after diagnosis of COVID-19 infection. 26

| Quality of life
The impact of post-COVID condition on quality of life was infrequently reported across the included systematic reviews. Four systematic reviews reported that individuals affected by post-COVID condition reported reduced quality of life. 11,18,24,38 One review identified that participants self-reported a clinically significant decrease in quality of life on average 48 ± 10.3 days postacute phase, which impacted reduced mobility, ability to self-care, participation in usual activities, pain/discomfort, and anxiety/depression as measured by the EuroQol intrument. 38

| Social impacts
Three systematic reviews identified that individuals affected by post-COVID condition experienced some problems with returning to work/employment at ∼3 months postacute phase. 11,33 A separate systematic review identified that patients affected by post-COVID condition reported a loss of income and ability to work secondary to fatigue. 33 Cognitive impairments and fatigue limited the prospect of individuals affected by post-COVID condition to find new employment or return to work. 11 It was estimated that 31% could not return to employment at 72 days postacute hospital discharge. 26

| Health system impacts on health
Only one review provided insight into the impact of the health system on recovery for individuals grappling with post-COVID condition. 24 People living with post-COVID condition reported that they felt a sense of "abandonment" or were being "dismissed" by healthcare providers and received limited or conflicting advice to inform their rehabilitation and self-management.

| Spiritual impacts
None of the reviews provided any information on the spiritual impacts of living with post-COVID condition.

| DISCUSSION
The main finding of this umbrella review, capturing almost 300 000 participants with post-COVID condition, is that there is an enormous The challenges of prolonged recovery from a critical illness are not new. 40  physiotherapy, occupational therapy, psychology, and more; however, given the known heterogeneity of symptom burden, multidisciplinary clinics may be best placed to provide comprehensive individually tailored interventions. In Australia, there is a dearth of such clinics with only two ICU follow-up clinics noted in a recent survey. 43 However, the prevalence of COVID-19 may accelerate proliferation of such clinics to enhance patients' recovery in the future. The evidence to support the efficacy of multidisciplinary clinics is a much-needed future research direction.
The evidence summarized in this review is highly skewed