In the UK we have been living in lockdown since 23 March 2020 in response to the Covid-19 pandemic, which has killed tens of thousands of people – an almost science-fiction-style scenario.
Even with this devastating death toll, many more people are experiencing the disease and surviving. As time goes on we are beginning to discover the complications that recovered patients – particularly those who have spent time in ICU – are living with. This article, Part 1, discusses the many manifestations of Covid-19 and Part 2 discusses how to structure a rehabilitation programme for Covid-19 survivors.
Content covered in this article includes:
- How the Virus Invades the Body
- Pathophysiology that Kills
- Changes in Lung Tissue and Function
- Is There a Risk For CFS?
- What will Covid-19 Rehabilitation Entail?
- How Can Rehabilitation be Executed?
By Kathryn Thomas BSc MPhil
Disclaimer: At the time of publication this article is based on published evidence available. To date there are no follow-up studies or trials that focus on the long-term management and recovery post-Covid-19. Apart from a few case reports, the Rehabilitation strategies suggested below are based on the understanding of how the Covid-19 virus attacks the body’s systems, and historic evidence from previous coronavirus outbreaks which have been extrapolated to management strategies of similar chronic illnesses.
As I write, we are currently in the grip of the Covid-19 pandemic – a disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). As we gain more experience of this infection, it’s clear that Covid-19 can be more than just a respiratory disease. It’s joined the ranks of other ‘great imitators’ – diseases that can look like almost any condition. It can be a gastrointestinal disease causing only diarrhoea and abdominal pain. It can cause symptoms that may be confused with a cold or the seasonal flu. It can cause pinkeye, a runny nose, loss of taste and smell, muscle aches, fatigue, loss of appetite, nausea and vomiting, whole-body rashes, and areas of swelling and redness in just a few spots. In more severe cases there have been reports of heart arrhythmia, heart failure, kidney damage, confusion, headaches, seizures, Guillain–Barré syndrome, and fainting spells (or altered levels of consciousness), along with new sugar-control problems. These symptoms and other ailments can’t be attributed to the ‘corona pneumonia’ alone. Yes, the primary and most common consequence of Covid-19 is respiratory distress and ultimately acute respiratory distress syndrome (ARDS); however, the virus can attack many other cells within the body causing a multitude of other complications.
To date, the focus of most publications and press coverage has been on patient demographics, risk factors, acute management, supportive care, prevention, medication, vaccines and life-saving strategies. But once the peak has been reached and isolation levels are eased there may be time to take a breath and consider: What now for the survivors? We clapped (and very deservedly so) for all the frontline workers and patients who survived and recovered from ICU, but will we still be clapping in 3 to 6 months’ time or even a year from now when we consider their recovery. When the dust has settled let us consider the millions of people with mild to moderate cases of coronavirus or those discharged from hospital – seemingly better – sent home to rest and recover. Concerns have been raised that it may not be so simple. This virus is unlike any seen before; knowing how it attacks the body’s cells and systems sheds some light on the fact that a little ‘R&R’ may not be the simple long-term recovery strategy for most patients.
One open question concerns the long-term effects for survivors. What does life look like after being on a ventilator or suddenly needing dialysis? Will we see decreases in heart, lung and kidney function that is long lasting and permanent, or will patients eventually recover? At present, there are no follow-up studies or case reports of patients once discharged from hospital. The opinion is that simple resolution of symptoms may not be the end of the story. The toll on the body may result in the development of a type of chronic fatigue syndrome (CFS). Physical therapy may be required long term, not only in the form of pulmonary Rehabilitation, but Rehabilitation of exercise tolerance, as well as managing complications from deep vein thromboses (DVTs), pulmonary embolism (PE), myalgia, and even stroke.
How the Virus Invades the Body
As mentioned, Covid-19 is not simply a pneumonia with severe alveolar damage but is often associated with rapid virus replication, infiltration of inflammatory cells and elevated responses to inflammatory proteins such as cytokines resulting in damage in internal organs and ARDS. The pathophysiology also shows it causes a severe ‘cytokine storm’ and possibly disseminated intravascular coagulation, disrupting blood clotting and causing thrombotic events. This is a complex disease; the disruption to the body’s functions is extensive, potentially lengthening the time it takes to fully recover.
When viral particles land in your eyes, nose or mouth, ‘spike proteins’ on the surface of the virus connect with a specific receptor, known as angiotensin-converting enzyme 2 (ACE2), on the surface of your cells, allowing entry. ACE2 receptors make a great target because they are found in organs throughout your body. Once the virus enters, it turns the cell into a factory, making millions and millions of copies of itself – which can then be breathed or coughed out to infect others.
In order to evade early detection, the coronavirus uses multiple tools to prevent the infected cells from calling out for help. The virus snips off distress signal proteins that cells make when they are under attack. It also destroys antiviral commands inside the infected cell. This gives the virus much more time to make copies of itself and infect surrounding areas before it is identified as an invader. This is part of the reason why the virus spreads before immune responses, such as fever, begin.
Once the virus is deeply embedded in the body, it begins to cause more severe disease. This is where direct attack on other organs that have ACE2 receptors can occur, including heart muscle, kidneys, blood vessels, the liver and, potentially, the central nervous system (CNS). This may be one reason for the vast array of symptoms that Covid-19 can cause. Early findings, including those from autopsy and biopsy reports, show that viral particles can be found not only in the nasal passages and throat, but also in tears, stool, the kidneys, liver, pancreas and heart.
Pathophysiology that Kills
1. Cytokine Storm
Severe damage to the lungs may be one trigger that activates and overstimulates the immune system through a barrage of signalling chemicals, known as cytokines. The flood of these chemicals can set off what is referred to as a ‘cytokine storm’ https://www.thelancet.com/pdfs/journals/lancet/PIIS0140-6736(20)30628-0.pdf)). This is a complex interplay of chemicals that can cause blood pressure to drop, attract more immune and inflammatory cells, and lead to even more injury within the lungs, heart, kidneys and brain. Some researchers say that cytokine storms may be the cause of sudden decompensation, leading to critical illness in Covid-19 patients (2).
When Covid-19 infects the respiratory tract it can cause mild or highly acute respiratory syndrome with consequent release of proinflammatory cytokines, including interleukin (IL)-1β and IL-6. The binding of Covid-19 to Toll-like receptor proteins causes the release of pro-IL-1β which is cleaved by caspase-1, followed by inflammasome activation and production of active mature IL-1β, which is a mediator of lung inflammation, fever and fibrosis.
Secondary haemophagocytic lymphohistiocytosis (sHLH) is an under-recognised, hyperinflammatory syndrome characterised by a sudden, severe and fatal hypercytokinaemia with multiorgan failure. A cytokine profile resembling sHLH is associated with Covid-19 disease severity, characterised by increased IL-2, IL-7, granulocyte colony-stimulating factor, interferon gamma-induced protein 10, monocyte chemoattractant protein 1, macrophage inflammatory protein 1-alpha, and tumour necrosis factor-alpha (TNF-α).
2. Abnormal Clotting
The pathogenesis of Covid-19 infection is not clearly understood. Inflammatory cytokine storms and viral evasion of cellular immune responses play a central role in disease progression and severity. Disseminated intravascular coagulation and coagulopathy can contribute to death. DVT and PE can occur in patients with Covid-19 pneumonia.
Historically, haematological changes have been seen with sudden acute respiratory distress syndrome (SARS), caused by SARS-CoV (also known as SARS-CoV-1) another strain of coronavirus very similar to that which causes Covid-19. These included lymphopenia, thrombocytopenia, and leukopenia. The possible mechanisms of coronavirus on the blood system may include:
- direct infection of blood cells and bone marrow stromal cells via cell determinant (CD)or CD66a proteins; and/or
- induce auto-antibodies and immune complexes to damage these cells.
In addition, lung damage in SARS patients may also play a role in inducing thrombocytopenia by:
- increasing the consumption of platelets/megakaryocytes; and/or
- reducing the production of platelets in the lungs (as the most common haematological changes in SARS patients were lymphopenia and immunodeficiency).
In clinical practice, frontline clinicians found that approximately 20% of Covid-19 patients had severe coagulation abnormalities, and almost all the patients with severe and critically ill Covid-19 infection showed major coagulation disorders. A very recent study showed that markedly elevated D-dimer and fibrinogen degradation products were very common in Covid-19-related deaths, indicating a disruption in the coagulation cascade. Moreover, an acute inflammation caused by severe infection or sepsis may affect coagulation and fibrinolysis in multiple ways, including a decrease of circulating protein C and antithrombin and an increase of plasminogen activator inhibitor-1 levels, which will finally activate the coagulation cascade and inhibit the fibrinolytic response, thus promoting thrombosis. Therefore, more attention should be paid to the occurrence of potential PE following the shedding of DVT.
3. Additional Laboratory Findings
The differences in abnormalities of laboratory findings between the deceased patients and the survivors were substantial, with deceased patients being more likely to have:
- developed leukocytosis, and one third of deceased patients had procalcitonin above 0.5ng/mL, indicating that a large proportion of deceased patients might have had secondary bacterial infection strongly associated with death;
- persistent and more severe lymphopenia suggesting a cellular immune deficiency state;
- impaired liver and kidney function (mild or moderate elevation of alanine aminotransferase, aspartate aminotransferase, total bilirubin, alkaline phosphatase, gamma-glutamyl transpeptidase, blood urea nitrogen, and creatinine and frequent hypoalbuminaemia, haematuria, and albuminuria);
- electrolyte disturbance (hyperkalaemia and hypernatraemia); and/or
- markedly higher concentrations of creatine kinase, lactate dehydrogenase, cardiac troponin I, and N-terminal pro-brain natriuretic peptide were seen in deceased patients than in recovered patients.
Essentially, in the later stages of the disease, patients who die may develop pulmonary and extrapulmonary organ damage, including ARDS, type I respiratory failure, sepsis, acute cardiac injury, heart failure, acute kidney injury, hypoxic encephalopathy, shock, acidosis or alkalosis, disseminated intravascular coagulation, and acute liver injury.
Changes in Lung Tissue and Function
The chest X-ray usually shows bilateral infiltrates which may be evident in early disease. However, bilateral multifocal consolidation can be seen in severe patients, partially fused into massive consolidation with small pleural effusions and even presenting with ‘white lung’.
The computed tomography scan (CT) is more sensitive and specific. CT imaging generally shows infiltrates, ground-glass opacity (GGO) and subsegmental consolidation. CT results can also be abnormal in asymptomatic patients/patients with no clinical evidence of lower respiratory tract involvement. In fact, abnormal CT scans have been used to diagnose COVID-19 in suspect cases with negative molecular diagnosis; many of these patients had positive molecular tests on repeat testing (1,9). In patients with Covid-19 pneumonia, focal or multifocal pure GGO and GGO with reticular and/or interlobular septal thickening as typical crazy-paving pattern have been observed.
From mild to severe, Covid-19 pneumonia mainly starts as small subpleural, unilateral or bilateral GGO in the lower lobes, which then develops into the crazy-paving pattern and subsequent consolidation. After more than 2 weeks, the lesions are gradually absorbed with residual GGO and subpleural parenchymal bands. In patients who recovered from Covid-19 pneumonia, four stages of lung involvement have been defined on CT:
1. Early stage (0–4 days after onset of the initial symptom)
In this stage, GGO was the main radiological demonstration distributed subpleurally in the lower lobes unilaterally or bilaterally.
2. Progressive stage (5–8 days after the onset of the initial symptom)
In this stage, the infection rapidly aggravated and extended to a bilateral multilobe distribution with diffuse GGO, crazy-paving pattern and consolidation.
3. Peak stage (9–13 days after the onset of the initial symptom)
In this stage, the involved area of the lungs slowly increased to the peak involvement and dense consolidation became more prevalent. Findings included diffuse GGO, crazy-paving pattern, consolidation, and residual parenchymal bands.
4. Absorption stage (≥14 days after the onset of the initial symptom)
In this stage, the infection was controlled and the consolidation was gradually absorbed. No crazy-paving pattern was present anymore. However, in this process, extensive GGO could be observed as the demonstration of the consolidation absorption. The absorption stage can be extended beyond 26 days.
All Covid-19 patients have features of diffuse alveolar damage with pronounced pulmonary oedema and hyaline membrane formation. In some areas, there was interstitial thickening, with mild to moderate fibrosis, but a disproportionately sparse infiltrate of inflammatory cells (mainly histiocytes, including multinucleated forms, and lymphocytes). Dilation of the airspaces was seen, as was focal honeycombing fibrosis. Intra-alveolar organisation of exudates was seen, with the formation of granulation tissues in small airways and airspaces in some cases. These lesions were typically located in the subpleural region and the cellular component consisted mainly of histiocytes.
What Causes ARDS?
Capillary permeability is a tightly regulated feature of microcirculation in all organ beds and is fundamentally altered in sepsis, resulting in net extravasation of fluid out of the vascular space and into tissues. A dramatic manifestation of this phenomenon is ARDS, a complication that occurs in up to 40% of patients with sepsis and is marked by leakage of fluid out of pulmonary capillaries and into alveolar septa and air spaces. Excess extravascular fluid in the lung impairs gas exchange across the alveolar membrane and decreases lung compliance. ARDS associated with sepsis has been correlated with adverse clinical outcomes, including 40% mortality.
It has been shown that the renin-angiotensin system in the lung is involved in ARDS. The interaction between angiopoietin-2 and its type 1 receptor causes a disruption of the endothelial architecture leading to pulmonary inflammation and capillary leakage, both of which contribute to the initiation and/or the aggravation of ARDS.
Is There a Risk For CFS?
This section refers to the recovering patients rather than the healthcare workers! Given the pathophysiology with which Covid-19 attacks the systems of the body and the consequential cascade of biological reactions, questions have been raised whether CFS/myalgic encephalomyelitis (ME) could become a common after-effect in survivors. CFS is a debilitating disorder with a hitherto unknown aetiology but of suspected multifactorial origin. After decades of neglect and misjudgement as mental disease there is growing evidence for a complex dysregulation of the immune and autonomic nervous system in CFS/ME. Common ‘triggers’ include severe viral infections and emotional stress. This illness is expected to be a complex, multisystem neuroimmune disease. Recently, some novel clues for CFS/ME were found, such as higher levels of immunosuppressive cytokines, especially transforming growth factor beta, an altered composition of the gut microbiome, and potential biomarkers from nanoelectronic assays. However, the clear mechanisms of CFS/ME or its objective diagnostic markers have not yet been found.
Recent findings show that the fatigue and somatic symptoms experienced with CFS are a clinical expression of dysregulated inflammatory, immune, oxidative and nitrosative stress (IO&NS) pathways (Fig. 1). Increased levels of proinflammatory cytokines, oxidative damage, increased cyclo-oxygenase 2 (COX-2) production, increased translocation by Gram-negative enterobacteria and so on, can generate fatigue and somatic symptoms, including fatigue, a flu-like malaise, pain, symptoms of irritable bowel syndrome, and neurocognitive disorders.
Figure 1: The inflammatory and oxidative and nitrosative (IO&NS) pathophysiology of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Figure first published in Maes M, Twisk FN. Chronic fatigue syndrome: Harvey and Wessely’s (bio)psychosocial model versus a bio(psychosocial) model based on inflammatory and oxidative and nitrosative stress pathways. BMC Med 2010;8:35 (https://doi.org/10.1186/1741-7015-8-35)) and reproduced under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0)
Considering a proposed (although not fully understood) pathophysiology behind the development of CFS (illustrated in Fig. 1), one might consider the very real possibility that the mechanism of attack of Covid-19 on one’s body could produce a similar picture to that of CFS. The viral infection [immunological and biological changes, with added symptoms of muscle pain, extended bedrest and inactivity (brought on by illness and/or isolation protocols)], combined with emotional and psychological stress of surviving Covid-19 and the resultant work, family, social, income, and lifestyle changes may all result in the development of the complex biopsychosocial condition of CFS.
CFS is characterised by severe fatigue and exhaustion (prolonged over 6 months), muscular and mental fatigue, exercise intolerance, post-exertional malaise (PEM) and a myriad of symptoms including impaired cognitive ability, poor sleep quality, muscle pain, multijoint pain without swelling or redness, or headache (15). Many patients suffer from symptoms of autonomic dysfunction including orthostatic intolerance and may complain of dizziness, spatial disorientation, sweating, palpitations or fainting. PEM, which is a hallmark of ME/CFS, is seen as an aggravation of all symptoms of ME/CFS. PEM involves an abnormal response (eg. an inappropriate loss of physical and mental stamina, rapid muscular and cognitive fatigability) following physical, cognitive, emotional or orthostatic exertion.
Patients with CFS/ME cannot carry out their normal social routines, work or leisure activities, and some of them are even home- or bed-bound. They experience lower health-related quality of life than those experiencing depression or stroke. The medical impact includes the high prevalence in the working-age population and particularly the high risk of suicide, which is approximately 7-fold higher than in healthy controls.
CFS may be an important condition to be aware of in the long-term management of recovering Covid-19 patients. Integrating a component of rehabilitation for CFS with pulmonary/cardiac rehabilitation may be an important consideration.
What will Covid-19 Rehabilitation Entail?
You may be questioning your role in the healthcare system during a time of an infectious disease pandemic. So what is the connection between physiotherapy and rehabilitation in the context of infectious disease outbreaks? Given the relatively high likelihood of survival after exposure to infectious disease, physiotherapy can mediate the deleterious pulmonary, respiratory and immobility complications that are commonplace. Moreover, rehabilitation can offer a cost-effective upstream strategy that can restore mental and emotional quality of life during and after medical intervention.
Our knowledge of the range of impairments and disabilities is still evolving and we do not know the long-term sequelae of the condition, but there is already information that will assist in estimating the scale and type of response. Covid-19 is a multisystemic condition and some of the effects seem to be long lasting. Experience from China and Italy suggests that at least a third of patients discharged from hospital require assistance in activities of daily living and a similar proportion have significant neurological sequelae.
There are some publications that highlight the range of impairments that may present following infection with Covid-19, and other coronavirus infections – and this literature is expanding daily. Table 1 sets out some of the more frequent complications that are likely to be encountered in patients recovering from moderate or severe disease.
Table 1: Complications in patients recovering from Covid-19
Clinical experience shows the main repercussions of Covid-19 infection are respiratory, CNS and cognitive, deconditioning, critical-illness myopathy and neuropathy, dysphagia, joint stiffness and pain, and psychiatric problems. Of SARS survivors, at 1-year follow-up, 24% had both significant impairment in diffusing capacity of the lung for carbon monoxide and reduced exercise capacity.
Rehabilitation of patients with lung fibrosis secondary to ARDS can be challenging. Several authors have published data on the long-term effects of ARDS and post-intensive care syndrome. Consequences of ARDS include:
- ICU-acquired weakness in 25–100% of cases, resulting in immobility, suboptimal glycaemic control and iatrogenic use of steroids and neuromuscular blocking agents.
- Cognitive impairment in the majority of survivors at hospital discharge and in around 10% of patients impairments are persistent at long-term follow-up. These include depression (29%), post-traumatic stress disorder (22%) and anxiety (34%) affecting survivors at 1 year.
A pre-Covid-19 study showed post-traumatic stress disorder in patients who had been in ICU for greater than 28 days. They described a clear history of severe weakness, functional impairment and prolonged recovery after hospital discharge. More than 90% still had significant weakness more than 5 years following the ICU stay.
Clinical experience from Italy shows that after critical Covid-19, some patients may have confusion, memory and executive function deficits, which may be due to a direct viral involvement of the CNS or the effect of hypoxemia. Considering that nearly 50% of ARDS survivors show cognitive sequelae at 2 years after the injury this could play a significant role in overall disability.
How Can Rehabilitation be Executed?
Rehabilitation will require a person-centred approach, but is likely to involve improving physical strength and stamina alongside optimising psychological health, and addressing neurological rehabilitation needs when necessary.
Factors affecting rehabilitation for individuals are:
- the range of impairments and disabilities experienced;
- the rate of recovery from these impairments; and
- personal and environmental circumstances including:
– premorbid functional abilities;
– psychological background of the person, such as their usual coping mechanisms, self-efficacy and abilities to adapt;
– the home environment or place that the individual will be discharged to;
– individual social context, such as the social group the person inhabits and their economic circumstances;
– occupation, whether paid, ‘informal’ or voluntary work; and
– other activities that the person finds fulfilling.
A further complication to rehabilitation is the infectious nature of Covid-19. Although some advice can be given from a distance, much of rehabilitation (especially in the context of severe physical disability) requires hands-on intervention. Some of the interventions are aerosol-generating procedures, which pose a significant health risk to the professionals who treat patients, as well as a risk of spreading infection to others. Regular and repeated testing for Covid-19 will be necessary to support segregation (of those still positive from those being negative) and it is essential that staff have access to the all the necessary personal protective equipment to be able to treat patients safely. It is strongly advised to implement teleconsultation and telerehabilitation devices, minimising exposure risk and implementing communication technologies to help patients and families reduce barriers imposed by isolation. Telehealth consultations may be the only initial treatment possible following discharge and during continued lockdown periods. One-on-one or group rehabilitation classes will be hugely beneficial to the patient provided strict social distancing and sanitising procedures can be followed.
Key Components of Rehabilitation Programmes After Covid-19 (18)
Exercise is likely to be needed by all patients, to overcome deconditioning, improve pulmonary and cardiac function and any neuromuscular complications. Graded exercise therapy is also a key element of CFS management.
Pulmonary rehabilitation is a key treatment strategy to reduce symptoms of breathlessness and improve lung function and capacity. It is well-documented to increase walking capacity and quality of life.
Practice of Activities
Re-establishing patient autonomy in important activities, either undertaken as before or done differently with/without equipment and aids.
Psychological input to offer cognitive behavioural therapy, acceptance and commitment therapy, and other input to help patients with the likely emotional sequelae – anxiety, depression, sleep disturbance, etc.
Education and Information
Provision of high-quality information both about the person’s situation and about their future. Teaching self-management and goal-setting skills to patients and families.
Some patients may need equipment or adaptations, at least in the short-term.
Rehabilitation from Covid-19 will entail a combination of treatment strategies, customised to the patient’s needs depending on any comorbidities from the virus. They may require:
- cardio-pulmonary rehabilitation;
- sports and exercise medicine;
- neurorehabilitation and neurological disability services; and/or
- vocational rehabilitation.
Specialist rehabilitation should be delivered by coordinated multidisciplinary rehabilitation teams comprising rehabilitation medicine, psychiatric and neuropsychiatric support, rehabilitation nursing, physiotherapy, occupational therapy, clinical psychology/neuropsychology, speech and language therapy, dietetics and social work.
- Covid-19 is not simply a pneumonia or respiratory virus.
- The pathophysiology shows infiltration of inflammatory cells and elevated responses to inflammatory proteins, such as cytokines, resulting in damage to internal organs and acute respiratory distress syndrome.
- Covid-19 causes disseminated intravascular coagulation, disrupting blood clotting resulting in thrombotic events, such as deep vein thrombosis, pulmonary embolism and stroke.
- In some patients who recovered from Covid-19 pneumonia, lesions within lung tissue were gradually absorbed but left extensive ground-glass opacity and subpleural parenchymal bands.
- The main repercussions of Covid-19 infection are respiratory, central nervous system and cognitive, deconditioning, critical-illness myopathy and neuropathy, dysphagia, joint stiffness and pain, and psychiatric problems.
- SARS survivors, at 1-year follow-up, had both significant reductions in lung function and reduced exercise capacity.
- A potential long-term risk of developing chronic fatigue syndrome has been raised. Common ‘triggers’ of this include severe viral infections and emotional stress, a dysregulation of immune and autonomic nervous system, not unlike Covid-19 survivors.
- Physical therapy can mediate the deleterious pulmonary, respiratory, and immobility complications following Covid-19 using graded exercise, respiratory exercises and manual hand-on therapy when necessary.
- Rehabilitation is complicated by the infectious nature of the virus whereby telehealth devices or teleconsultations may be the first option available.
- A team of medical services may be required including physical therapy, occupational therapy, social work, psychiatry, specialist physicians, and speech therapy.
- Given the pathophysiology of the virus, what conditions and patient complaints do you feel are going to present most frequently in survivors seeking rehabilitation?
- Do you fear there has been little focus and/or an underestimation on the long-term medical requirements still needed in rehabilitating Covid-19 patients?
- What do you believe will be the biggest barrier in the recovery of Covid-19 patients?
“It’s clear that Covid-19 can be more than just a respiratory disease”
“A little ‘R&R’ may not be the simple long-term recovery strategy for most patients”
“The mechanism of attack of Covid-19 could produce a similar picture to that of chronic fatigue syndrome”
“Experience from China and Italy suggests that at least a third of patients discharged from hospital require assistance in activities of daily living”
“Sports rehabilitation will require a person-centred approach, but is likely to involve improving physical strength and stamina alongside optimising psychological health, and addressing neurological rehabilitation needs when necessary”
- Singhal T. A review of coronavirus disease-2019 (COVID-19). The Indian Journal of Pediatrics 2020;87:281–286
- Conti P, Ronconi G, Caraffa A et al. Induction of pro-inflammatory cytokines (IL-1 and IL-6) and lung inflammation by Coronavirus-19 (COVI-19 or SARS-CoV-2): anti-inflammatory strategies. Journal of Biological Regulators and Homeostatic Agents 2020;34(2):doi:10.23812/CONTI-E
- Mehta P, McAuley D, Brown M et al. COVID-19: consider cytokine storm syndromes and immunosuppression. The Lancet 2020;395(10229):1033–1034
- Poggiali E, Bastoni D, Ioannilli E et al. Deep vein thrombosis and pulmonary embolism: two complication of COVID-19 pneumonia? European Journal of Case Reports in Internal Medicine 2020;7:doi:10.12890/2020_001646
- Yang M, Hon KL, Li K et al. The effect of SARS coronavirus on blood system: its clinical findings and the pathophysiologic hypothesis. Zhongguo Shi Yan Xue Ye Xue Za Zhi 2003;11(3):217–221
- Zhai Z, Li C, Chen Y et al. Prevention and treatment of venous thromboembolism associated with coronavirus disease 2019 infection: a consensus statement before guidelines. Thrombosis and Haemostasis 2020;doi:10.1055/s-0040-1710019
- Chen T, Wu Di, Chen Huilong et al. Clinical characteristics of 113 deceased patients with coronavirus disease 2019: retrospective study. BMJ 2020;368:m1091
- Huang C, Wang Y, Li X et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. The Lancet 2020;395(10223):497–506
- Zu ZY, Jiang MD, Xu PP et al. Coronavirus disease 2019 (COVID-19): a perspective from China. Radiology 2020;200490
- Pan F, Ye T, Sun P et al. Time course of lung changes on chest CT during recovery from 2019 novel coronavirus (COVID-19) pneumonia. Radiology 2020;200370
- Tse GM, To KF, Chan PK et al. Pulmonary pathological features in coronavirus associated severe acute respiratory syndrome (SARS). Journal of Clinical Pathology 2004;57(3):260–265
- Geier MR, Geier DA. Respiratory conditions in coronavirus disease 2019 (COVID-19): Important considerations regarding novel treatment strategies to reduce mortality. Medical Hypotheses 2020;140:109760
- Parikh SM, Mammoto T, Schultz A et al. Excess circulating angiopoietin-2 may contribute to pulmonary vascular leak in sepsis in humans. PLoS Medicine 2006;3(3):e46
- Essig M, Matt M, Massy Z. The COVID-19 outbreak and the angiotensin-converting enzyme 2: too little or too much? Nephrology Dialysis Transplantation 2020;pii:gfaa113
- Kim DY, Lee JS, Park SY et al. Systematic review of randomized controlled trials for chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME). Journal of Translational Medicine 2020;18(1):7
- Maes M, Twisk FN. Chronic fatigue syndrome: Harvey and Wessely’s (bio)psychosocial model versus a bio(psychosocial) model based on inflammatory and oxidative and nitrosative stress pathways. BMC Medicine 2010;8:35
- Landry MD, Tupetz A, Jalovcic D et al. The novel coronavirus (COVID-19): making a connection between infectious disease outbreaks and rehabilitation. Physiotherapy Canada 2020;e20200019
- Philips M, Turner-Stokes L, Wade D et al. Rehabilitation in the wake of Covid-19 – a phoenix from the ashes. British Society of Rehabilitation Medicine 2020;1 27.4.2020
- Carda S, Invernizzi M, Bavikatte G et al. The role of physical and rehabilitation medicine in the COVID-19 pandemic: the clinician’s view [Letter; not peer reviewed]. Annals of Physical and Rehabilitation Medicine 2020;pii:S1877-0657(20)30076-2
- Ahmed H, Patel K, Greenwood D et al. Long-term clinical outcomes in survivors of coronavirus outbreaks after hospitalisation or ICU admission: a systematic review and meta-analysis of follow-up studies. medRxiv 2020;doi:https://doi.org/10.1101/2020.04.16.20067975 [Pre-print; not peer reviewed]
- Simpson R, Robinson L. Rehabilitation after critical illness in people with COVID-19 infection. American Journal of Physical Medicine & sports rehabilitation 2020;doi:10.1097/PHM.0000000000001443 [Epub ahead of print]