Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the pathogen responsible for the coronavirus disease 2019 (COVID-19) pandemic, which has resulted in global healthcare crises and strained health resources. As the population of patients recovering from COVID-19 grows, it is paramount to establish an understanding of the healthcare issues surrounding them. COVID-19 is now recognized as a multi-organ disease with a broad spectrum of manifestations. Similarly to post-acute viral syndromes described in survivors of other virulent coronavirus epidemics, there are increasing reports of persistent and prolonged effects after acute COVID-19. Patient advocacy groups, many members of which identify themselves as long haulers, have helped contribute to the recognition of post-acute COVID-19, a syndrome characterized by persistent symptoms and/or delayed or long-term complications beyond 4 weeks from the onset of symptoms. Here, we provide a comprehensive review of the current literature on post-acute COVID-19, its pathophysiology and its organ-specific sequelae. Finally, we discuss relevant considerations for the multidisciplinary care of COVID-19 survivors and propose a framework for the identification of those at high risk for post-acute COVID-19 and their coordinated management through dedicated COVID-19 clinics.

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Post-acute COVID-19 syndrome.

The pandemic of coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has caused an unprecedented global social and economic impact, and high numbers of deaths. Many risk factors have been identified in the progression of COVID-19 into a severe and critical stage, including old age, male gender, underlying comorbidities such as hypertension, diabetes, obesity, chronic lung diseases, heart, liver and kidney diseases, tumors, clinically apparent immunodeficiencies, local immunodeficiencies, such as early type I interferon secretion capacity, and pregnancy. Possible complications include acute kidney injury, coagulation disorders, thoromboembolism. The development of lymphopenia and eosinopenia are laboratory indicators of COVID-19. Laboratory parameters to monitor disease progression include lactate dehydrogenase, procalcitonin, high-sensitivity C-reactive protein, proinflammatory cytokines such as interleukin (IL)-6, IL-1β, Krebs von den Lungen-6 (KL-6), and ferritin. The development of a cytokine storm and extensive chest computed tomography imaging patterns are indicators of a severe disease. In addition, socioeconomic status, diet, lifestyle, geographical differences, ethnicity, exposed viral load, day of initiation of treatment, and quality of health care have been reported to influence individual outcomes. In this review, we highlight the scientific evidence on the risk factors of severity of COVID-19.

Risk factors for severe and critically ill COVID-19 patients: A review.

Since its emergence in Wuhan, China, covid-19 has spread and had a profound effect on the lives and health of people around the globe. As of 4 July 2021, more than 183 million confirmed cases of covid-19 had been recorded worldwide, and 3.97 million deaths. Recent evidence has shown that a range of persistent symptoms can remain long after the acute SARS-CoV-2 infection, and this condition is now coined long covid by recognized research institutes. Studies have shown that long covid can affect the whole spectrum of people with covid-19, from those with very mild acute disease to the most severe forms. Like acute covid-19, long covid can involve multiple organs and can affect many systems including, but not limited to, the respiratory, cardiovascular, neurological, gastrointestinal, and musculoskeletal systems. The symptoms of long covid include fatigue, dyspnea, cardiac abnormalities, cognitive impairment, sleep disturbances, symptoms of post-traumatic stress disorder, muscle pain, concentration problems, and headache. This review summarizes studies of the long term effects of covid-19 in hospitalized and non-hospitalized patients and describes the persistent symptoms they endure. Risk factors for acute covid-19 and long covid and possible therapeutic options are also discussed.

https://www.bmj.com/content/bmj/374/bmj.n1648.full.pdf

Long covid-mechanisms, risk factors, and management.

The Coronavirus Disease 2019 (COVID-19) pandemic has become a global crisis and is more devastating than any other previous infectious disease. It has affected a significant proportion of the global population both physically and mentally, and destroyed businesses and societies. Current evidence suggested that immunopathology may be responsible for COVID-19 pathogenesis, including lymphopenia, neutrophilia, dysregulation of monocytes and macrophages, reduced or delayed type I interferon (IFN-I) response, antibody-dependent enhancement, and especially, cytokine storm (CS). The CS is characterized by hyperproduction of an array of pro-inflammatory cytokines and is closely associated with poor prognosis. These excessively secreted pro-inflammatory cytokines initiate different inflammatory signaling pathways via their receptors on immune and tissue cells, resulting in complicated medical symptoms including fever, capillary leak syndrome, disseminated intravascular coagulation, acute respiratory distress syndrome, and multiorgan failure, ultimately leading to death in the most severe cases. Therefore, it is clinically important to understand the initiation and signaling pathways of CS to develop more effective treatment strategies for COVID-19. Herein, we discuss the latest developments in the immunopathological characteristics of COVID-19 and focus on CS including the current research status of the different cytokines involved. We also discuss the induction, function, downstream signaling, and existing and potential interventions for targeting these cytokines or related signal pathways. We believe that a comprehensive understanding of CS in COVID-19 will help to develop better strategies to effectively control immunopathology in this disease and other infectious and inflammatory diseases.

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The signal pathways and treatment of cytokine storm in COVID-19.

Acute respiratory distress syndrome (ARDS) in COVID-19 is associated with high mortality. Mesenchymal stem cells are known to exert immunomodulatory and anti-inflammatory effects and could yield beneficial effects in COVID-19 ARDS. The objective of this study was to determine safety and explore efficacy of umbilical cord mesenchymal stem cell (UC-MSC) infusions in subjects with COVID-19 ARDS. A double-blind, phase 1/2a, randomized, controlled trial was performed. Randomization and stratification by ARDS severity was used to foster balance among groups. All subjects were analyzed under intention to treat design. Twenty-four subjects were randomized 1:1 to either UC-MSC treatment (n = 12) or the control group (n = 12). Subjects in the UC-MSC treatment group received two intravenous infusions (at day 0 and 3) of 100 ± 20 × 106 UC-MSCs; controls received two infusions of vehicle solution. Both groups received best standard of care. Primary endpoint was safety (adverse events [AEs]) within 6 hours; cardiac arrest or death within 24 hours postinfusion). Secondary endpoints included patient survival at 31 days after the first infusion and time to recovery. No difference was observed between groups in infusion-associated AEs. No serious adverse events (SAEs) were observed related to UC-MSC infusions. UC-MSC infusions in COVID-19 ARDS were found to be safe. Inflammatory cytokines were significantly decreased in UC-MSC-treated subjects at day 6. Treatment was associated with significantly improved patient survival (91% vs 42%, P = .015), SAE-free survival (P = .008), and time to recovery (P = .03). UC-MSC infusions are safe and could be beneficial in treating subjects with COVID-19 ARDS.

https://stemcellsjournals.onlinelibrary.wiley.com/doi/pdf/10.1002/sctm.20-0472

Umbilical cord mesenchymal stem cells for COVID-19 acute respiratory distress syndrome: A double-blind, phase 1/2a, randomized controlled trial.

Rationale: Coronavirus disease (COVID-19) is a global threat to health Its inflammatory characteristics are incompletely understoodObjectives: To define the cytokine profile of COVID-19 and to id

Characterization of the Inflammatory Response to Severe COVID-19 Illness.

The success of any donation process requires that potential brain-dead donors (PBDD) are detected and referred early to professionals responsible for their evaluation and conversion to actual donors. The intensivist plays a crucial role in organ donation. However, identification and referral of PBDDs may be suboptimal in the critical care environment. Factors influencing lower rates of detection and referral include the lack of specific training and the need to provide concomitant urgent care to other critically ill patients. Excellent communication between the ICU staff and the procurement organization is necessary to ensure the optimization of both the number and quality of organs transplanted. The organ donation process has been improved over the last two decades with the involvement and commitment of many healthcare professionals. Clinical protocols have been developed and implemented to better organize the multidisciplinary approach to organ donation. In this manuscript, we aim to highlight the main steps of organ donation, taking into account the following: early identification and evaluation of the PBDD with the use of checklists; donor management, including clinical maintenance of the PBDD with high-quality intensive care to prevent graft failure in recipients and strategies for optimizing donated organs by simplified care standards, clinical guidelines and alert tools; the key role of the intensivist in the donation process with the interaction between ICU professionals and transplant coordinators, nurse protocol managers, and communication skills training; and a final remark on the importance of the development of research with further insight into brain death pathophysiology and reversible organ damage.

Management of donation after brain death (DBD) in the ICU: the potential donor is identified, what's next?

Advances in transplant surgical techniques and immunosuppressive therapies have led to increasing numbers of patients with end-stage organ failure being treated with an organ transplant. There is increasing evidence that success rates of transplantation can be improved with optimal management of the potential organ donor [1]. Thus it is important, after diagnosis of brain death, that optimal physiological support is maintained to allow the option of organ donation if this was the patient’s known wish. The guidelines as outlined should be implemented only after the diagnosis of brain death in patients who are potential organ donors. Before the diagnosis of brain death, patients should be managed as appropriate for their underlying condition. After the diagnosis of brain death, should the patient have wished to become an organ donor, treatment becomes oriented toward optimising organs that may be retrieved for transplantation rather than toward neuroprotection. Appropropriate adjustments must be made for paediatric organ donors; these guidelines are written solely for adults. The guidelines are informed by critical appraisal of the relevant literature, recommendations/guidelines from jurisdictions such as Canada [2], USA [3], UK [4] and Australian & New Zealand [5], and our own experience of clinical practice in Ireland. These guidelines are primarily aimed at supporting those Intensive Care Units (ICUs) where potential organ donors are managed infrequently. Where more advanced or specialist advice is needed, we suggest early involvement of an Organ Donor Nurse Manager (ODNM) or Clinical Lead in Organ Donation (CLOD).

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Alan Gaffney

Papers

Characterization of the Inflammatory Response to Severe COVID-19 Illness.

Management of donation after brain death (DBD) in the ICU: the potential donor is identified, what's next?

Intensive Care Society of Ireland - Guidelines for management of the potential organ donor (2018-2nd edition)