Covid-19: a complex multisystem clinical syndrome 

Mike Roberts and colleagues summarise key aspects of this complex multi-system clinical syndrome

A covid-19 infection starts as a local upper respiratory tract infection, but can spread to affect multiple organ systems with consequences that are only now being understood. When it does spread in this way, the result is multi-system critical illness associated with a high risk of death.

The multi-system manifestation of a covid-19 infection is caused by a combination of specific host defence responses with associated inflammatory activity and (micro) vascular involvement with distinct coagulopathy and a strong propensity to develop thromboembolic complications. The hyper-inflammatory tissue response, going hand in hand with a compromised circulatory system, leads to fulminant multiple organ dysfunction affecting lungs, heart, kidneys, nerves, muscles, gastrointestinal tract and brain. In the patients most severely affected, a cytokine “storm” occurs, characterized by very high levels of pro-inflammatory cytokines and Tumour Necrosis Factor (TNF)-α, interleukins, granulocyte-colony stimulating factor, and several chemokines. These patients are those at highest risk of multi-system failure and significant mortality. Males and those with pre-existing hypertension or coronary disease are at higher risk of severe disease, consistent with known correlates of ACE2 expression; the ACE2 gene is located on the X chromosome.

The widespread nature of these effects reflects in large part the ability of the SARS-CoV-2 virus to infect endothelial cells via the ACE2 receptors, with likely release of cytokines that make them more adhesive and increased coagulation; patients with covid-19 can manifest hypercoagulability, with high levels of D-dimer, fibrinogen, and factor VIII, leading to venous thromboembolism and a mixture of large proximal pulmonary artery thrombi and fibrin micro-thrombi in the presence of vascular inflammation. Thus, in the lungs, post-mortem samples from critically ill patients reveal local haemorrhage.

Starting with the cardiovascular system, cardiac enzyme release can be observed even in the early stages, suggesting myocardial inflammation and damage. Cardiologists have reported patients presenting with chest pain as the primary symptoms in the absence of pyrexia and other disease manifestations. 

Renal failure is a common complication of severe covid-19. Proximal renal tubular cells express ACE-2 and direct infection by SARS-CoV-2 may cause the renal insult, but indirect injury may occur through endothelial inflammation or as a consequence of medical management. Reduced fluid administration to minimise pulmonary vascular congestion, aggravated by elevated positive end-expiratory pressure as a ventilatory strategy with ARDS, may increase pressure in the renal vein, impairing renal blood flow. 

Gut and liver dysfunction, manifest by deranged tests of liver function and slow tolerance of enteral feeding, are well recognised and occur more frequently in severe illness. 

Neurologic abnormalities are documented in up to 50% of the most severely ill patients, including impaired consciousness, acute cerebrovascular events, and muscle disease. SARS-CoV-2, may directly invade the central nervous system and neuromuscular tissue both via a vascular route and by retrograde neuronal transmission. 

It is in the ICU setting where organ failure in covid-19 is most studied. The April ICNARC data reports 93% patients requiring basic and 25% advanced cardiac support, 20% renal, 5% neurological and 0.4% hepatic support. Covid-19 is clearly a complex clinical syndrome and not a straightforward viral pneumonia. Moreover, it is one where there is an ever present risk of iatrogenic damage, given the known hazards of prolonged ventilation and the need to keep pace with the rapidly increasing understanding of the pathological processes involved and the opportunities to intervene. 

Clinicians managing covid-19 should have an awareness of this multi-system impact and actively seek evidence of organ involvement outside of the respiratory tract. Early involvement of the myocardium may be an important prognostic factor, with increasing trajectory of troponin associated with a fivefold risk in the need for ventilation and in mortality suggesting early monitoring would be helpful. Early proactive management to support renal function could improve later survival in ICU and aggressive thrombo-prophylaxis may reduce pulmonary emboli, while understanding the extent of organ involvement will guide escalation management decision making. These clinically driven interventions in medical care require urgent, real time evaluation of effectiveness.

It is too early to know what the long-term consequences of covid-19 will be. They are likely to include the effects of post intensive care syndrome. More than a quarter of patients suffer cognitive impairment with variable duration, psychological distress and physical detriment. There will in addition be sequelae of covid-19 infection itself as yet undefined. The experience of survivors of Severe Acute Respiratory Syndrome (SARS) points to a risk of sustained reductions in lung and exercise capacity and high levels of psychological distress. We must now urgently report studies of the follow up of discharged survivors of this multi-system disease to inform the provision of rehabilitation services and to better equip our primary care and community teams to manage the challenge of  patients with multi-system impairment discharged to home.

C Michael Roberts, Integrated Care Respiratory Physician, Professor of Medical Education and Managing Director, UCLPartners Academic Health Science System. 

Marcel LeviChief Executive and Professor of Medicine, Consultant in Acute Medicine and Haematology, University College London Hospitals NHS Foundation Trust. 

Richard SchillingProfessor of Cardiology, Nightingale Hospital, London.

Wei Shen LimConsultant Respiratory Physician, Honorary Professor of Respiratory Medicine, Nottingham University Hospitals NHS Trust.

Michael PW GrocottProfessor of Anaesthesia and Critical Care Medicine, University Hospital Southampton Foundation Trust.

Martin McKeeProfessor of European Public Health, London School of Hygiene and Tropical Medicine.

Acknowledgment: Thomas Vaudin: Cometh the Storm.

Competing interests: CMR: Expenses for delivering educational non promotional workshops to primary care teams from Pfizer Astra Zeneca. UCLPartners is an academic alliance between 9 HEIs and 23 NHS Trusts. MPWG: Travel expenses and payment for preparation and delivery of a presentation from Astra Zeneca.