Gupta, Ayushman
(2024)
Dynamic assessment of multi-organ level dysfunction in patients recovering from COVID-19.
PhD thesis, University of Nottingham.
Abstract
Since its emergence, the impact of acute coronavirus disease (COVID-19) on mortality has
been profound. However, in June 2020 there was an emerging picture of prolonged recovery
of people who had survived the acute infection. A huge proportion of individuals experienced
persisting and debilitating symptoms, such as fatigue, after resolution of the acute infection,
with many affected previously devoid of pre-existing medical conditions and disability. This
has resulted in increased time off from or return to work. In an era where the initial project
for this PhD was put on hold due to recruitment of patients that were vulnerable to severe
infection (assessment of cerebrovascular and cardiovascular haemodynamic response to
exercise in patients with COPD), the focus turned to addressing the long term impacts of
COVID-19. Whilst 3 years on there is now an abundant literature on symptoms, the
mechanisms remain poorly understood. In this thesis, a detailed physiological and metabolic
phenotyping was conducted of patients who survived severe acute respiratory syndrome
coronavirus 2 (SARS-CoV-2) related hospitalisation and healthy control volunteers, focussing
on muscle, metabolic, cardiovascular and cerebrovascular properties to elicit mechanisms
that drive symptoms +/- organ impairment.
Patients (n=21) recovering from severe hospitalisation of SARS-CoV-2 infection and without
previous diabetes, cardiovascular or cerebrovascular disease, were recruited 5-7 months after
discharge along with controls (n=10), with similar age, and sex. Validated state-of-the-art
magnetic resonance imaging (MRI) and spectroscopy (MRS) protocols during resting and
supine exercise were used to stress the body and best elucidate cardiovascular and
cerebrovascular pathophysiology as well quantifying skeletal muscle mitochondrial oxidative
capacity. These in-bore exercise procedures were previously optimised and their feasibility
addressed within healthy and different disease populations including volunteers with chronic
obstructive pulmonary disease (COPD). An oral glucose tolerance test (OGTT) in conjunction
with fuel oxidation enabled dynamic assessment of whole body insulin sensitivity, glucose
disposal and fuel utilisation. Resting MRI of the brain, heart and muscle assessed any organ
injury or dysfunction. Additional measures included: venous blood sampling for biomarkers
of muscle, cardiac, liver, metabolic dysfunction and inflammatory markers, dual energy X-ray
absorptiometry, short physical performance battery (SPPB), hand grip strength, intramuscular
electromyography, quadriceps strength and fatigability, step count and participant reported
outcome measures (PROMs). In particular, fatigue severity scale (FSS) was used to quantify
perception of fatigue. To further examine mechanisms contributing to fatigue, a sub-group
analysis between patients with (FSS >36) and without (FSS<36) perception of fatigue was
conducted.
In summary, there was a larger insulin response during the OGTT in patients vs controls
suggestive of a greater degree of insulin resistance. Blood glucose response and carbohydrate
oxidation rate were not different. The insulin resistance was not explained by systemic
inflammatory mediators or whole-body/leg muscle adiposity but reduced step count and
presence of fatty liver were independent factors associated with reduced whole body insulin
sensitivity in patients, possible drivers for peripheral and hepatic insulin resistance. Patients
displayed worse FSS and SPPB scores. Leg muscle volume, strength, force-loss, motor unit
properties and mitochondrial function were comparable. Further, cardiac and cerebral
architecture and function (rest and exercise-based) were not different. In the sub-group
analysis patients with a perceived fatigue exhibited worse SPPB scores, reduced step count
and blunted cerebral blood flow response to supine exercise compared to non-fatigued
patients.
Taken collectively, the multifaceted approach to characterising the long term effects of COVID-19 revealed that individuals without previous morbidity who survived severe COVID 19 were limited in habitual function and exhibited insulin resistance, providing essential information for rehabilitation strategies.
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