Viral-associated pulmonary aspergillosis in the Intensive Care Unit
Evidence of the last decades supports the establishment of severe influenza as an important risk factor for invasive pulmonary aspergillosis (IPA) development on intensive care units (ICU). Similar to influenza, invasive mould infections were observed in COVID-19 critically ill patients, though at a lower frequency and with more debate on the clinical relevance of the diagnosis. In this thesis, we aimed to investigate IPA in ICU patients with severe viral respiratory failure, to strengthen current evidence arguing for viral-associated pulmonary aspergillosis (VAPA) inclusion in the ever-evolving list of risk factors for IPA development.
Our antifungal prophylaxis chapter prospectively validated the frequent occurrence of influenza-associated pulmonary aspergillosis in ICU-admitted influenza patients. Moreover, early diagnostic evaluations identified that IAPA occurs very soon after or upon ICU admission, thereby arguing against a universal antifungal prophylaxis approach. With our histological investigation of VAPA, we identified tissue-based proof of invasive fungal disease frequently and with similar histological pattern amongst critically ill influenza and COVID-19 cases, underscoring the invasive nature of IPA in both viral contexts. Shifting our attention to COVID-19 host responses in the final presented research data chapter, we used a multi-omics approach to investigate COVID-19 disease severity. A marked and disproportionate, myeloid-driven immunopathology was identified in ICU-admitted patients. Similar approaches towards unraveling host-pathogen interactions in the setting of CAPA (and VAPA) are now warranted.
Overall, the data presented build a strong case for diagnostic awareness of IPA in ICU-admitted influenza and COVID-19 patients, with a need to further study differentiated management approaches, including targeted or universal prophylaxis. High-resolution multi-omics studies are necessary to further unravel the pathophysiology of VAPA.
Early corticosteroid therapy may increase ventilator-associated lower respiratory tract infection in critically ill patients with COVID-19: a multicenter retrospective cohort study
Some patients with severe COVID-19 develop acute hypoxemic respiratory failure with profound hypoxia, which likely requires invasive mechanical ventilation during prolonged periods. Corticosteroids have become a cornerstone therapy for these patients, though only little data are available regarding their potential risk of ventilator-associated lower respiratory tract infection (VA-LRTI). This study compared in patients undergoing MV for severe SARS-CoV2 pneumonia the occurrence of VA-LRTI between patients who received and those who did not receive early corticosteroid therapy (<7 days since hospital admission). In our multicenter retrospective cohort of COVID-19 patients undergoing MV, early corticosteroid therapy was independently associated with VA-LRTI.
ON THE LONG-TERM FOOTPRINT OF PEDIATRIC CRITICAL ILLNESS AND HOW THIS IS AFFECTED BY ACUTE MACRONUTRIENT RESTRICTION
Critically ill children suffer from an extensive legacy in the long-term, affecting their growth and neurocognitive development. In this PhD thesis, we showed that part of this legacy, more specifically the emotional and behavioural problems observed 4 years after admission, was prevented by a macronutrient restriction in the first week in PICU, and at least partially mediated by the prevention of altered DNA methylation. We also unraveled the dynamics during the acute phase of pediatric critical illness of the thyroid- and HPA-axis, both key role players in growth and development of children. These insights are opening up new perspectives for possible treatment options to improve clinical outcome of critically ill children.
CLINICAL PREDICTION MODELS IN CRITICAL ILLNESS: FROM COMPUTER TO BEDSIDE
Detecting patients most vulnerable to specific organ deterioration is of
great interest in the intensive care unit, as patients’ clinical situation
may vary rapidly. In this PhD thesis, we approached this challenge by
applying big data analytics in different fields of intensive care.
including the development and validation of machine learning models for
prediction of acute kidney injury, the advanced statistical analysis of
times-series to identify the benefit of cerebral oxygen saturation in
children with congenital heart disease, and knowledge discovery in patients
with severe traumatic brain injury. We successfully translated two of the
developed applications to the patient bedside, which open up avenues for
prospective interventional studies to assess whether they can improve the
process of care and patient outcomes.
Autophagy, FGF21 and glucagon during critical illness: interactions and therapeutic perspectives
Multiple organ failure is a leading cause of morbidity and mortality among critically ill patients, of which the underlying mechanisms are incompletely understood. In this project, we investigated the underlying metabolic mechanisms of critical illness induced organ failure. We identified a crucial role of autophagy in the pathogenesis of organ failure and discovered Fibroblast Growth Factor 21 as new adaptive cellular stress-induced hormone, which opens new therapeutic perspectives for the treatment of multiple organ failure. Finally, we showed that glucagon is a key mediator of the deranged amino acid metabolism during critical illness by promoting hepatic amino acid catabolism, without affecting muscle wasting.
Energy expenditure and nutritional therapy in critically ill patients
In critically ill patients, a multitude of factors are responsible for the metabolic state and energy expenditure (EE). In daily clinical practice, patients are frequently left without adequate prescription of calories and proteins. This clinical research enlarged the knowledge in this field. Physicians in charge of nutritional therapy use total energy expenditure to guide their nutritional prescription. Indirect calorimetry (IC) is increasingly advocated to determine basal metabolic rate. We evaluated the indications, feasibility and the use of IC. We assessed whether measurements obtained by IC reached agreement with the results of mathematical equations used to calculate EE. We developed the technical possibility and a theoretical model to perform IC in an ECMO-setting. After evaluation of available research data, we suggest recommendations for nutritional therapy in patients undergoing continuous renal replacement therapy.
Brain and sepsis: from macro to microcirculation
Brain dysfunction is a frequent complication of sepsis and is usually defined as "sepsis-associated encephalopathy" (SAE). Its pathophysiology is complex and related to a number of processes and pathways, while the exact mechanisms producing neurological impairment in septic patients have not been completely elucidated. Alterations in cerebral blood flow (CBF) have been suggested as a key component for the development of SAE. More importantly, the natural mechanisms that protect the brain from reduced/inadequate CBF can be impaired in septic patients, especially in those with shock, and this further contributes to cerebral ischemia if blood pressure drops below a critical threshold. Hypercapnia is associated with a narrower autoregulatory plateau, which may potentially results in large CBF variations when mean arterial pressure (MAP) varies within usual targets. Finally, as SAE occurs also in patients without hemodynamic instability, alterations in brain tissue perfusion could occur independently from hypotension; thus, alterations in cerebral microcirculation, which largely regulates regional flow and blood-cellular nutrients exchanges, could contribute to SAE.
Pathophysiology of cholestatic liver dysfunction during critical illness
ICU patients commonly develop cholestatic liver dysfunction, which has been associated with adverse outcome. Cholestasis or decreased bile flow can lead to an accumulation of bilirubin/bile acids and is presumed to induce cell damage. This research focused on unravelling the hepatobiliary changes at biochemical/molecular level during critical illness and the possibility that mild hyperbilirubinemia may be adaptive and beneficial.
Metabolic stress, mitochondria and organ failure during critical illness: Underlying mechanisms revealing therapeutic potential”
In this project, we studied mechanisms how prevention of hyperglycemia and relative starvation may protect against critical illness-induced multiple organ failure. A crucial role for mitochondrial damage was found. Moreover, activation of autophagy - an essential cellular repair process that is potently suppressed by nutrients and by anabolic hormones - was identified as potential therapeutic strategy for this condition.
Nutrients, insulin and muscle wasting during critical illness
We gained more insight in the impact of the combination of intravenous nutrition with the infusion of insulin to maintain normoglycemia, on severe muscle wasting during prolonged critical illness. We concluded that parenteral feeding during critical illness may reduce muscle catabolism at the expense of a threat to vital organs by impairing autophagy, the physiological systems to clear cellular damage.
Computerized data management in the Intensive Care Unit : Predictive modeling, time series analysis and opportunities for support of care
The amount of patient related data generated in the ICU exceeds human cognitive capacity by far. Computerized data analysis, using automatically learning methods, allows to develop applications such as clinical decision support tools and predictive models, adapted to a specific clinical context. This doctoral project is a first step in this exciting and novel research domain.
Peripheral and Respiratory Muscle Weakness in ICU : Causes and Consequences
We showed that normalising glycaemia reduced the incidence of CIP/CIM and the need for prolonged mechanical ventilation in a medical ICU. This benefit was confirmed in a meta-analysis and in daily care. Diaphragmatic force measured with bilateral anterior magnetic phrenic nerve stimulation showed a logarhitmtic decline with increasing duration of mechanical ventilation, fitting the concept of ventilator induced diaphragmatic function.