Purpose:

The primary purpose of this research is to identify an early warning for
hyperinflammation in COVID19 so that interventional trials of anti-inflammatory agents
can target this sub-group.

Background Mortality from SARS-CoV-2 infection causing COVID-19 is estimated to be 3.7%
globally. The principal cause of death due to COVID-19 is respiratory failure due to
acute respiratory distress syndrome. Early reports have suggested that a subgroup of
individuals suffer a hyperinflammatory state with a high mortality which is associated
with high levels of IL-6 and CRP. Recent randomised controlled trial data has shown that
the anti-inflammatory agent dexamethasone can reduce mortality in severe COVID-19 in an
unselected COVID-19 cohort. Whilst impressive, these results suggest that if the
anti-inflammatory interventions could be targeted early to individuals with
hyperinflammation, even greater benefit in mortality may be seen, and this approach may
additionally reduce the morbidity of COVID-19 by preventing escalation to high dependency
and intensive care. The purpose of our study is to identify hyperinflammation early
because there are specific therapies which are in clinical use which treat
hyperinflammation.

Hyperinflammation has been previously described secondary to acute infection and termed
cytokine release syndrome / cytokine storm (CRS / CS), macrophage activation syndrome
(MAS), macrophage-cytokine self-amplifying loop (MCSAL) and secondary haemophagocytic
lymphohistiocytosis (sHLH). Viral infections are the commonest cause of sHLH, and
symptoms of hyperinflammation resemble those of general sepsis, therefore
hyperinflammation has generally been under-recognised at an early stage leading to a high
mortality. Blockade of the key pathways in hyperinflammation such as IL-1 have been shown
to be effective in sepsis triggered cases without increased adverse events . Early data
in a single arm open label study of 21 severely ill COVID-19 patients with increased IL-6
expression, showed that inhibition of IL-6 signaling with tocilizumab caused rapid
clinical improvement in 75% of cases, with some improvement in all cases .

During COVID19 infection, the initial viral invasion of epithelial tissues causes direct
cytotoxic damage but subsequently progresses to an inflammatory response at 7-10 days.
While an inflammatory response is likely to be needed to eliminate virus, there is a risk
of ongoing activation with inflammatory mediators causing end organ damage. Therefore, it
seems that targeting hyperinflammation (e.g. IL-6) during acute SARS-CoV-2 infection
requires the timing of blockade to be finely balanced to avoid early on impairment of
host antiviral responses. Similarly, intervening too late is likely to show minimal
benefit. Due to the urgency, despite this uncertainty, clinical trials to address the
effectiveness of anti-IL-6 are already underway with Tocilizumab (ClinicalTrials.gov
Identifier: NCT04317092, REMAP-CAP, RECOVERY) and Sarilumab (ClinicalTrials.gov
Identifier: NCT04315298). The entry criteria for the UK trials of such interventions have
largely been unselected, ie not specifically targeting individuals who have
hyperinflammation.

However, it is not yet clear how to identify those COVID-19 cases in whom
anti-hyperinflammation strategies are required. Retrospective examination of IL-6
expression in 150 cases of COVID-19, estimated that in survivors median IL-6 level was
approximately 6.9ng/ml (5-8.8 ng/ml), whereas in those who died was 11.25 ng/ml
(7.75-16.25) (p<0.001) . Overall, 46 cases with IL-6 >7.75 ng/ml 63% died whereas 47
cases IL-6 <7.75ng/ml showed only 23% mortality. Similar data were identified in a second
study to examine IL-6 levels, but only showed these to be elevated in 6 out of 48 cases
(mortality 50% in IL-6 high) . This suggests that IL-6 expression levels may provide a
useful biomarker of outcome, but IL-6 measurement alone is not sufficient and
additionally this is not widely available. Although dexamethasone has been reported to
reduce mortality in unselected cases with severe COVID-19, dexamethasone has a well-known
side effect profile and risk of complications. Indeed, it is not surprising that for
those patients with less severe COVID the non-significant trend was that dexamethasone
caused harm (death compared to controls, OR 1.22, [0.86 to 1.75]). Therefore, it is
likely that strategies to identify hyperinflammation and targeted intervention will offer
the most effective approach to management of COVID-HI. Indeed, as well as anti-IL-6 other
cytokines released in hyperinflammation for which existing biologic therapies are
available are also potential targets for intervention including TNF-α (Infliximab), IL-1
(Anakinra), and JAK-inhibitors (e.g. Ruxolitinib). In addition, secondary events may
prove potential check-points in hyperinflammation for blockade and IL-6 is also known to
regulate Th17 differentiation and induction of CD8 cytotoxic T cells which are important
in anti-viral responses.

To facilitate diagnosis of hyperinflammation, the 'HScore' which is a validated score and
was developed in the context of secondary sHLH because of evidence that early recognition
and intervention is beneficial. Some authors have recommended using the HScore in
COVID-19 to identify hyperinflammation. However, very few COVID patients fulfil the
current HScore criteria. So, it is unclear whether COVID hyperinflammation (COVID-HI) is
an attenuated form of sHLH but with a similar mechanism or whether it is a distinct
entity. Indeed, there are unique aspects to SARS-CoV-2 infection such as the unusual
coagulopathy that arises in up to 67% of cases which suggests that perhaps COVID-HI is a
unique entity.

This proposal aims to examine the HScore parameters in NHS clinical and laboratory
records of patients admitted to Southampton with confirmed SARS-CoV-2 infection, with an
aim to determine the relevance to COVID19, and will explore whether other routine NHS
parameters could be incorporated to enhance the sensitivity of hyperinflammation
diagnosis. To facilitate a validation of this scoring approach, the study will confirm
how such a scoring system differentiates between the COVID-19 cohort and control cohort
of hospitalised patients stratified for key parameters. This analysis primary objective
is to develop a clear algorithm (COVID-HI score) for identification of the COVID19 subset
with COVID-HI, and expect these results will inform the next phase of COVID19
interventional clinical trial design in anti-hyperinflammation therapy, such as the
ACCORD study (CI, Prof T Wilkinson, Southampton) . To identify hyperinflammation, the
investigators will specifically examine the data for trajectory changes in individual
patients that reflect a hyperinflammatory response.

Hypothesis Our primary hypothesis is that it is possible to develop a scoring system from
existing NHS clinical and laboratory parameters to facilitate early identification of
COVID-HI. Our secondary hypothesis, for examination in a subsequent study, is that this
score will offer an important pre-screening tool for COVID19 cases for entry to clinical
trials of anti-hyperinflammation therapies.

To address the primary hypothesis, the aims are:

1. Correlate the existing HScore with outcomes in our dataset.

2. Examine in granular detail those cases who meet or partially meet the HScore
threshold for hyperinflammation.

3. Utilise non-hypothesis driven approaches to determine other clinical or laboratory
data which would improve the sensitivity of the identification of hyperinflammation
in COVID19 to identify a Soton HI score.