Emergency PWAS in Respiratory Infectious Disease

Introduction

Pandemic Preparedness

The COVID-19 pandemic has affected over 220 million people, claimed over 450 000 lives and invoked variable responses across the world. Delays in acquiring quality clinical and scientific material on the transmissibility, clinical nature, outcomes and lethality of novel and known infectious diseases (ID) translate into healthcare inefficiencies, societal and economic stress, and increased morbidity and mortality. Regions with greater success in the fight against COVID-19 were well prepared before the pandemic.

Pathogens

The pathogens most likely to cause annual epidemics and pandemics are respiratory viruses. In Asia, viral infections account for 30-40% of sepsis cases. Each year there are 100 million cases of viral community-acquired pneumonia (CAP) of which 60% progress to sepsis. These viruses cause host-mediated, inflammatory, immune responses which progresses through three phases: preliminary regulated inflammation; intermediate dysregulated proinflammation; and late dysregulated hypoinflammation.

Clinical Spectrum

RID is a heterogeneous population of patients. This complex spectrum of heterogeneity extends throughout the underlying molecular biology and pathophysiology from genome to phenome. It includes significant individual variation in regulated and dysregulated systemic inflammatory host responses to infection in the presence and absence of organ dysfunction. Critical illness from any ID involves both host susceptibility to the pathogen and host propensity to develop dysregulated inflammation and organ failure (e.g. pulmonary inflammation and/or acute kidney injury).

PanorOmics-Wide Association Studies

In the five years prior to the COVID-19 pandemic, the United Kingdom's Genetics Of Mortality In Critical Care (GenOMICC) study recruited patients with a spectrum of critical illness syndromes (e.g. influenza, sepsis, and emerging infections) to better understand host mechanisms that lead to life-threatening outcomes. As a result, the GenOMICC investigators, along with collaborators from Spain and Italy, were well placed to perform genomic-association studies on critically ill COVID-19 patients and to make recommendations for future studies.

An integrated panorOmics approach has the potential to uncover causal associations and linkages across the entire spectrum of host biology including genomics, epigenomics, transcriptomics, proteomics, metabolomics and lipidomics, through to clinical phenotype. However, panorOmics as a discipline faces the same challenges as Genome-wide association studies (GWAS), only more so. Although GWAS correlate genomic loci with complex signatures and traits, efficient detection is hindered by false positives, linkage disequilibrium, and high expense. True causal variations and real underlying associations require multiple filters if they are to be detected.

The investigators propose to develop an ED-based system of dynamic studies on blood and saliva samples taken from patients at an early stage of ID. Early stage refers to a process in the patient pathway that precedes most patient recruitment in other studies i.e. on wards or ICU. The two primary objectives are a) to develop an ED-ID biobank; and b) to undertake preliminary discovery and targeted research for the discovery of novel diagnostics, prognostics and therapeutics.

The investigators will define early multiOmics signatures of RID and identify relationships to known and novel ID. Few studies have been published on the integrated panorOmics of COVID-19, and few if any address the early phases of illness or differentiating features in comparison to other respiratory illnesses.

In disease stratified, case-control matched comparisons of adult patients with scaRID attending EDs, what panorOmic signatures differentiate low risk from high risk across a 30-day WHO-Clinical Progression Scale (WHO-CPS)?

For the purpose of this study, scaRID is defined as:

• A fever or a temperature >37.5°C; AND
• One or more relevant symptoms:

• respiratory symptoms (e.g. cough, shortness of breath), OR
• systemic symptoms (e.g. chills, rigors, myalgia), OR
• gastrointestinal symptoms (e.g. nausea, vomiting, diarrhoea); AND
• No obvious alternative cause (see exclusion criteria).

PanorOmic associations will be derived from liquid biopsy samples, including whole blood, plasma, serum, white cell pellet, red cell effluent, salivary supernatant, and salivary cells. Liquid biopsy biomarkers include genomic, transcriptomic, proteomic, metabolomic, lipidomic and haematological contents.

Hypothesis The investigators hypothesise that in propensity-matched, adult patients with pathogen-specific and disease specific RID (e.g. SARS-CoV-2, Influenza A) there are significant differences in panorOmic signatures that delineate host susceptibility and host response for mild to severe disease.

Objectives

The purpose of this proposal is to develop an emergency PanorOmics Wide Association Study (ePWAS) biobank for the early, rapid biological and pathophysiological characterisation of scaRID. More specifically, in adult patients presenting to EDs with scaRID and within 10 days of symptom onset, we aim:

• To develop an ED-ePWAS-RID biobank of blood and saliva samples
• To use this databank for exploratory and targeted research in the search for diagnostic and prognostic markers and to understand underlying mechanisms of disease

The goals of the biobank and the ePWAS-RID repository are:

• to develop the infrastructure for a sustainable ED-based biobank of blood and saliva samples matched to clinical phenotypes and critical outcomes.
• to develop the repository according to international standards thereby minimising heterogeneity and rendering the material suitable for international research frameworks that aims to facilitate access to human biological materials.
• to prepare a repository for preliminary discovery of novel diagnostic, prognostic, and therapeutic markers.
• to facilitate targeted research on the pathogenesis of respiratory infections, host susceptibility, and host response.
• to derive biomarker platforms of training set models for early RID detection, pathogen differentiation, monitoring, risk stratification and prognosis; and to validate those models using independent and external datasets.

Inclusion criteria

Patients eligible for enrolment include:

With reference to previous inclusion criteria are:

• Adults ≥18 years of age; AND
• Suspected, acute, community-acquired, respiratory, infectious disease (scaRID)*; AND
• Informed consent.

Note: scaRID is defined according to ALL three criteria:

• Community acquired (not hospitalised for <28 days); AND
• Acute infection (defined as symptom onset <8 days and any ONE of reported fever or chills or aural temperature >37.5°C or hypothermia or leucocytosis or leucopaenia or new altered mental status); AND
• Probable respiratory infection - According to any ONE of:

• new cough or new sputum production or
• chest pain or
• dyspnoea or
• tachypnoea or
• abnormal lung examination or
• respiratory failure; or
• physician's judgment (presenting with systemic or gastrointestinal symptoms).

Control subjects will be drawn from two groups:

• The worried well - adult patients with a National Early Warning Score (NEWS) <3 and a temperature <37.5°C.
• Relatives or accompanying friends with no acute illness.

Exclusion criteria

• Refusal of consent;
• Recent hospitalisation (<28 days);
• Enrolled in another clinical trial
• Cellulitis;
• Skin or orthopaedic infections;
• Urinary tract infection;
• Acute abdominal sepsis;
• Sexual transmitted disease;
• Human immunodeficiency virus (HIV) infection;
• Immunocompromised/potential neutropenic fever;
• Solid organ or haematopoietic stem-cell transplant within the previous 90 days;
• Active graft-versus-host disease or bronchiolitis obliterans;
• Severe traveller's disease requiring urgent hospitalisation and management including malaria, dengue, typhoid and other rickettsial diseases;
• Stroke;
• Toxidrome;
• Non-organic acute psychosis.