What is the clinical course of patients hospitalised for COVID-19 treatment Ireland: a retrospective cohort study in Dublin’s North Inner City (the ‘Mater 100’)

Background: Since March 2020, Ireland has experienced an outbreak of coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). To date, while several cohorts from China have been described, our understanding is limited, with no data describing the epidemiological and clinical characteristics of patients with COVID-19 in Ireland. To improve our understanding of the clinical characteristics of this emerging infection we carried out a retrospective review of patient data to examine the clinical characteristics of patients admitted for COVID-19 hospital treatment. Methods: Demographic, clinical and laboratory data on the rst 100 adult patients admitted to Mater Misericordiae University Hospital (MMUH) for in-patient COVID-19 treatment after onset of the outbreak in March 2020 was extracted from clinical and administrative records. Missing data were excluded from the analysis. Results: Fifty-eight per cent were male, 63% were Irish nationals, 29% were GMS eligible, and median age was 45 years (interquartile range [IQR] =34-64 years). Patients had symptoms for a median of ve days before diagnosis (IQR=2.5-7 days), most commonly cough (72%), fever (65%), dyspnoea (37%), fatigue (28%), myalgia (27%) and headache (24%). Of all cases, 54 had at least one pre-existing chronic illness (most commonly hypertension, diabetes mellitus or asthma). At initial assessment, the most common abnormal ndings were: C-reactive protein >7.0mg/L (74%), ferritin >247μg/L (women) or >275μg/L (men) (62%), D-dimer >0.5μg/dL (62%), chest imaging (59%), NEWS Score (modied) of ≥ 3 (55%) and heart rate >90/min (51%). Twenty-seven required supplemental oxygen, of which 17 were admitted to the intensive care unit - 14 requiring ventilation. Forty received antiviral treatment (most commonly hydroxychloroquine or lopinavir/ritonavir). Four died, 17 were admitted to infection 4 5 . Patients present with fever, cough, dyspnoea and fatigue, with some developing acute respiratory distress syndrome (ARDS), multi-organ damage and secondary bacterial infections 6 7 . Manifestations of COVID-19 infection vary according to disease severity and a person’s characteristics 4 5 8 . Many are asymptomatic 9 , some show mild to moderate symptoms 4 5 , and some develop a severe, potentially life threatening illness involving ARDS, myocardial injury, and / or secondary bacterial infection 4 8 . COVID-19 infection is linked to a range of blood, cellular, and genetic abnormalities 4 5 . Those most at risk of severe illness as a result of infection include elderly males and/or people with underlying health conditions (e.g. hypertension, chronic heart disease, chronic lung disease and diabetes mellitus) 4 8 9 . Older age, elevated lactate dehydrogenase (LDH) and elevated D-dimer levels are also associated with adverse outcomes 10 . Results of clinical trials will inform best treatment approaches but results of these are pending 4 . IVIG – intravenous immunoglobulin, HFNC - high flow nasal canulae, NIV- non-invasive ventilation, IMV – invasive mechanical ventilation, ECMO – extra corporeal membrane oxygenation, OT – oxygen therapy, ARDS – acute respiratory distress syndrome, ICU – intensive care unit, CT computer tomography, PT – prothrombin time, CRP – C-reactive protein, LDH – lactate dehydrogenase, LBT- liver blood tests.


Background
Since March 2020, Ireland has experienced an outbreak of coronavirus disease 2019 , caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). To date, while several cohorts from China have been described, our understanding is limited, with no data describing the epidemiological and clinical characteristics of patients with COVID-19 in Ireland. COVID-19 was declared a global pandemic on 11/3/2020 1 . As of 18 April 2020, 2,197,593 cases of COVID-19 (in accordance with the applied case de nitions and testing strategies in the affected countries) have been reported and 153,090 deaths worldwide 2 . As of the same date, in Ireland, 14,758 con rmed cases and 571 deaths, have been reported Page 4/23 3 . In Ireland, the median age of people infected with COVID-19 is 48 years, 44% of those infected are male, and 2168 (16% of case) have been hospitalised, of whom 296 have been treated in Intensive Care Unit 3 .
Most people are susceptible to COVID-19 infection 4 5 . Patients present with fever, cough, dyspnoea and fatigue, with some developing acute respiratory distress syndrome (ARDS), multi-organ damage and secondary bacterial infections 6 7 . Manifestations of COVID-19 infection vary according to disease severity and a person's characteristics 4 5 8 . Many are asymptomatic 9 , some show mild to moderate symptoms 4 5 , and some develop a severe, potentially life threatening illness involving ARDS, myocardial injury, and / or secondary bacterial infection 4 8 . COVID-19 infection is linked to a range of blood, cellular, and genetic abnormalities 4 5 . Those most at risk of severe illness as a result of infection include elderly males and/or people with underlying health conditions (e.g. hypertension, chronic heart disease, chronic lung disease and diabetes mellitus) 4 8 9 . Older age, elevated lactate dehydrogenase (LDH) and elevated D-dimer levels are also associated with adverse outcomes 10 . Results of clinical trials will inform best treatment approaches but results of these are pending 4 .
A lot is known about the epidemiology of COVID-19 at a whole-population level in Ireland, as from mid-March 2020 Ireland's Government has reported on deaths, numbers hospitalised and number infected on a daily basis 11 .
However, little is known about those who are hospitalised and clinical outcomes. To address this knowledge gap, we examined the baseline clinical characteristics, treatments and clinical outcomes among patients with COVID-19 receiving in-patient hospital treatment under the care of the Infectious Diseases department at our institution.

Setting
The study was conducted at the Mater Misericordiae University Hospital (MMUH). In addition to the local services for the catchment area, the hospital provides a range of frontline and specialist services on a regional and national level, treating 24,750 inpatients, 221,956 outpatients and 82,307 emergency department visits last year. The hospital is located in Dublin's north inner city with many of Ireland's most deprived neighbourhoods are situated in the hospital's catchment area. Re ecting this demographic, infectious diseases care locally has involved addressing communicable diseases such as HIV and hepatitis C in partnership with local communities. Most recently this has involved initiatives involving prisoners 12 , homeless populations 13 and patients attending General Practice 14 .
The MMUH Infectious Diseases Department contains the National Isolation Unit (NIU), a six-bed unit with isolation rooms under negative-pressure ventilation, donning and do ng areas of a high speci cation. During the 'Containment Phase' (January to March 2020), our strategy was to contain suspected/con rmed cases of COVID-19 in the NIU. During the 'Delay Phase', with rising numbers of cases, the hospital established a 'COVID pathway', whereby unscheduled admissions with possible COVID infection were streamed in a parallel system with patients managed on dedicated wards by the team. Once patients were t for discharge and had appropriate accommodation to self-isolate, they were discharged utilising a mobile health platform (Patient-M-Power®) to monitor their progress.
As in most hospitals in Ireland, from late March, patients were admitted under the care of a 'COVID Team', whereby one or all of Infectious Diseases, Respiratory Medicine, Acute Medicine, and Intensive Care specialties, among others, would input to patient care based on the predominant issue requiring clinical intervention.

Subjects
Patients admitted to the COVID pathway with SARS-CoV-2 detected by PCR were included.

Data collection and study instrument
Anonymised data was collected on baseline demographics, clinical parameters and health outcome measures from clinical records, including: age; gender; type of health insurance; dates of presentation, admission and discharge; presence of pre-existing morbidity or other illnesses at admission; subsequent clinical care; and treatment outcomes. This data was collected by a member of the clinical team (CC, BOK, SC, EOC, and JL) and anonymised to allow data analysis by the research team (SC, TMH, GA, and WC).

Data analysis
Frequency counts were presented in respect of categorical and ordinal data, and median / interquartile range (IQR) in respect of numerical data where such data was not normally distributed. We examined patient characteristics (e.g. age, gender, pre-existing morbidity [any], pre-existing cardiorespiratory morbidity 15 , GMS status), ndings on clinical assessment [e.g. National Early Warning Score (NEWS) 16 / NEWS2 Score 17 ]) and laboratory parameters (e.g. lymphopaenia 18 , D-dimer, CRP, ferritin, abnormal chest imaging). For laboratory results, we also assessed whether the measurements were outside the normal range. We used SPSS (version 26.0) for all analyses. If it was not possible to nd data on clinical parameters this 'missing data' was treated in accordance with 'STROBE Guidance' 19 . As such, when reporting proportions for speci c variables, the observed nding is presented as a percent of the total number of cases on whom data was available.

Ethical issues
In designing this study we have taken cognisance of best practice in conducting health research during times of major disasters 20 . Data was collected from clinical and administrative records by a member of the clinical team. All data was anonymised at the time of data collection. All anonymised data was stored as password protected les on a secure server at the University College Dublin Catherine McAuley Research Centre, where it was analysed by the research team. The study was approved by the MMUH Research Ethics Committee (8 th April 2020; reference 1/3782141).

Patient and public involvement
Due to the pandemic nature of Covid-19 it was not feasible to include patient and public involvement. Patients were not invited to comment on any aspect of the study design nor were they invited to contribute to the drafting or editing of this manuscript.

Discussion
Key results Our ndings reinforce the consensus that COVID-19 is an acute, life threatening disease that is associated with considerable mortality. The study highlights the importance of clinical, laboratory and radiological parameters in assessing disease severity. At admission, the most common abnormalities identi ed among our cohort were elevated levels of C-reactive protein, ferritin, D-dimer, abnormal chest imaging, a NEWS Score (Modi ed) of ≥3 and tachycardia.

Correlation with other centres' experiences
To date, most data on COVID-19 disease has been reported from China although in recent weeks literature has started to emerge from Europe and the United States (Table 4). The baseline clinical characteristics of our population show striking similarities to those reported in studies from China, with regards in particular to male predominance, high prevalence of cough and fever, blood test abnormalities (including lymphopenia and elevated CRP, ferritin and D-dimer levels) and high frequency of abnormalities on chest imaging 10 22-25 . Cohorts reported from outside of China (e.g. Korea, Europe and United States) also identi ed these ndings [26][27][28][29][30] . HTN -hypertension, DM -diabetes mellitus, CAD -coronary artery disease, COPD -chronic obstructive pulmonary disease, CKD -chronic kidney disease, CLD -chronic liver disease, CCF -congestive cardiac failure, OSA -obstructive sleep apnoea, HepB -hepatitis B, SOB-shortness of breath, ALT -alanine aminotransferase. IVIG -intravenous immunoglobulin, HFNC -high flow nasal canulae, NIV-non-invasive ventilation, IMV -invasive mechanical ventilation, ECMO -extra corporeal membrane oxygenation, OT -oxygen therapy, ARDS -acute respiratory distress syndrome, ICU -intensive care unit, CT computer tomography, PT -prothrombin time, CRP -C-reactive protein, LDH -lactate dehydrogenase, LBT-liver blood tests.
There is little consensus in the published literature to date regarding optimum therapeutic strategies. For example, the use of antibiotics has ranged from 23-95% 10 22-24 . Antiviral choice and use is also variable, with one study reporting use of lopinavir/ritonavir (LPV/r) in 21% 10 , two studies describing oseltamivir in 90% and 35% of patients, respectively 22 23 , and one study reporting 'antiviral' administration in 94% without specifying which drugs were used 24 . The reported rates of systemic corticosteroids has ranged from 3% 24 to 45% 22 and the reported rates of use of intravenous immunoglobulin (IVIG) has ranged from 13 24 -24% 10 . The reported rates requiring supplemental oxygenation for COVID-19 infection has ranged from 21% 10 to 90% 24 with reported rates of ventilation ranging from 0% 24 to 17% 10 .
Spiteri et al describe the rst 38 cases in Europe with comparable prevalence of IMV at 9% of hospitalized patients. Since the studies from the United States and Italy (see Table 4) primarily describe patients in an Intensive Care Unit (ICU) setting, the proportion of patients requiring ventilation is higher at 71-88% 28 30 . The median length of stay in studies from China has ranged from 10-12 days where such data was available 4 10 23 . This is comparable to our cohort who spent a median of nine days in hospital.
Furthermore, the rate of complications including requirement for ICU admission, development of ARDS and death also appear comparable to that reported previously.
To date, the largest cohorts have been reported by Guan et al 23  Italy). Our ndings are comparable with these other centres with regard to male gender, age, symptoms at presentation, treatment requirements and laboratory abnormalities. Of our cohort, 75% have been discharged and this is higher than that reported by Wang et al 22 and Yang et al 24 . However, our observed mortality rate of 4% died is the same as that reported by Wang et al 22 . Finally, our cohort characteristics are consistent with those reported in Ireland overall, in terms of age and those most at risk of severe illness being those with an underlying health condition 3 .
Our ndings differ from that reported in other cohorts in that more people had a pre-existing chronic illness. While respiratory symptoms and fever were common among our sample, we also observed less speci c symptoms such as myalgia, fatigue and gastrointestinal symptoms (e.g. nausea, diarrhoea) more commonly than has been previously reported.
In our sample, the application (albeit post hoc) of standard 'early warning scores' 16 17 would have resulted in less than half of people who required admission actually being admitted (45% using NEWS and 48% using NEWS2 parameter, respectively). We therefore recommend against relying on these measures alone when assessing requirement for patient admission, since these scoring systems were developed to aid in decision making for patients with bacterial sepsis as opposed to viral pneumonitis due to COVID-19.

Methodological considerations
This paper reports on real world data from a University teaching hospital in Dublin with a high incidence of COVID-19 disease. As the disease has unfolded it has become apparent that communities living in our local catchment area are especially at risk of the infection and its deleterious consequences 31 and this nding has been reported in other large cities 32 . The data was collected as our understanding of the natural history of this disease was unfolding. In that regard, while we endeavoured to ensure that the dataset is as complete as possible, this was not always possible and some data points were therefore missing. Nonetheless, we strove to minimise the bias resulting from this by reviewing clinical and administrative records and treating such missing data in accordance with 'STROBE Guidance' 19 .
We acknowledge a number of limitations in our study. Firstly, there may have been a low threshold to admit patients for hospital treatment due to an initial containment strategy and relative absence of capacity constraints at the outbreak's onset. This may continue to change as both hospital bed capacity and our understanding of the factors associated with worse outcomes evolves in the months ahead. The sample size, while small, is nonetheless, at the time of writing, one of the ten largest cohorts reported to date and to our knowledge the rst such from Ireland or the UK.

Conclusion
Implications for clinical practice COVID-19 is a new disease caused by an emergent virus and is not yet well characterised. Clinical manifestations are different to illness caused by other coronaviridae. Our ndings provide a guide on the clinical predictors of patients requiring hospital treatment. The epidemiological characteristics and clinical manifestations of COVID-19 in our cohort appears consistent with ndings in cohorts reported to date. Men in their fth decade appear especially at risk, while elevated levels of C-reactive protein, ferritin and D-dimer, in addition to abnormalities on chest imaging, elevated NEWS Score (Modi ed) score and tachycardia appear to be important predictors of disease severity. Further research involving larger samples followed longitudinally is a priority and such research will be key to identifying those parameters which best predict disease outcomes and best allocate resources. For clinicians, our key message is that relying exclusively on clinical assessment and tools such as early warning scores alone may not identify those who require hospital care.

Supplementary Files
This is a list of supplementary les associated with this preprint. Click to download. STROBEchecklist.docx