Total patient load, regional disparities and in-hospital mortality of intubated COVID-19 patients

in Greece, September 2020 to May 2021

Theodore Lytras1, Sotirios Tsiodras2,3

1. School of Medicine, European University Cyprus, Nicosia, Cyprus

2. National Public Health Organization, Athens, Greece

3. 4th Department of Internal Medicine, Attikon University Hospital, Medical School, National

and Kapodistrian University of Athens, Greece

Corresponding author:

Theodore Lytras, MD, PhD

School of Medicine, European University Cyprus

6 Diogenous str., 2404 Engomi, Nicosia, Cyprus

Email: t.lytras@euc.ac.cy
Abstract

Aims: While healthcare services have been expanding capacity during the COVID-19 pandemic,

quality of care under increasing patient loads has received less attention. We examined in-hospital

mortality of intubated COVID-19 patients in Greece, in relation to total intubated patient load,

Intensive Care Unit (ICU) availability and hospital region.

Methods: Anonymized surveillance data were analyzed from all intubated COVID-19 patients in

Greece between 1 September 2020 and 6 May 2021. Poisson regression was used to estimate the

hazard of dying as a function of fixed and time-varying covariates.

Results: Mortality was significantly increased above 400 patients, with an adjusted Hazard Ratio of

1.25, 95%CI: 1.03-1.51), rising progressively up to 1.57 (95%CI: 1.22-2.02) for 800+ patients.

Hospitalization outside an ICU or away from the capital region of Attica were also independently

associated with significantly increased mortality.

Conclusions: Our results indicate that in-hospital mortality of severely ill COVID-19 patients is

adversely affected by high patient load even without exceeding capacity, as well as by regional

disparities. This highlights the need for more substantial strengthening of healthcare services, focusing

on equity and quality of care besides just expanding capacity.

Keywords (MeSH)

COVID-19; pandemic; healthcare disparities; intensive care units; right to health; quality of care;

intubation; mortality

Word count

1,320 (full text), 185 (abstract)

Introduction

During the COVID-19 pandemic, healthcare systems’ capacity and resilience has been in the spotlight

[1]. However, less attention has focused on how the actual stress placed on healthcare services by

COVID-19 has affected their performance [2, 3]. Even without exceeding nominal capacity, a high

patient load could plausibly compromise quality of care, especially if occurring in a context of chronic

underfunding or poor pandemic preparedness [4, 5].

In this context, the aim of our study was to examine how in-hospital mortality of intubated COVID-19

patients in Greece is affected by patient load, intensive care unit (ICU) availability and regional

disparities.

Methods

In Greece the National Public Health Organization (NPHO) is responsible for COVID-19 surveillance,

and does active case finding and follow-up of all laboratory-confirmed COVID-19 cases in the country

that are intubated or hospitalized in an ICU. We obtained from NPHO anonymized patient data for all

intubated cases from 1 September 2020 to 6 May 2021, including dates of intubation, extubation, ICU

admission and discharge. As the study used only anonymous surveillance data from which no patient

can be identified, no ethical approval was necessary. The analyzed data and analysis code are available

online in the journal website.

For all cases follow-up time from intubation until extubation or death was split finely into days, and

Poisson regression was used to estimate the hazard of dying (fatality rate per day of hospitalization) as

a function of fixed and time-varying covariates [6]. To avoid bias, deaths occurring up to five days

after extubation were classified as deaths at the end of follow-up. The current total of intubated

COVID-19 patients at each time point during follow-up was used as an indicator of healthcare system

stress, and was included as a time-varying categorical variable in the model (reference: 0-199 patients,

vs 200-299, 300-399 etc up to 800+ patients). Age was modelled with a natural cubic spline with 1

internal knot. Other covariates included sex, a linear time trend, ICU hospitalization (vs non-ICU, for
each day of follow-up) and hospital region (the metropolitan regions of Attica and Thessaloniki, vs the

rest of Greece, Supplementary Figure S1). Model-based effect estimates (Hazard Ratios) were also

used to calculate Population Attributable Fractions [7]. Furthermore, we examined how the age

distribution of patients varied in relation to patient load, region and ICU hospitalization, in order to

better interpret the findings. All analyses were done in the R software environment version 4.0.4 [8].

Results

During the study period, two epidemic waves were observed in Greece; the first peaked in November

2020 and was focused in Central and Northern Greece, whereas the second was associated with the

B.1.1.7 variant and affected Athens and the entire country. The series of new intubations, deaths

among the study population, and total intubated COVID-19 patients are illustrated in Figure 1.

After excluding 296 cases with incomplete covariate information, 6282 cases were analyzed (Table 1)

of whom 3988 died (63.5%). Most patients spent part or all of their hospital stay in an ICU

(5971/6282, with 93951/97601 person-days total). Among those not admitted to an ICU, 275 (88.4%)

died compared to 3713 (62.2%) among those admitted (p<0.001).

Model results, expressed as adjusted Hazard Ratios (HR) and 95% Confidence Intervals (CI), are

shown in Figure 2. There was a significant association between mortality and total intubated patients

above 400, with its magnitude increasing progressively: from 1.25 (95%CI: 1.03–1.51) for 400-499

patients, up to 1.57 (95%CI: 1.22–2.02) for 800+ patients. Being intubated outside an ICU was

strongly associated with mortality (HR 1.87, 95%CI: 1.65–2.12), as was age, particularly after 60

years old. Interestingly, being hospitalized outside the capital region of Attica was also associated with

increased in-hospital mortality, with HRs of 1.35 (95%CI: 1.24–1.47) for Thessaloniki and 1.40

(95%CI: 1.30–1.51) for the rest of the country. There was no association with sex, but there was a

small negative time trend (HR 0.97 per month, 95%CI 0.94–1.00, p=0.02) indicating gradually lower

mortality as the pandemic progressed.

Given the above associations, out of 3988 deaths reported, 947 (95%CI: 343–1460) were attributable
to the high load (≥200) of intubated COVID-19 patients, 133 (95%CI: 101–169) to being outside an

ICU, and 656 (95%CI: 526–790) to being hospitalized away from Attica. A combined total of 1535

deaths (95%CI: 1053–1947) was attributable to these three factors collectively.

There was no association between patient age and total patients intubated, offering no evidence of

patient selection with higher patient loads (Supplementary Figure S2). In contrast, patients who never

entered an ICU were older on average (median 73 vs 68 years, p<0.001). Also, patients hospitalized in

Thessaloniki were slightly younger than those in Attica and other regions (median 67 vs 69 years,

p<0.001).

Discussion

Our analysis provides national-level evidence that in-hospital mortality of severely ill COVID-19

patients is adversely affected by high patient load. Importantly, this occurs not only when healthcare

capacity is stressed to depletion, but also at intermediate stress levels, when the availability of

resources and care is not nominally restricted. This represents a major preventable factor to limit

avoidable deaths from COVID-19, and highlights the need for more extensive investment in healthcare

beyond the minimum to meet peak demand during the pandemic, thereby ensuring adequate quality of

care. Similar findings for COVID-19 patients have been recently reported from Veterans Affairs

hospitals in the United States [2], and a large referral hospital in Northern Italy [3].

Our study further demonstrated important regional disparities, as in-hospital mortality was

substantially lower for people hospitalized in Attica compared to the rest of the country. This

highlights the chronically uneven regional distribution of healthcare resources in Greece, with beds,

equipment and trained healthcare workers concentrated in metropolitan areas [9] (Supplementary

Figure S1). It also compounds other existing health inequities that define the rural-urban divide,

resulting in a higher COVID-19 case fatality ratio in underserved and rural areas despite higher

exposure and mortality in cities [10, 11].

Our results must be interpreted with caution; as this is an observational study, there is a possibility that
patient selection (prioritizing for care those most in need and with a worse prognosis) might have

influenced our associations. However, the lack of association between total patient load and the age of

newly intubated patients suggests that those needing care did indeed receive it. In addition, patients in

Thessaloniki were younger than those in Attica, thus residual confounding by age cannot explain their

increased mortality. In contrast, patients treated outside an ICU were slightly older, thus some of them

might have been deemed “too ill to benefit” from the ICU. A clear limitation of our analysis is the lack

of information on comorbidities and baseline health status (at presentation to the hospital). However,

both these factors are unlikely to be distributed differently over time, and are both correlated with and

eclipsed by age, which is the major determinant of the risk of death and which we carefully adjusted

for [12, 13]. Therefore the observed associations most likely reflect real and avoidable differences in

the quality of care for COVID-19 patients, due to increased patient load, ICU availability and regional

disparities. The precise mechanisms by which patient load is associated with increased mortality need

to be investigated in future research, to allow for targeted interventions.

Nevertheless, these findings already highlight the need for strengthening healthcare systems in the

context of pandemic preparedness, as scaling up capacity during a pandemic is constrained by factors

such as the availability of trained healthcare staff. In Greece the increased healthcare worker needs due

to COVID-19 were largely met with staff redeployments, short-term hirings, and requisitioning of

private practitioners’ services [14, 15]. These might have been insufficient to counter the chronic

underfunding and understaffing of public healthcare services as a consequence of the long economic

crisis [16]. It is therefore essential to make long-term investments in health also for the post-COVID

era, ensuring equitable access to high-quality care for all [17].

Acknowledgements

We acknowledge the staff of the National Public Health Organization for their hard work in

coordinating the surveillance of COVID-19 in Greece.

Author contributions

Original idea: ST; Data analysis: TL; Data interpretation: TL, ST; First draft of the manuscript: TL;

Revision of the manuscript for important intellectual content: TL, ST

Conflicts of Interest

None. ST is an advisor to the Greek Ministry of Health; views expressed here are his own.

Funding

No funding was received for this study

References

[1] Sagan A, Thomas S, McKee M, et al. COVID-19 and health systems resilience: lessons going
forwards. Eurohealth; 26.

[2] Bravata DM, Perkins AJ, Myers LJ, et al. Association of Intensive Care Unit Patient Load and
Demand With Mortality Rates in US Department of Veterans Affairs Hospitals During the
COVID-19 Pandemic. JAMA Netw Open 2021; 4: e2034266.

[3] Soria A, Galimberti S, Lapadula G, et al. The high volume of patients admitted during the
SARS-CoV-2 pandemic has an independent harmful impact on in-hospital mortality from
COVID-19. PLoS One 2021; 16: e0246170.

[4] Oppenheim B, Gallivan M, Madhav NK, et al. Assessing global preparedness for the next
pandemic: development and application of an Epidemic Preparedness Index. BMJ Glob Health
2019; 4: e001157.

[5] Gabler NB, Ratcliffe SJ, Wagner J, et al. Mortality among patients admitted to strained
intensive care units. Am J Respir Crit Care Med 2013; 188: 800–806.

[6] Carstensen B. Who needs the Cox model anyway?, http://bendixcarstensen.com/WntCma.pdf

(2019).

[7] Greenland S, Drescher K. Maximum likelihood estimation of the attributable fraction from
logistic models. Biometrics 1993; 49: 865–872.

[8] R Core Team. R: A Language and Environment for Statistical Computing. Vienna, Austria: R
Foundation for Statistical Computing, http://www.R-project.org/ (2019).

[9] Economou C, Kaitelidou D, Karanikolos M, et al. Greece: health system review. Health
Systems in Transition 2017; 19: 1–192.

[10] Iyanda AE, Boakye KA, Lu Y, et al. Racial/Ethnic Heterogeneity and Rural-Urban Disparity of
COVID-19 Case Fatality Ratio in the USA: a Negative Binomial and GIS-Based Analysis. J
Racial Ethn Health Disparities. Epub ahead of print February 26, 2021. DOI: 10.1007/s40615-
021-01006-7.

[11] Karim SA, Chen H-F. Deaths From COVID-19 in Rural, Micropolitan, and Metropolitan Areas:
A County-Level Comparison. J Rural Health 2021; 37: 124–132.

[12] Petrilli CM, Jones SA, Yang J, et al. Factors associated with hospital admission and critical
illness among 5279 people with coronavirus disease 2019 in New York City: prospective cohort
study. BMJ 2020; 369: m1966.

[13] Williamson EJ, Walker AJ, Bhaskaran K, et al. Factors associated with COVID-19-related
death using OpenSAFELY. Nature 2020; 584: 430–436.

[14] European Observatory on Health Systems and Policies. COVID-19 Health System Response
Monitor: Greece, https://www.covid19healthsystem.org/countries/greece/countrypage.aspx
(accessed May 9, 2021).

[15] eKathimerini. Draft cards delivered to private sector doctors in Attica,

https://www.ekathimerini.com/news/1157656/draft-cards-delivered-to-private-sector-doctors-
in-attica/ (accessed May 9, 2021).
[16] Economou C, Kaitelidou D, Kentikelenis A, et al. The impact of the financial crisis on the
health system and health in Greece. In: Economic crisis, health systems and health in Europe:
country experience. Copenhagen: European Observatory on Health Systems and Policies,
https://www.ncbi.nlm.nih.gov/books/NBK447857/ (2015, accessed May 9, 2021).

[17] Paremoer L, Nandi S, Serag H, et al. Covid-19 pandemic and the social determinants of health.
BMJ 2021; 372: n129.
Table 1: Characteristics of the study population; laboratory-confirmed COVID-19 cases in

Greece intubated between 1 September 2020 and 6 May 2021

Total Survived Died p-value*

Number of patients 6282 2294 3988
Median age, years (IQR) 68 (60–75) 63 (54–71) 71 (63–77) <0.001
Sex 0.53
Female 2191 (100) 812 (37) 1379 (63)
Male 4091 (100) 1482 (36) 2609 (64)
Hospitalization type <0.001
In the ICU 5971 (100) 2258 (38) 3713 (62)
Outside the ICU 311 (100) 36 (12) 275 (88)
Hospital region <0.001
Attica 2811 (100) 1199 (43) 1612 (57)
Thessaloniki 1492 (100) 511 (34) 981 (66)
Rest of Greece 1979 (100) 584 (30) 1395 (70)
Total number of people intubated
<0.001
(at date of intubation)
0-199 496 (100) 172 (35) 324 (65)
200-299 514 (100) 186 (36) 328 (64)
300-399 678 (100) 215 (32) 463 (68)
400-499 831 (100) 256 (31) 575 (69)
500-599 1007 (100) 258 (26) 749 (74)
600-699 805 (100) 242 (30) 563 (70)
700-799 1021 (100) 419 (41) 602 (59)
800+ 930 (100) 546 (59) 384 (41)
* Mann-Whitney test for continuous variables, Fisher’s test for categorigal variables
Figure Legends

Figure 1: Distribution over time of total intubated COVID-19 patients, new intubations and deaths

among the study population, Greece, 1 September 2020 to 6 May 2021.

Figure 2: Multivariable (adjusted) associations between in-hospital mortality of intubated COVID-19

patients and age, sex, hospitalization type, hospital region and patient load, Greece, 1 September 2020

to 6 May 2021.

Supplementary Figure 1: Study regions in Greece and distribution of ICU beds, as of 20 April 2021

Supplementary Figure 2: Patient age distribution in relation to patient load, hospitalization type

(inside/outside ICU) and hospital region, Greece, 1 September 2020 to 6 May 2021.
 Total intubated
800
New intubations

80
New deaths

70

New intubations / New deaths

600

60
Total patients intubated

50
400

40
30
200

20
10
0

0
Sep 01 Oct 01 Nov 01 Dec 01 Jan 01 Feb 01 Mar 01 Apr 01 May 01

Date
Total intubated patients (vs: 0–199) HR (95% CI)
200-299 1.16 (0.94–1.43)
300-399 1.14 (0.93–1.39)
400-499 1.25 (1.03–1.51)
500-599 1.35 (1.13–1.62)
600-699 1.32 (1.09–1.61)
700-799 1.39 (1.10–1.77)
800+ 1.57 (1.22–2.02)
Patient sex (vs: female)
Male 0.99 (0.92–1.05)
Hospitalization type (vs: in ICU)
Outside an ICU 1.87 (1.65–2.12)
Hospital region (vs: Attica)
Thessaloniki 1.35 (1.24–1.47)
Rest of Greece 1.40 (1.30–1.51)

0.8 1.0 1.5 2.0

Adj. Hazard Ratio

7

95% CI
6
Adj. Hazard Ratio

5
4
3
2
1

0 20 40 60 80 100
Age (years)
 Kruskal-Wallis p=0.2
100
80
60
Age

40
20
0

0-199 200-299 300-399 400-499 500-599 600-699 700-799 800+

Total number of intubated patients (at day of intubation)

Kruskal-Wallis p<0.001 Kruskal-Wallis p<0.001

100

100
80

80
60

60
Age

Age
40

40
20

20
0

0utside an ICU In an ICU Attica Thessaloniki Rest of Greece

Hospitalization type Hospital region