Inflammatory biomarkers at hospital discharge are associated with readmission and death in patients hospitalized for COVID-19.

Introduction

Even though the survival of patients admitted with coronavirus disease 2019 (COVID-19) has increased with approximately 20% over the past year [1], readmission and mortality rates remain high (19.9% and 9.1%, respectively, within 2 months after hospital discharge (ward and intensive care unit (ICU)—admissions combined) [2]. In community-acquired pneumonia, elevated interleukin (IL)-6 and IL-10 at hospital discharge are associated with mortality in the subsequent 3 and 6 months, despite initial clinical recovery [3]. We aim to evaluate whether elevated levels of IL-6 and IL-10 at hospital discharge are associated with readmissions and mortality in the following 12 months in patients with COVID-19.

Methods

This study was part of the Amsterdam University Medical Centers (UMC) COVID-19 biobank. Patients were prospectively included in the biobank if they were admitted to the Amsterdam UMC with COVID-19 and had provided written informed consent or not used the opt-out form. COVID-19 was defined as a positive severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) polymerase chain reaction (PCR). IL-6 and IL-10 were measured in serial blood samples from March to May 2020 [4]. Patients who died during admission were excluded. Since biomarkers were measured in the first wave in The Netherlands, patients did not receive immunomodulatory therapy. Readmissions and mortality after hospital discharge were ascertained by contacting the general practitioner (GP). Biomarker measurements were done by using a Luminex platform [4]. Normally distributed data were analyzed by a t-test and nonparametric continuous data by Mann–Whitney U test. The ethics committee of the Amsterdam UMC approved the study.

Results

One-hundred sixty-one patients who were discharged alive formed our cohort. The mean age was 62 years (SD 11.76), 106 (68%) were male, and patients had an average of one comorbidity (IQR [1-3]). Seventy-five patients (47%) required ICU care during admission. Thirty-four (21%) were readmitted (median time to readmission was 29 days, IQR [6-97]), and six (4%) died (median time to death 85 days, IQR [20-169]) in the 12 months following the initial hospitalization for COVID-19. Twenty-three patients were readmitted once, six patients twice, and five patients three or more times. The primary cause of the first readmission was dyspnea or respiratory insufficiency in fourteen (41%) patients, cardiovascular disease in seven (21%), and other causes in thirteen (38%) patients. Compared to patients without readmissions and/or mortality after discharge, patients with these adverse outcomes were older (p = 0.031) and suffered from more comorbidities (p = 0.001, Table 1).

Table 1

Clinical characteristics, stratified for readmissions and/or mortality in the first 2 months and 12 months after discharge

	Short term (2 months)			Long term (12 months)
	Readmission and/or mortality (n = 23)	No readmission and/or mortality (n = 138)	P value	Readmission and mortality (n = 37)	No readmission and/or mortality (n = 124)	P value
Demographics
Age, mean (SD)	68.07 (12.67)	60.96 (11.33)	0.007	65.62 (13.33)	60.88 (11.08)	0.031
Gender, male, no. (%)	16 (69.6%)	90 (65.2%)	0.865	24 (64.9%)	82 (66.1%)	1.000
BMI, median [IQR]	27.46 [24.56, 29.23]	27.75 [25.22, 32.14]	0.161	27.71 [24.57, 30.97]	27.36 [25.19, 31.87]	0.690
Number of comorbidities1, median [IQR]	3.00 [1.50, 4.00]	1.00 [0.00, 3.00]	0.001	3.00 [1.00, 4.00]	1.00 [0.00, 3.00]	0.001
Admission
qSOFA, median [IQR]	1.00 [0.00, 1.00]	1.00 [0.50, 1.00]	0.051	1.00 [0.00, 1.00]	1.00 [0.00, 1.00]	0.648
MEWS, median [IQR]	2.00 [1.00, 4.00]	4.00 [2.00, 5.00]	0.033	3.00 [1.00, 5.00]	4.00 [2.00, 5.00]	0.302
CT Severity Score2, mean (SD)	10.59 (6.62)	12.73 (5.64)	0.177	11.57 (7.26)	12.58 (5.34)	0.476
Days between onset and admission, median [IQR]	10.00 [7.75, 14.00]	10.00 [7.00, 14.00]	0.828	10.00 [7.00, 14.00]	10.00 [7.00, 14.00]	0.860
Do not resuscitate order at admission3, no. (%)	15 (71.4%)	14 (14.7%)	< 0.001	18 (60.0%)	11 (12.8%)	< 0.001
Do not intubate order at admission3, no. (%)	9 (42.9%)	8 (8.4%)	< 0.001	11 (36.7%)	6 (7.0%)	< 0.001
Discharge
Length of hospital stay (days), median [IQR]	6.00 [4.00, 8.00]	11.00 [6.00, 22.00]	0.002	7.00 [5.00, 17.00]	11.00 [6.00, 20.00]	0.121
Discharge location, no. (%)			0.003			0.047
Home	11 (47.8%)	56 (40.6%)		17 (45.9%)	50 (40.3%)
Nursing home	3 (13.0%)	1 (0.7%)		3 (8.1%)	1 (0.8%)
Other	2 (8.7%)	6 (4.3%)		3 (8.1%)	5 (4.0%)
Rehabilitation	5 (21.7%)	66 (47.8%)		11 (29.7%)	60 (48.4%)
Abnormal Halm’s criteria for clinical stability at discharge4,6, no. (%)			0.499			0.462
0	10 (55.6)	57 (60.0)		15 (60.0)	52 (59.1)
1	8 (44.4)	33 (34.7)		10 (40.0)	31 (35.2)
2	0 (0.0)	5 (5.3)		0 (0.0)	5 (5.7)
Complications during admission
Venous thromboembolism, no. (%)	6 (26.1)	38 (27.5)	1.000	10 (27.0)	34 (27.4)	1.000
Required ICU stay, no. (%)	5 (21.7)	70 (50.7)	0.019	13 (35.1)	62 (50.0)	0.161
Mechanical ventilation, no. (%)	4 (17.4)	67 (48.9)	0.010	12 (33.3)	59 (47.6)	0.185
Laboratory values at discharge5
White blood cell count (10^9/L), median (SD)	6.14 (2.34)	6.89 (2.34)	0.497	6.57 (2.54)	6.88 (2.31)	0.707
Lymphocytes (10^9/L), median [IQR]	0.68 [0.61, 0.70]	1.33 [1.07, 1.94]	0.007	0.70 [0.66, 1.45]	1.33 [1.07, 1.94]	0.103
Neutrophils (10^9/L), median [IQR]	3.96 [3.18, 4.99]	4.35 [3.00, 5.36]	0.760	4.90 [3.18, 5.72]	4.19 [3.00, 5.26]	0.734
Platelets (10^9/L), median [IQR]	202.00 [157.00, 204.00]	387.00 [272.00, 429.00]	0.002	215.50 [169.00, 349.50]	389.50 [272.75, 425.25]	0.031
C-reactive protein (mg/L), median [IQR]	61.25 [45.35, 80.78]	36.10 [17.30, 61.70]	0.225	46.50 [28.22, 80.78]	36.10 [17.30, 61.70]	0.473
LDH (U/L), median [IQR]	328.50 [296.75, 358.00]	282.50 [231.75, 363.50]	0.447	290.00 [249.50, 328.50]	287.00 [232.50, 368.50]	0.963
D-dimer (mg/L), median [IQR]	1.47 [1.18, 1.76]	2.40 [1.38, 4.16]	0.243	2.27 [2.05, 3.12]	2.22 [1.33, 4.07]	0.979

Significant values are shown in bold

Abbreviations: BMI body mass index, ICU intensive care unit, LDH lactate dehydrogenase, MEWS modified early warning score, n number, qSOFA quick sequential organ failure assessment

1Comorbidities include chronic cardiac disease, hypertension, chronic pulmonary disease, asthma, chronic kidney disease, liver disease, chronic neurologic disease, malignancy, chronic hematologic disease, HIV or aids, diabetes, rheumatic disorder, auto-immune disease, and dementia

2−5Percentage of missing values: 2 44%, 3 28%, 4 14%, 5 between 51 and 64%

6One of the seven Halm’s criteria (the ability to maintain oral intake) was not record

At time of hospital discharge, most patients in both groups had zero or one abnormal vital parameter according to Halm’s criteria [5] (criteria for clinical stability at hospital discharge). Lymphocytes and platelets were significantly lower at discharge in patients who were readmitted or died in the first 2 months following discharge (p = 0.002 and p = 0.007, respectively). The median concentrations of IL-6 and IL-10 at discharge were significantly higher in patients with these adverse outcomes in the first month (p = 0.005 and p < 0.001, respectively) and first 2 months (p = 0.031 and p = 0.017, respectively) following discharge (Fig. 1). At 12 months, the IL-6 and IL-10 concentration did not show significant differences. Biomarkers representing discharge were measured in the last 4 days before discharge. For the biomarker concentrations, we used 26 age and gender-matched controls from the outpatients clinic, with a mean age of 64 years (SD 15.5) of whom 18 (69%) were male (Fig. 1).

Fig. 1

Concentration interleukin-6 and interleukin-10 at hospital discharge, stratified for readmission and/or mortality

Discussion

This study shows that after hospitalization for COVID-19, elevated IL-6 and Il-10 concentrations at time of hospital discharge are associated with increased readmission and/or mortality rates over the subsequent 2 months. A similar association was found for lower lymphocyte and platelet concentration at discharge. Previous studies show that lymphopenia and low platelets have been associated with more severe infection [6] and IL-6 concentration is correlated with COVID-19 severity and in-hospital mortality [7]. Our findings could be of special relevance for patients who did not receive tocilizumab, since this recombinant humanized anti-IL-6 receptor monoclonal antibody inhibits the binding of IL-6 to both membrane and soluble IL-receptors [8].

This study has several limitations. Biomarkers representing hospital discharge were measured in the 4 days prior to discharge and were available in 70 (43%) patients. Second, we could not ascertain readmissions in ten (6%) patients in our cohort. Third, due to the lack of controls without COVID-19, we could not investigate if our findings are also true for other diseases. Fourth, the use of tocilizumab, which has been recommended by the World Health Organization as treatment for severely or critically ill patients with COVID-19 [9], will have influence of the IL-6 concentration at discharge. Even so, this study shows that COVID-19 patients with elevated IL-6 and IL-10 levels at hospital discharge were associated with an increased risk of readmission and/or death up to 2 months after hospital discharge when compared with those with normal circulating biomarkers.

Agtmael	Michiel	van	Agtmael	Department of Infectious Diseases	Prof. dr	M.A. van Agtmael	agtmael@amsterdamumc.nl
Algera	Anne Geke		Algera	Department of Intensive Care	Drs	A.G. Algera	a.g.algera@amsterdamumc.nl
Appelman	Brent		Appelman	Department of Infectious Diseases	Drs	B. Appelman	b.appelman@amsterdamumc.nl
Baarle	Frank	van	Baarle	Department of Intensive Care	Drs	F.E.H.P. van Baarle	f.e.vanbaarle@amsterdamumc.nl
Bax	Diane		Bax	Experimental Immunology	Drs	D.J.C. Bax	d.j.bax@amsterdamumc.nl
Beudel	Martijn		Beudel	Department of Neurology	Dr	M. Beudel	m.beudel@amsterdamumc.nl
Bogaard	Harm Jan		Bogaard	Department of Pulmonology	Prof. dr	H J Bogaard	hj.bogaard@amsterdamumc.nl
Bomers	Marije		Bomers	Department of Infectious Diseases	Dr	M. Bomers	m.bomers@amsterdamumc.nl
Bonta	Peter		Bonta	Department of Pulmonology	Dr	P.I. Bonta	p.i.bonta@amsterdamumc.nl
Bos	Lieuwe		Bos	Department of Intensive Care	Dr	L.D.J. Bos	l.d.bos@amsterdamumc.nl
Botta	Michela		Botta	Department of Intensive Care	Drs	M. Botta	m.botta@amsterdamumc.nl
Brabander	Justin	de	Brabander	Department of Infectious Diseases	Drs	J. de Brabander	j.debrabander@amsterdamumc.nl
Bree	Godelieve		Bree	Department of Infectious Diseases	Dr	G.J. de Bree	g.j.debree@amsterdamumc.nl
Bruin	Sanne	de	Bruin	Department of Intensive Care	Drs	S. de Bruin	s.debruin1@amsterdamumc.nl
Bugiani	Marianna		Bugiani	Department of Pathology	Dr	M. Bugiani	m.bugiani@amsterdamumc.nl
Bulle	Esther		Bulle	Department of Intensive Care	Drs	E.B. Bulle	e.b.bulle@amsterdamumc.nl > ,
Chouchane	Osoul		Chouchane	Department of Infectious Diseases	Drs	O. Chouchane	o.chouchane@amsterdamumc.nl
Cloherty	Alex		Cloherty	Experimental Immunology	Drs	A.P.M. Cloherty	a.p.cloherty@amsterdamumc.nl
David	Buis T.P		Buis	Department of Infectious Diseases	Drs	D.Buis	d.t.p.buis@amsterdamumumc.nl
de Rotte	Maurits C.F.J		de Rotte	Department of Clinical Chemistry	dr	M. C.F.J. de Rotte	m.derotte@amsterdamumc.nl
Dijkstra	Mirjam		Dijkstra	Department of Clinical Chemistry		M. Dijkstra	mirjam.dijkstra@amsterdamumc.nl
Dongelmans	Dave A		Dongelmans	Department of Intensive Care	Dr	D.A. Dongelmans	d.a.dongelmans@amsterdamumc.nl
Dujardin	Romein W.G		Dujardin	Department of Intensive Care		R.W.G Dujardin	r.w.dujardin@amsterdamumc.nl
Elbers	Paul		Elbers	Department of Intensive Care	Dr	P.E. Elbers	p.elbers@amsterdamumc.nl
Fleuren	Lucas		Fleuren	Department of Intensive Care	Drs	L.M. Fleuren	l.fleuren@amsterdamumc.nl
Geerlings	Suzanne		Geerlings	Department of Infectious Diseases	Prof. dr	S.E. Geerlings	s.e.geerlings@amsterdamumc.nl
Geijtenbeek	Theo		Geijtenbeek	Department of Experimental Immunology	Prof. dr	T.B.H. Geijtenbeek	t.b.geijtenbeek@amsterdamumc.nl
Girbes	Armand		Girbes	Department of intensive care	Prof. dr	A.R.J. Girbes	arj.girbes@amsterdamumc.nl
Goorhuis	Bram		Goorhuis	Department of Infectious Diseases	Dr	A. Goorhuis	a.goorhuis@amsterdamumc.nl
Grobusch	Martin P		Grobusch	Department of Infectious Diseases	Prof. dr	M.P. Grobusch	m.p.grobusch@amsterdamumc.nl
Hafkamp	Florianne		Hafkamp	Department of Experimental Immunology	Drs	F.M.J. Hafkamp	f.m.hafkamp@amsterdamumc.nl
Hagens	Laura		Hagens	Department of Intensive Care	Drs	L.A. Hagens	l.a.hagens@amsterdamumc.nl
Hamann	Jorg		Hamann	Amsterdam UMC Biobank Core Facility	Dr	J. Hamann	j.hamann@amsterdamumc.nl
Harris	Vanessa		Harris	Department of Infectious Diseases	Dr	V. C. Harris	v.c.harris@amsterdamumc.nl
Hemke	Robert		Hemke	Department of Radiology	Dr	R. Hemke	r.hemke@amsterdamumc.nl
Hermans	Sabine M		Hermans	Department of Infectious Diseases	Dr	S.M. Hermans	s.m.hermans@amsterdamumc.nl
Heunks	Leo		Heunks	Department of Intensive Care	Dr	L.M.A. Heunks	l.heunks@amsterdamumc.nl
Hollmann	Markus		Hollmann	Department of Anesthesiology	Prof. dr	m.w.Hollmann	m.w.hollmann@amsterdamumc.nl
Horn	Janneke		Horn	Department of Intensive Care	Dr	J. Horn	j.horn@amsterdamumc.nl
Hovius	Joppe W		Hovius	Department of Infectious Diseases	Prof. dr	J.W. Hovius	j.w.hovius@amsterdamumc.nl
Jong	Menno D	de	Jong	Department of Medical Microbiology	Prof. dr	M.D. de Jong	m.d.dejong@amsterdamumc.nl
Koning	Rutger		Koning	Department of Neurology	Drs	R. Koing	r.koning1@amsterdamumc.nl
Lim	Endry H.T		Lim	Department of Intensive Care	Drs	E.H.T. Lim	e.lim@amsterdamumc.nl
Mourik	Niels	van	Mourik	Department of Intensive Care	Drs	N. van Mourik	n.vanmourik@amsterdamumc.nl
Nellen	Jeannine		Nellen	Department of Infectious Diseases	Dr	J.F Nellen	f.j.nellen@amc.uva.nl
Nossent	Esther J		Nossent	Department of Pulmonology	Dr	E.J. Nossent	e.nossent@amsterdamumc.nl
Paulus	Frederique		Paulus	Department of Intensive Care	Dr	F. Paulus	f.paulus@amsterdamumc.nl
Peters	Edgar		Peters	Department of Infectious Diseases	peter	E. Peters	e.peters@amsterdamumc.nl
Piña-Fuentes	Dan A.I		Piña-Fuentes	Department of neurology	Drs	D.Piña-Fuentes	d.a.i.pinafuentes@amsterdamumc.nl
Poll	Tom	van der	Poll	Department of Infectious Diseases	Prof. dr	T. van der Poll	t.vanderpoll@amsterdamumc.nl
Preckel	Bennedikt		Preckel	Department of Anesthesiology	Prof. dr	b.preckel	b.preckel@amsterdamumc.nl
Prins	Jan M		Prins	Department of Infectious Diseases	Prof. dr	J.M. Prins	j.m.prins@amc.uva.nl
Raasveld	Jorinde		Raasveld	Department of Intensive Care	Drs	s.j.raasveld	s.j.raasveld@amsterdamumc.nl
Reijnders	Tom		Reijnders	Department of Infectious Diseases	Drs	T.D.Y. Reijnders	t.d.reijnders@amsterdamumc.nl
Schinkel	Michiel		Schinkel	Department of Infectious Diseases	Drs	M. Schinkel	m.schinkel@amsterdamumc.nl
Schrauwen	Femke A.P		Schrauwen	Department of Clinical Chemistry		F.A.P. Schrauwen	f.a.schrauwen@amsterdamumc.nl
Schultz	Marcus J		Schultz	Department of Intensive Care	Prof. dr	M.J. Schultz	m.j.schultz@amsterdamumc.nl
Schuurman	Alex		Schuurman	Department of Internal Medicine	Drs	A.R. Schuurman	a.r.schuurman@amsterdamumc.nl
Schuurmans	Jaap		Schuurmans	Department of Intensive Care	Drs	J. Schuurmans	j.schuurmans2@amsterdamumc.nl
Sigaloff	Kim		Sigaloff	Department of Infectious Diseases	Dr	K. Sigaloff	k.sigaloff@amsterdamumc.nl
Slim	Marleen A		Slim	Department of Intensive Care and Infectious Diseases	Drs	M.A. Slim	m.a.slim@amsterdamumc.nl
Smeele	Patrick		Smeele	Department of Pulmonology	Drs	P. Smeele	p.smeele@amsterdamumc.nl
Smit	Marry		Smit	Department of Intensive Care	Drs	M.R. Smit	m.r.smit@amsterdamumc.nl
Stijnis	Cornelis S		Stijnis	Department of Infectious Diseases	Dr	C. Stijnis	c.stijnis@amsterdamumc.nl
Stilma	Willemke		Stilma	Department of Intensive Care	Drs	W. Stilma	w.stilma@hva.nl
Teunissen	Charlotte		Teunissen	Neurochemical Laboratory	Prof. dr	C.E. Teunissen	c.teunissen@amsterdamumc.nl
Thoral	Patrick		Thoral	Department of Intensive Care	Drs	P. Thoral	p.thoral@amsterdamumc.nl
Tsonas	Anissa M		Tsonas	Department of Intensive Care	Drs	A.M. Tsonas	a.m.tsonas@amsterdamumc.nl
Tuinman	Pieter R		Tuinman	Department of Intensive Care	Dr	P.R. Tuinman	p.tuinman@amsterdamumc.nl
Valk	Marc	van der	Valk	Department of Infectious Diseases	Dr	M. van der Valk	m.vandervalk@amsterdamumc.nl
Veelo	Denise		Veelo	Department of Anesthesiology	Dr	d.p.veelo	d.p.veelo@amsterdamumc.nl
Volleman	Carolien		Volleman	Department of Intensive Care		C. Volleman	c.volleman@amsterdamumc.nl
Vries	Heder	de	Vries	Department of Intensive Care	Drs	H. de Vries	h.vries@amsterdamumc.nl
Vught	Lonneke A		Vught	Department of Intensive Care and Infectious Diseases	Dr	L.A. van Vught	l.a.vanvught@amsterdamumc.nl
Vugt	Michèle	van	Vugt	Department of Infectious Diseases	Prof. dr	M. van Vugt	m.vanvugt@amsterdamumc.nl
Wouters	Dorien		Wouters	Department of Clinical Chemistry		D. Wouters	d.wouters@amsterdamumc.nl
Zwinderman	A. H (Koos)		Zwinderman	Department of Clinical Epidemiology, Biostatistics and Bioinformatics	Prof. dr	A.H. Zwinderman	a.h.zwinderman@amsterdamumc.nl
Brouwer	Matthijs C		Brouwer	Department of Neurology	Dr	M.C. Brouwer	m.c.brouwer@amsterdamumc.nl
Wiersinga	W. Joost		Wiersinga	Department of Infectious Diseases	Prof. dr	W.J. Wiersinga	w.j.wiersinga@amsterdamumc.nl
Vlaar	Alexander P.J		Vlaar	Deparment of Intensive Care	Dr	A.P.J. Vlaar	a.p.vlaar@amsterdamumc.nl
Beek	Diederik	van de	Beek	Department of Neurology	Prof. dr	D. van de Beek	d.vandebeek@amsterdamumc.nl