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.
Acknowledgements
We would like to thank all medical, paramedical, laboratory, and nursing staff involved in the care of the COVD-19 patients for making it possible to build the Amsterdam UMC COVID-19 Biobank in the middle of the COVID-19 outbreak in The Netherlands.
Appendix
Collaborators Amsterdam UMC COVID-19 biobank study group
| 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 |
Author contribution
All authors contributed to the study conception and design. Material preparation, data collection, and analysis were performed by Marleen A. Slim, Brent Appelman, and Lonneke A. van Vught. The first draft of the manuscript was written by Marleen A. Slim, W. Joost Wiersinga, and Lonneke A. van Vught, and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.
Funding
This study was funded by the Amsterdam UMC, Amsterdam UMC Corona Research Fund. Lonneke A. van Vught was supported by a VENI grant from ZonMW (grant number 09150161910033).
Declarations
Conflict of interest
The authors declare no competing interests.
Collaborators Amsterdam UMC COVID-19 biobank study group
See Appendix.
Footnotes
Publisher's note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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