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. 2021 Apr 1;49(4):661-670.
doi: 10.1097/CCM.0000000000004862.

Capillary Leukocytes, Microaggregates, and the Response to Hypoxemia in the Microcirculation of Coronavirus Disease 2019 Patients

Emanuele Favaron  1   2 , Can Ince  1 , Matthias P Hilty  1   3 , Bülent Ergin  1 , Philip van der Zee  1 , Zühre Uz  1 , Pedro D Wendel Garcia  3 , Daniel A Hofmaenner  3 , Claudio T Acevedo  4 , Wim Jan van Boven  2 , Sakir Akin  1   5 , Diederik Gommers  1 , Henrik Endeman  1
Affiliations

Capillary Leukocytes, Microaggregates, and the Response to Hypoxemia in the Microcirculation of Coronavirus Disease 2019 Patients

Emanuele Favaron et al. Crit Care Med. .

Abstract

Objectives: In this study, we hypothesized that coronavirus disease 2019 patients exhibit sublingual microcirculatory alterations caused by inflammation, coagulopathy, and hypoxemia.

Design: Multicenter case-controlled study.

Setting: Two ICUs in The Netherlands and one in Switzerland.

Patients: Thirty-four critically ill coronavirus disease 2019 patients were compared with 33 healthy volunteers.

Interventions: None.

Measurements and main results: The microcirculatory parameters quantified included total vessel density (mm × mm-2), functional capillary density (mm × mm-2), proportion of perfused vessels (%), capillary hematocrit (%), the ratio of capillary hematocrit to systemic hematocrit, and capillary RBC velocity (μm × s-1). The number of leukocytes in capillary-postcapillary venule units per 4-second image sequence (4 s-1) and capillary RBC microaggregates (4 s-1) was measured. In comparison with healthy volunteers, the microcirculation of coronavirus disease 2019 patients showed increases in total vessel density (22.8 ± sd 5.1 vs 19.9 ± 3.3; p < 0.0001) and functional capillary density (22.2 ± 4.8 vs 18.8 ± 3.1; p < 0.002), proportion of perfused vessel (97.6 ± 2.1 vs 94.6 ± 6.5; p < 0.01), RBC velocity (362 ± 48 vs 306 ± 53; p < 0.0001), capillary hematocrit (5.3 ± 1.3 vs 4.7 ± 0.8; p < 0.01), and capillary-hematocrit-to-systemic-hematocrit ratio (0.18 ± 0.0 vs 0.11 ± 0.0; p < 0.0001). These effects were present in coronavirus disease 2019 patients with Sequential Organ Failure Assessment scores less than 10 but not in patients with Sequential Organ Failure Assessment scores greater than or equal to 10. The numbers of leukocytes (17.6 ± 6.7 vs 5.2 ± 2.3; p < 0.0001) and RBC microaggregates (0.90 ± 1.12 vs 0.06 ± 0.24; p < 0.0001) was higher in the microcirculation of the coronavirus disease 2019 patients. Receiver-operating-characteristics analysis of the microcirculatory parameters identified the number of microcirculatory leukocytes and the capillary-hematocrit-to-systemic-hematocrit ratio as the most sensitive parameters distinguishing coronavirus disease 2019 patients from healthy volunteers.

Conclusions: The response of the microcirculation to coronavirus disease 2019-induced hypoxemia seems to be to increase its oxygen-extraction capacity by increasing RBC availability. Inflammation and hypercoagulation are apparent in the microcirculation by increased numbers of leukocytes and RBC microaggregates.

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Conflict of interest statement

Dr. Ince has received honoraria and independent research grants from Fresenius-Kabi, Bad Homburg, Germany; La Jolla Pharmaceutical, La Jolla, CA; and Cytosorbents Monmouth, NJ. He has developed sidestream dark field imaging, which is the handheld video microscope and is listed as the inventor on related patents commercialized by MicroVision Medical (MVM) under a license from the Academic Medical Center. He receives no royalties or benefits from this license. He has been a consultant for MVM in the past but has not been involved with this company for more than 5 years now and holds no shares of stock. Braedius Medical, a company owned by a relative of Dr. Ince, has developed and designed the incident dark field device used in this study. Dr. Ince has no financial relationship with Braedius Medical of any sort and has never owned shares, or received consultancy or speaker fees from Braedius Medical. The MicroTools software is being developed by Dr. Hilty and owned by Active Medical BV Leiden, The Netherlands, of which Drs. Ince and Hilty are shareholders. Active Medical runs an Internet site called microcirculationacademy.org, which offers educational courses and services related to clinical microcirculation. Dr. Ince’s institution received funding from La Jolla Pharmaceuticals and Cytosorbents Monmouth, and he received funding from Fresenius-Kabi. Drs. Ince and Hilty disclosed that the MicroTools software that was used for analysis of the images in the current study is owned by Active Medical, of which Drs. Ince and Hilty own shares. The remaining authors have disclosed that they do not have any potential conflicts of interest.

Figures

Figure 1.
Figure 1.
The coronavirus disease 2019 (COVID-19) patients had a lower hemoglobin (Hb) (A) and systemic hematocrit (sHct) (B) and a higher heart rate (HR) (C) than volunteers. D, The mean arterial pressure (MAP) in the COVID-19 patients and volunteers was similar.
Figure 2.
Figure 2.
Analysis of the microhemodynamics of the coronavirus disease 2019 (COVID-19) patients in comparison with those of the volunteers. COVID-19 patients had higher ratio capillary-to-systemic hematocrit (cHct/sHct) ratio (A) than in volunteers and higher functional capillary density (FCD) (B) than the volunteers. C, There was no evidence of plugged vessels in the COVID-19 patients as evidenced by a proportion of perfused vessel (PPV) > 94% in both groups. D, RBC velocity (RBCv) was significantly higher in COVID-19 patients than in the volunteers. E, Receiver-operating-characteristic curve analysis of the different microcirculatory hemodynamic parameters identifies cHct/sHct and RBCv as the parameters with the highest specificity and sensitivity for distinguishing the COVID-19 patients from the healthy volunteers. AUC = area under the curve.
Figure 3.
Figure 3.
Microcirculatory leukocytes in coronavirus disease 2019 (COVID-19) patients. A, Examples of leukocytes present in the microcirculation are shown. B, Presence of leukocytes can be seen in a space time diagram as slanted white lines as they travel down the length of a capillary (y-axis) over time (x-axis). The number of such white lines per 4-s clip is used to calculate the number of leukocytes. The dark slanted lines measure the presence of the RBC lines. The slopes of these lines are used to calculate RBC velocities. C, The total number of leukocytes measured in capillary-postcapillary venule units shows that there are significantly more microcirculatory leukocytes in the COVID-19 patients than in the volunteers.
Figure 4.
Figure 4.
Microaggregates in coronavirus disease 2019 (COVID-19) patients. A, An example of a plugged vessel with microaggregates. B, Receiver-operating-characteristic curve analysis of the number of leukocytes, RBC microaggregate, the capillary-to-systemic hematocrit (cHct/sHct) ratio, and RBC velocity (RBCv) show that the number of leukocytes, cHct/sHct, and RBCv show the highest sensitivity and specificity for distinguishing COVID-19 patients from volunteers. C, The raised number of microaggregates measured in the image segments of the COVID-19 patients was much higher than that found in the volunteers. D, Presence of an RBC microaggregate as a dark thick band in the space time diagram indicative of RBC clumping in this capillary vessel. AUC = area under the curve.
See this image and copyright information in PMC

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