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. 2021 May 19:12:630038.
doi: 10.3389/fphys.2021.630038. eCollection 2021.

Alteration of Autonomic Nervous System Is Associated With Severity and Outcomes in Patients With COVID-19

Yuchen Pan  1   2   3   4 , Zhiyao Yu  1   2   3   4 , Yuan Yuan  1   2   3   4 , Jiapeng Han  1   2   3   4 , Zhuo Wang  1   2   3   4 , Hui Chen  1   2   3   4 , Songyun Wang  1   2   3   4 , Zhen Wang  1   2   3   4 , Huihui Hu  1   2   3   4 , Liping Zhou  1   2   3   4 , Yanqiu Lai  1   2   3   4 , Zhen Zhou  1   2   3   4 , Yuhong Wang  1   2   3   4 , Guannan Meng  1   2   3   4 , Lilei Yu  1   2   3   4 , Hong Jiang  1   2   3   4
Affiliations

Alteration of Autonomic Nervous System Is Associated With Severity and Outcomes in Patients With COVID-19

Yuchen Pan et al. Front Physiol. .

Abstract

Background: Previous studies suggest that coronavirus disease 2019 (COVID-19) is a systemic infection involving multiple systems, and may cause autonomic dysfunction.

Objective: To assess autonomic function and relate the findings to the severity and outcomes in COVID-19 patients.

Methods: We included consecutive patients with COVID-19 admitted to the 21st COVID-19 Department of the east campus of Renmin Hospital of Wuhan University from February 6 to March 7, 2020. Clinical data were collected. Heart rate variability (HRV), N-terminal pro-B-type natriuretic peptide (NT-proBNP), D-dimer, and lymphocytes and subsets counts were analysed at two time points: nucleic-acid test positive and negative. Psychological symptoms were assessed after discharge.

Results: All patients were divided into a mild group (13) and a severe group (21). The latter was further divided into two categories according to the trend of HRV. Severe patients had a significantly lower standard deviation of the RR intervals (SDNN) (P < 0.001), standard deviation of the averages of NN intervals (SDANN) (P < 0.001), and a higher ratio of low- to high-frequency power (LF/HF) (P = 0.016). Linear correlations were shown among SDNN, SDANN, LF/HF, and laboratory indices (P < 0.05). Immune function, D-dimer, and NT-proBNP showed a consistent trend with HRV in severe patients (P < 0.05), and severe patients without improved HRV parameters needed a longer time to clear the virus and recover (P < 0.05).

Conclusion: HRV was associated with the severity of COVID-19. The changing trend of HRV was related to the prognosis, indicating that HRV measurements can be used as a non-invasive predictor for clinical outcome.

Keywords: COVID-19; N-terminal Pro-B-type natriuretic peptide; autonomic nervous system; clinical outcomes; d-dimer; heart rate variability; lymphocyte.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
HRV measurements in mild and severe patients with COVID-19. (A) LF/HF (B) SDNN (C) SDANN are shown.
FIGURE 2
FIGURE 2
ROC analysis for significant HRV variables. The sensitivity and specificity of SDNN, SDANN, and LF/HF for the severity of COVID-19.
FIGURE 3
FIGURE 3
The comparison of the D-dimer, NT-proBNP, lymphocytes, and lymphocyte subsets in the mild group and the severe group. The comparison of (A) NT-proBNP, (B) lymphocytes, (C) D-dimer, (D) CD3+ T cells, CD4+ T cells, CD8+ T cells, B cells, and NK cells in different groups.
FIGURE 4
FIGURE 4
The correlation between HRV and NT-proBNP, D-dimer, and lymphocytes. (A) LF/HF and NT-proBNP, (B) SDANN and NT-proBNP, (C) SDNN and NT-proBNP, (D) LF/HF and D-dimer, (E) SDANN and D-dimer, (F) SDNN and D-dimer, (G) LF/HF and lymphocytes, (H) SDANN and lymphocytes, (I) SDNN and lymphocytes.
FIGURE 5
FIGURE 5
The comparison of the HRV variables between the two time points (nucleic acid test positive and negative) in group A (blue) and group B (red). The (A) LF/HF, (B) SDNN, (C) SDANN in different groups. P-Values were provided for comparison as follows: P1: Nucleic acid test positive vs nucleic acid test negative for group A. P2: Nucleic acid test positive vs nucleic acid test negative for group B.
FIGURE 6
FIGURE 6
The comparison of the laboratory examination variables between the two time points (nucleic acid test positive and negative) in group A (blue) and group B (red). The (A) NT-proBNP, (B) D-dimer, (C) CD3+ T cells, (D) CD4+ T cells, (E) CD8+ T cells, (F) B cells, (G) NK cells, (H) lymphocytes in different groups. P-values were provided for comparison as follows: P1: Nucleic acid test positive vs nucleic acid test negative for group A. P2: Nucleic acid test positive vs nucleic acid test negative for group B.
FIGURE 7
FIGURE 7
Kaplan–Meier curve analysis for the proportion of viral RNA negative conversion (A) and recovered (B) stratified by group A (blue) and group B (red).
FIGURE 8
FIGURE 8
Alteration of autonomic nervous system is associated with severity and outcomes in patients with COVID-19. All patients were divided into a mild group and a severe group, and the severe group was then further divided into two categories according to the trend of HRV indices, which showed a consistent trend with immune function, D-dimer, and NT-proBNP. The results showed that severe patients without improved HRV parameters needed a longer time to clear the virus and recover.
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