The role of the peripheral chemoreceptor reflex in non-hospitalised patients with post-COVID-19 syndrome
Authors: El-Medany A , Adams Z , Blythe H , Hope K , Abdala A , Kendrick A , Nightingale A K , Hart E C 
Published: November 2023

Abstract

Background
Long COVID (post COVID-19 syndrome) is a common debilitating illness. Little is known regarding the underlying mechanisms driving ongoing symptoms, which include lethargy, breathlessness, dysregulated breathing, and exercise intolerance. The carotid body is important in the control of breathing, is abundant in ACE2 (cell entry mechanism for SARS-CoV-2) and is known to drive similar symptoms in patients with heart failure (HF). We hypothesised that the carotid chemoreflex becomes hyperreactive in patients with long COVID-19 syndrome, which could be important in driving several ongoing symptoms.

Purpose
We aimed to examine whether carotid chemoreflex sensitivity was elevated in patients with long COVID (with initial mild-moderate symptoms) versus an age-matched control group and whether this could help to explain dysregulated breathing and poor exercise tolerance in long COVID.

Methods
Long COVID participants (n=14; 12F) were prospectively recruited from a tertiary cardiology long COVID clinic (after being cleared for cardiac conditions) and from advertising publicly. Patients were non-hospitalised and had received a diagnosis of long COVID via their GP or long COVID clinic. Participants had a positive PCR or sero-positive antibody test for their initial infection. Controls were healthy with no diagnosed comorbidities (n=14; 11F). Eight controls had a confirmed previous infection and did not develop ongoing symptoms.
Participants completed baseline spirometry, a resting 12-lead electrocardiogram, and an incremental cardiopulmonary exercise test (CPET) to volitional exhaustion on a cycle ergometer. On a separate day, the carotid chemoreflex sensitivity was measured using the hypoxic ventilatory response (HVR) [1]. Averaged group data were compared using statistical software (GraphPad, Prism). Data are mean ± SD unless stated otherwise.

Results
Age and body mass index were similar between groups (Table 1). Resting spirometry indicated that lung function was similar between groups (Table 1). The long COVID group had a lower maximum volume of inspired oxygen (VO2 peak) and a similar maximum heart rate (as a % of predicted) vs. controls (Table 1). Ventilatory efficiency (VE/VCO2) slope, VE/VCO2 ratio at anaerobic threshold (AT), and VE/VCO2 nadir were higher in the long COVID group, indicating poor breathing efficiency, similar to the level observed in HF (Table 1) [2]. Finally, the HVR was elevated in the long COVID group (-0.45±0.23 l/min/SpO2%) versus the control group (-0.18±0.13 l/min/SpO2%, Figure 1, P=0.0007). The HVR correlated with the VE/VCO2 slope (r=0.54, P=0.0012).

Conclusions
These data suggest that the carotid chemoreflex is sensitised in people with long COVID and may help to explain dysregulated breathing in these patients. The carotid chemoreflex could be a viable target to help improve symptoms in people suffering with ongoing symptoms following even a mild original SARS-CoV-2 infection, but more research is needed.Table 1Figure 1