Sex-differences in the longitudinal recovery of neuromuscular function in COVID-19 associated acute respiratory distress syndrome survivors

Abstract

Introduction: Patients admitted to the intensive care unit (ICU) following severe acute respiratory syndrome 2 (SARS-CoV-2) infection may have muscle weakness up to 1 year or more following ICU discharge. However, females show greater muscle weakness than males, indicating greater neuromuscular impairment. The objective of this work was to assess sex differences in longitudinal physical functioning following ICU discharge for SARS-CoV-2 infection.

Methods: We performed longitudinal assessment of physical functioning in two groups: 14 participants (7 males, 7 females) in the 3-to-6 month and 28 participants (14 males, 14 females) in the 6-to-12 month group following ICU discharge and assessed differences between the sexes. We examined self-reported fatigue, physical functioning, compound muscle action potential (CMAP) amplitude, maximal strength, and the neural drive to the tibialis anterior muscle.

Results: We found no sex differences in the assessed parameters in the 3-to-6-month follow-up, indicating significant weakness in both sexes.Sex differences emerged in the 6-to-12-month follow-up. Specifically, females exhibited greater impairments in physical functioning, including lower strength, walking lower distances, and high neural input even 1 year following ICU-discharge.

Discussion: Females infected by SARS-CoV-2 display significant impairments in functional recovery up to 1 year following ICU discharge. The effects of sex should be considered in post-COVID neurorehabilitation.

Keywords: COVID-19; intensive care unit; motor unit; neuromuscular function; sex differeces.

Figure 1

A: Protocol set-up: (A) Stimulator bar placed over the common peroneal nerve. (B) Surface electrodes for the identification of the CMAP-TA. (C) Stimulator ground electrode and (D) Ground electrode for the (E) EMG amplifier to prevent interference with biopotential signals. (F) Analog force amplifier to amplify the force signal detected by the (G) Load cell. The foot of the patient was strapped in a (H) carbon ankle-ergometer. (I) 64 Electrode Matrix was placed over the belly of the tibialis anterior muscle. B: Experimental protocol: With the help of the visual feedback, patients were asked to perform three maximal voluntary contractions (MVC) involving ankle dorsiflexion followed by submaximal trials at 30, 50 and 70% MVC. During the tasks at different MVC levels, the patients were required to keep the yellow dot between the red lines through ankle dorsiflexion.

Figure 2

Mean maximal strength in males and females across different follow-up months. Black lines in the bar graphs denote means. Colored bars with lines denote 95% confidence intervals with standard errors. Scatter dots represent individual participant data. Brackets with stars denote significant differences between sexes or months. (A) Mean maximal strength for females (white) and males (blue) at 3 and 6 month follow-up. No sex differences existed across follow-up months. (B) Mean maximal strength for females (white) and males (blue) at 6 and 12 month follow-up. Males had greater maximal strength at 12 compared to 6 months. Males also had greater maximal strength than females at 12 months, but not at 6 month follow-up.

Figure 3

Mean motor unit firing rates in males and females across different follow-up months for 30, 50 and 70% submaximal tasks. Black lines in the bar graphs denote means. Colored bars with lines denote 95% confidence intervals with standard errors. Scatter dots represent individual participant data. Brackets with stars denote significant differences between sexes or months. (A) Mean motor unit firing rate for females (white) and males (blue) for 30% MVC at 3 and 6 month follow-up. No differences in mean motor unit firing rates were observed across months or sex. (B) Mean motor unit firing rate for females (white) and males (blue) for 50% MVC at 3 and 6 month follow-up. No differences in mean motor unit firing rates were observed across months or sex. (C) Mean motor unit firing rate for females (white) and males (blue) for 70% MVC at 3 and 6 month follow-up. No differences in mean motor unit firing rates were observed across months or sex. (D) Mean motor unit firing rate for females (white) and males (blue) for 30% MVC at 6 and 12 month follow-up. At 6-month follow-up, no sex differences in mean motor unit firing rates existed, but at a 12-month follow-up, mean motor unit firing rates were greater in females than males. Males also had lower mean motor unit firing rates at 12- compared to 6-months, while mean motor unit firing rates in females did not differ between the two visits. (E) Mean motor unit firing rate for females (white) and males (blue) for 50% MVC. Females had greater motor unit firing rates than males irrespective of the follow-up month (6 versus 12). (F) Mean motor unit firing rate for females (white) and males (blue) for 70% MVC at 6 and 12 month follow-up. No differences in mean motor unit firing rates were observed across months or sex.