Even Asymptomatic And Mild COVID-19 Causes Neuromuscular Damage To The Diaphragm Resulting In The Long COVID Manifestations Of Fatigue And Dyspnea!

Long COVID research: A new study by researchers from Northwestern University, Chicago-USA has found that even asymptomatic or mild to moderate SARS-CoV-2 infections can cause direct and indirect neuromuscular damage to the diaphragm resulting in the Long COVID manifestations of fatigue and dyspnea!


 
The diaphragm, located below the lungs and heart, is the major muscle of respiration. It is a large, dome-shaped muscle that contracts rhythmically and continually, and most of the time, involuntarily. Upon inhalation, the diaphragm contracts and flattens and the chest cavity enlarges, this creates a vacuum effect that pulls air into the lungs. When you exhale, the diaphragm relaxes and the air is pushed out of lungs.
 
The key aim of the study was to define the sonographic diaphragm phenotype of Long COVID patients with non-specific dyspnea and fatigue.
 
The study team analyzed patients referred from a pulmonary medicine COVID clinic without any intrinsic cardiopulmonary explanation for their new symptoms. The study team also additionally reported the functional outcomes of patients who completed an outpatient cardiopulmonary physical therapy program.
 
The research involved a retrospective cohort study (n = 37) of consecutive patients referred for neuromuscular assessment centered on B-mode ultrasound of the diaphragm muscle. Patients were recruited from a single academic hospital between February 25, 2021 and October 7, 2021.
 
Interestingly, sonographic abnormalities were identified in 65% (24/37) of patients, and in the vast majority of cases (23/24) was defined by low diaphragm muscle thickness. Thinner diaphragm muscles positively correlated with lower serum creatinine and creatine kinase values, but there was no association with markers of systemic inflammation.
 
Eighteen patients participated in outpatient cardiopulmonary physical therapy that included respiratory muscle training, and 77.8% (n=14) had documented improvement.
The study findings showed that in the outpatient rehabilitation setting, patients with Long COVID frequently display low diaphragm muscle thickness, but intact muscle contractility on sonographic studies.
 
The study team said that this could represents a form of disuse atrophy, which has a good response rate to cardiopulmonary physical therapy.
 
The study findings were published on a preprint server and are currently being peer reviewed. https://www.medrxiv.org/content/10.1101/2022.06.29.22277054v1
 
The study team previously reported on neuromuscular pathophysiological changes underlying chronic functional impairments among severe COVID-19 patients requiring inpatient rehabilitation for recovery.
https://pubmed.ncbi.nlm.nih.gov/34247452/
 
However, the extent of neuromuscular involvement among patients with lesser COVID-19 needed further research, and ultrasonographic findings among long COVID patients in outpatient rehabilitation settings are yet to be reported.
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The study team extended their previous analysis and investigated if dysfunction of the diaphragm muscle contributed to persistent long COVID symptoms such as dyspnea and/or fatigue.
 
The research cohort comprised 37 polymerase chain reaction (PCR)-confirmed (81%) or clinically diagnosed long COVID patients referred for ultrasonic neuromuscular assessment from a pulmonary medicine clinic without a clearly defined cardiopulmonary etiology for their symptoms. Out of the study cohort, 27 were never hospitalized due to COVID-19 and none of the patients required mechanical ventilation.
 
The research participants were enrolled for the study between 25 February 2021 and 7 October 2021.
 
For detailed comparison, published datasets of healthy individuals (n=150) and a prior dataset of severe COVID-19 patients requiring inpatient rehabilitation (n = 21) were used.
 
The study team performed the B-mode ultrasound of the diaphragm for all the participants, in which diaphragmatic thickness was assessed based on the total lung capacity (TLC) and functional reserve capacity (FRC).
 
The study team additionally reported functional outcomes among patients who completed an outpatient cardiopulmonary physical therapy program which included cardiovascular conditioning, with continual monitoring of heart rate, oxygen saturation (SpO2), and perceived exertion rate.
 
In order to determine the impact of systemic inflammation markers on muscle wasting, the serum creatine kinase (CK), C-reactive protein (CRP), creatinine, D-Dimer, albumin, bicarbonate, and neutrophil to lymphocyte ratio were assessed.
 
For the study, before the ultrasound referral, the medical history of all patients was obtained and the participants underwent a physical examination. Patients received respiratory muscle training with a home exercise based on resistance during the periods of inspiration and expiration to be completed five times per day.
 
The study participants were additionally educated on the strategies for diaphragmatic, shortness of breath, and cardiovascular conditioning habit-forming strategies.
 
Furthermore, in addition, 70% (n=26) patients underwent computed tomography (CT) radiographic examination, pulmonary function tests were obtained in 31 patients (84%), and 81% patients (n=30) underwent six-minute walk tests.
 
In all, over 88% of patients (n=33) underwent electrodiagnostic tests which included phrenic nerve conduction analysis and limited needle electromyography examination of the vastus lateralis and/or biceps brachii muscle.
 
Importantly, sonographic pathological abnormalities were detected among 65% of patients (n=24), of which most of the patients (n=23) demonstrated low hemi-diaphragmatic thickness (<0.15 cm) at FRC and thinner diaphragm musculature correlated positively with lower serological CK and creatinine values.
 
Interestingly, no association was observed with systemic inflammatory markers.
 
The study team speculated that the study findings represented a type of disuse atrophy, a condition responsive to cardiopulmonary physical therapy. In accordance, among the patients, 78% (14 out of 18) who underwent outpatient cardiopulmonary therapy and 75% (n=6) patients who took the six-minute walk tests showed functional improvements.
 
It was found that the average values for both the left and right hemi-diaphragmatic thickness were 0.17 ± 0.07 cm with average corresponding thickness ratios for the left and right hemi-diaphragms of 2.0 ± 0.4 cm and 2.0 ± 0.5 cm, respectively.
 
When compared to the reference population requiring inpatient rehabilitation, the study participants (requiring outpatient rehabilitation) exhibited substantially lesser thickness and higher diaphragmatic thickening ratios for the right and left hemi-diaphragms.
 
It was found that in the study cohort, the medians for FVC, TLC, and the forced expiratory volume in one second (FEV1) were 89%, 95.5%, and 91%, respectively. The medians for FEV1/FVC ratio and the diffusing capacity for carbon monoxide (DLCO) were 79% and 84%, respectively.
 
Significantly, the most common CT abnormalities among the patients were pulmonary nodules (most of which were sized <5.5mm) and opacities (band-like or ground glass-like) denoting fibrosis. In the electromyography analysis, no abnormalities were observed among the patients, indicative of unaltered muscle contractility in the study cohort and none of the participants were diagnosed with phrenic neuropathies.
 
The research findings showed that the diaphragm muscle thickness is lower among long COVID patients with lower COVID-19 severity (and unspecific dyspnea and fatigue) who require outpatient rehabilitation compared to those with less severe COVID-19 and inpatient rehabilitation requirements.
 
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