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 study team previously reported on neuromuscular pathophysiological changes underlying chronic functional impairments among severe COVID-19 patients requiring inpatient rehabilitation for recovery.
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
This study defines a distinct Long COVID diaphragm phenotype in the outpatient rehabilitation setting for patients with persistent respiratory symptoms not accounted for by intrinsic cardiopulmonary pathology. In an unexpectedly high percentage of cases (62%) these Long COVID patients presented with decreased diaphragm muscle thickness (atrophy), but intact diaphragm muscle thickening ratio (contractility).
This distinguishes them from our prior study on more severe COVID-19 survivors who were assessed while in the inpatient rehabilitation setting and predominantly had impaired diaphragm contractility on sonographic exam.2 The mechanism for Long COVID diaphragm atrophy is unclear, but we did not find serological markers of persistent inflammatory or cachexia-like state correlated with atrophy (thickness) of the diaphragm muscle to account for this effect (Supplemental Table 1).
General neuromuscular causes of diaphragm dysfunction include motor neuron disease, advanced polyneuropathy, myopathy, generalized muscle wasting (e.g. cachexia), and phrenic mononeuropathy.10, 11 In patients with severe COVID-19 infection, other proposed mechanisms include ventilator-induced diaphragm dysfunction and direct viral infiltration of SARS-CoV-2 through angiotensin converting enzyme 2 (ACE2).12,13
In our cohort of predominantly non-hospitalized patients (73%), there was no clinically diagnosed cases of phrenic mononeuropathy, polyneuropathy, or electrodiagnostic evidence of a myopathy. Additionally, while the atrophy was likely not due to an active inflammatory state, the positive correlation between diaphragm thickness, serum creatinine, and CK implies generalized loss of muscle mass may contribute to this phenotype.
This is extrapolated from the use of creatinine as a proxy marker of muscle mass in other neuromuscular disease states assuming intact kidney function.14, 15 Based on the activity intolerance reported by many of our Long COVID patients, muscle disuse atrophy should be considered as a potential factor.
Furthermore, this may explain why a clear majority of our patients responded favorably to cardiopulmonary physical therapy, including documented improvements in function by physical therapist or enhanced 6 minute walk test performance (Figure 2A-B).
This rehabilitation framework was proposed by Severin and colleagues early in the pandemic,17 and in addition to the current results it is supported by a large meta-analysis showing positive effects of pulmonary rehabilitation on dyspnea, and quality of life.18
A small percentage of our cohort did not tolerate physical therapy, which raises the question of how best to approach treatment of their functional deficits and whether this status changes spontaneously over time.
Limitations of our study include a small sample size and the retrospective nature of the study. In addition, quantitative functional outcome data pre- and post-COVID infection and physical therapy intervention was limited. Future research on diaphragm dysfunction in Long COVID should include a larger sample and consider prospective study designs.
Additionally, repeat diaphragm measurements and correlation with functional outcomes would be informative. To better assess the full impact of cardiopulmonary physical therapy, a randomized controlled trial with intent to treat analysis is desirable.
In this retrospective cohort study, we were able to identify evidence of diaphragm dysfunction, characterized by sonographic muscle atrophy with intact contractility, in Long COVID patients. The pathophysiologic mechanism of this finding is unclear, but we hypothesize it may be a form of disuse muscle atrophy.
Our evidence suggests that patients with persistent respiratory symptoms after COVID-19 infection, which is not accounted for by an intrinsic cardiopulmonary etiology, may be referred for neuromuscular and sonographic evaluation. If referred for cardiopulmonary physical therapy, it appears more likely than not, that patients who are able to participate will experience improvement in symptoms and functional status.