Symptom burden correlates to impairment of diffusion capacity and exercise intolerance in long COVID patients

The main findings of this study are as follows: (1) the severity of the initial COVID-19 disease and female sex are associated with higher symptom burden in the context of long COVID; (2) the extent of physical and mental impairment in the self-assessment using SF-36 as well as the initial disease severity correlate significantly with DLCO and distance in the 6-MWT and (3) there was no correlation of symptom burden to markers of the left ventricular function in transthoracic echocardiography.

A predominance of the female gender has been described in other long COVID cohorts^1,14. Immunological and psychological causes were discussed, with a potential overlap. Under the assumption of T-cell abnormalities or autoantibodies leading to long COVID, the reported higher number of T-cells and autoantibodies during and shortly after COVID-19 could be potentially causative for ongoing symptoms^15,16. On the other hand, women are more prone to depression and anxiety disorders because of their higher oestrogen levels^17,18,19. Since the causes of a long COVID syndrome have not yet been fully understood and a multi-causality is likely, the female predominance cannot be adequately explained.

A positive correlation of pulmonary restriction in follow-up with COVID-19 severity was described earlier, especially in hospitalised patients^20,21. Data on mild or even asymptomatic courses are scarce. In a study carried out in Wuhan by Huang et al., 1733 patients were examined six months after the reduced walking distance in the 6-MWT, and diffusion impairment dependent on the in-hospital course of the initial COVID-19 disease has been shown during hospital discharge²². In another trial with hospitalised patients, a DLCO reduction could be associated with female sex and radiological abnormalities in follow-up examinations after 3–12 months²¹. In contrast, our cohort consisted of all clinical courses, including outpatient and asymptomatic, with a mean follow-up time of six months. We could show a correlation of well-being to functional values of diffusion testing and the 6-MWT. While neuropsychological factors can influence symptoms during the 6-MWT and walking distance, the reduction in DLCO suggests an at least transient organic correlate. Whether the numerical differences in DLCO, some of which are small, are actually causal for the patients’ dyspnea remains questionable. Patients with a low DLCO can be rehabilitated well and improvements in DLCO and 6-MWT go hand in hand²³. Therefore, our results are of clinical relevance, as they illustrate that rehabilitative therapy of dyspnea and exercise capacity also improves patients’ self-assessed physical and mental health; thus, no separate therapeutic approach is necessary for this.

In the longitudinal trial by Steinbeis et al., an improvement in respiratory function has been shown, including DLCO over time²⁰. Considering the possible time course of DLCO and the significantly different observation times of the cohorts after COVID-19 infection in our collective, a possible confounder or coincidence is possible here.

In another trial, a time dependency of symptom burden in the context of long COVID has been shown in 13.3% of participants with symptoms lasting more than 28 days after COVID-19 and only 2.3% for more than 12 weeks¹. This is in line with the assumption that most cases of long COVID are another form of post-infectious syndromes, which have also shown time dependency^7,24,25. It currently remains unclear to what extent an improvement in lung function can be achieved and by which measures this process can be positively influenced. In a synopsis of the achievable final state and, if necessary, further imaging examinations, a distinction can ultimately be made between functional impairment (“functional” long COVID) and actual organ damage as an expression of a distinct disease (e.g. myocarditis, pulmonary embolism, pulmonary restriction). In this context, the increased levels of D-dimers in comparison between more symptomatic and less symptomatic patients may be of interest. These findings are potential indications of prothrombotic conditions, possibly associated with an increased incidence of pulmonary embolism. However, this condition is only suggestive and should be investigated in further studies.

Long COVID is affecting patients regardless of the initial severity of the disease²⁶. It is pointed to a missing or even inverse relationship between COVID-19 severity and the ongoing symptoms in some studies. No differences in symptom burden and walking distance in the 6-MWT between different clinical courses of COVID-19 have been found in a study by Townsend et al.²⁷. There was a relevant selection bias risk with only 153 out of 487 patients (31%) who accepted the offer for the examination in their trial. In return, there is also the possibility of selection bias in our setting of a long COVID unit. There were apparent differences between the self-assessed symptom severity in our cohort of previously hospitalised, outpatient and asymptomatic/oligosymptomatic patients. Initial disease severity was further associated with changes in body plethysmography (specifically total lung capacity, FVC, and DLCO) in our study. From this, it could be inferred that the association of symptom burden and functional parameters would be rather coincidental in nature. Since patients with higher self-assessed symptom severity also had worse outcomes in the subgroups according to initial disease severity, we assume a combined effect. Because the cohorts of initially hospitalized and asymptomatic/oligosymptomatic patients are very small, our results in these groups can only be considered hypothesizing. Cardiac inflammation signs as part of post-COVID-19 sequelae were frequently reported earlier^28,29,30. Most of them showed elevated levels of markers for inflammation in non-invasive tissue characterisation using cardiovascular magnetic resonance (CMR) imaging (T1, T2 and ECV). It was unclear whether these data were attributable to long-lasting symptoms after COVID-19. In our cohort, we found no correlation between more severe symptoms and LVEF or LV GLS. In another trial by Joy et al., CMR scans were carried out in seropositive and seronegative healthcare workers, and no differences in markers for inflammation were found. Since there was only one hospitalised patient because of COVID-19 in their cohort, cardiac involvement or impairment is possibly correlated with the severity of the initial COVID-19 course. Elevated markers of myocardial inflammation with normalisation in a follow-up visit have been shown in another trial with 58 hospitalised patients (36.1% admission to intensive care unit)³¹. The researchers also carried out functional lung tests, blood samples and cardiopulmonary exercise tests, finding no correlation to the symptoms of the patients. The difference in our data may be a consequence of COVID-19 severity or the fact that symptoms were assessed categorically rather than gradually in our study. Interestingly, they found a significant difference in right ventricular ejection fraction and volume between baseline and a follow-up visit, with an improvement over time, unfortunately not evaluated in our data. This could be a goal for further investigation as the right ventricular strain is easy to assess by transthoracic echocardiography³².