A new phenotype of patients with post-COVID-19 condition is characterised by a pattern of complex ventilatory dysfunction, neuromuscular disturbance and fatigue symptoms

Abstract

Background: Patients with post-COVID-19 condition frequently suffer from chronic dyspnoea. The causes and mechanism for dyspnoea in these patients without evidence of structural lung disease are unclear.

Methods: Patients treated for COVID-19 at Charité University Hospital in Berlin received pulmonary function testing including respiratory muscle strength tests and completed health-related quality-of-life questionnaires during follow-up. Patients with post-COVID-19 condition during outpatient follow-up with fatigue and exertional intolerance (PCF) were compared to patients with post-COVID-19 condition with evidence of chronic pulmonary sequelae (post-COVID-19 restriction (PCR)) as well as to patients without post-COVID-19 condition (NCF).

Results: A total of 170 patients presented for follow-up. 36 participants met criteria for PCF, 28 for PCR and 24 for NCF. PCF patients reported dyspnoea in 63.8%. % predicted value of respiratory muscle strength (median (IQR)) was reduced in PCF (55.8 (41.5-75.9)) compared to NCF and PCR (70.6 (66.3-88.9) and 76.8 (63.6-102.2), respectively; p=0.011). A pattern of reduced forced vital capacity (FVC), but normal total lung capacity (TLC), termed complex ventilatory dysfunction defined as TLC - FVC >10% predicted was observed and occurred more frequently in PCF (88.9%) compared to NCF and PCR (29.1% and 25.0%, respectively; p<0.001).

Conclusion: Dyspnoea in PCF is characterised by reduced respiratory muscle strength and complex ventilatory dysfunction indicating neuromuscular disturbance as a distinct phenotype among patients with post-COVID-19 condition. These observations could be a starting point for developing personalised rehabilitation concepts.

FIGURE 1

Study flow chart: 643 hospitalised and 41 outpatient participants were enrolled into the Pa-COVID-19 study. 170 patients presented for the first time between month 3 and 8 post symptom onset for follow-up in the outpatient department. These patients were stratified into patients with post-COVID-19 condition with fatigue (PCF) and post-exertional malaise (PEM), patients without chronic COVID-19 fatigue (NCF) and patients with post-COVID-19 condition and chronic pulmonary sequelae (PCR). SGRQ: St. George's Respiratory Questionnaire; PHQ: Patient Health Questionnaire.

FIGURE 2

Symptom burden of patients with post-COVID-19 condition. a) Cumulative abundance of the 15 most frequently occurring symptoms in PCF, NCF and PCR shows similar overall symptom burden in patients with PCF and PCR with divergent distribution. b–f) The five most common symptoms stratified by PCF, NCF and PCR. As per definition, dyspnoea was present in all PCR patients; however, it was also observed in a high proportion of PCF patients. PCF: post-COVID-19 condition with fatigue and PEM; PEM: post-exertional malaise; NCF: COVID-19 convalescents with no fatigue; PCR: post-COVID-19 condition with chronic respiratory sequelae.

FIGURE 3

Pulmonary function and gas exchange. a,b,g,h) Pulmonary restriction and impaired D_LCO are hallmarks of PCR after severe and critical acute COVID-19; however, they are not seen in PCF. c,e) Reduced respiratory muscle strength and complex ventilatory dysfunction (P_Imax; TLC − FVC) are however associated with PCF. i–k) No alterations in gas exchange were seen between different phenotypes. PCF: post-COVID-19 condition with fatigue and post-exertional malaise (PEM); NCF: COVID-19 convalescents with no fatigue; PCR: post-COVID-19 condition with chronic respiratory sequelae; TLC: total lung capacity; FVC: forced vital capacity; P_0.1: airway occlusion pressure; D_LCO: diffusing capacity of the lung for carbon monoxide; K_CO: transfer coefficient of the lung for carbon monoxide; P_Imax: respiratory muscle strength; P_CO2: carbon dioxide tension; P_O2: oxygen tension.

FIGURE 4

Patient-reported outcome: a) Respiratory quality of life was equally impaired in PCF and PCR as expressed by SGRQ score. b) Cumulative score of the fatigue questionnaire assessing post-COVID-19 chronic fatigue syndrome-specific symptoms based on the Canadian consensus criteria was highest in patients with PCF, and markedly lower in PCR and NCF controls. c,d) Total score of PHQ depression was increased in PCF compared to patients with NCF and PCR, with no marked differences regarding post-traumatic stress disorder (PCL-5). PCF: post-COVID-19 condition with fatigue and post-exertional malaise (PEM); NCF: COVID-19 convalescents with no fatigue; PCR: post-COVID-19 condition with chronic respiratory sequelae; SGRQ: St. George's Respiratory Questionnaire; PHQ: Patient Health Questionnaire.