Dysfunctional breathing symptoms, functional impact and quality of life in patients with long COVID-19: a prospective case series

Introduction

Dyspnoea frequently persists after SARS-CoV-2 infection, independent of abnormalities on chest imaging or pulmonary function tests (PFTs) and initial disease severity.1 Deconditioning and respiratory limitation (RL) evaluated by cardiopulmonary exercise testing (CPET) are the main exercise-limiting factors after severe SARS-CoV-2 necessitating hospitalisation.2–8 However, the mechanisms of persisting dyspnoea after uncomplicated mild SARS-CoV-2 infection are poorly understood. One possible mechanism could be dysfunctional breathing (DB), defined as dyspnoea associated with an abnormal breathing pattern after exclusion of a significant cardiopulmonary disease that could cause dyspnoea, or dyspnoea occurring out of proportion with an underlying cause (eg, cardiopulmonary or metabolic diseases and deconditioning) and associated with an abnormal breathing pattern.9 DB may cause symptoms at rest and during various daily life situations, including exercise. Different types have been described with hyperventilation syndrome (HVS) and periodic deep sighing (PDS) identified as the most common subtypes.9 In the classification by Boulding et al, PDS encompasses frequent sighs as well as erratic breathing (EB). Here, we use the term EB/PDS to describe this combination of abnormal breathing patterns.9 Given its complex features, there is currently no gold standard for the diagnosis of DB.9

Although the Nijmegen Questionnaire was validated as a tool to detect subjective symptoms associated with HVS,10 its lack of diagnostic accuracy has been acknowledged.10 11 In addition, its use has been extrapolated to other types of DB, but lacks a rigorous validation.9 CPET has been recently recommended as an attractive tool for the diagnosis of DB as it provides evidence of abnormal breathing patterns and allows the exclusion of significant cardiopulmonary disease-limiting exercise.11 12 Thus, a combined approach using formal symptom assessment and CPET is recommended for the diagnosis of DB.11

As DB is associated with diverse respiratory and non-respiratory symptoms, it could explain some persisting symptoms often described in long COVID patients, such as chest tightness, sensation of restriction during inspiration, chest pain and paresthesia.13 HVS has been described in a case series of patients following SARS-CoV-2 infection and was further suspected in a larger patient population.14 15 EB/PDS was described as the second type of possible DB following SARS-CoV-2.16 17 A significant burden of symptoms associated with DB in long COVID patients has been described in a small number of patients, but it has not been systematically quantified so far.14 Our objective was to describe the symptoms, quality of life (QoL) and functional outcome using subjective and objective measures in a large case series of long COVID patients having DB.

Methods

Results

From 1 March 2021 to 31 October 2021, 264 patients were evaluated. Among these, 48 (female, 68.8%; mean age, 48.5 (SD, 15.0) years) were included in the study (figure 1). Baseline characteristics of patients are shown in table 1. In general, patients were previously healthy, never smoked (68.8%) and had mild severity acute COVID-19 (WHO severity score 1 (70.8%)). In most cases, hospitalisation was not required (85.4%). Before COVID-19, 12.5%, 39.6%, 33.3% and 14.6% of patients were sedentary, mildly, moderately or intensively active, respectively. Most patients (93.6%) did not report dyspnoea before COVID-19 and had an mMRC score of 2 (42.6%) or 3 (34.0%) at the time of the visit. Median delay between diagnosis and clinical evaluation with CPET was 212 (IQR 118) days. Patients with EB/PDS had a more frequent history of asthma (7/22 (31.8%)) than other subgroups (0% in HVS and mixed type, p=0.008) (online supplemental table S3).

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Table 2 shows the general symptoms at the time of the initial visit. Patients exhibited a high burden of variable symptoms affecting breathing, cognition, mood and muscular function (median number of reported symptoms, 12 (IQR 6)). The mixed type and hyperventilation groups reported loss of appetite more frequently (37.5% and 44.4%, respectively) compared with the EB/PDS group (9.1%) (p=0.035). The mixed type group reported a more frequent weight loss (43.8%) compared with the other two subgroups (p=0.009). Symptoms were otherwise similar between groups (online supplemental table S4).

Table 3 shows the most frequently selected items of the Nijmegen Questionnaire (≥3 points). After dyspnoea, the five main selected items were faster or deeper breathing (75.6%), palpitations (63.8%), sighs (48.7%), unable to breathe deeply (46.3%) and yawning (46.2%); 68.9% of patients had a total Nijmegen score ≥23 points. The Nijmegen mean total score did not differ between the three groups of diagnosed DB (EB/PDS, HVS, mixed) (online supplemental table S5). Table 4 summarises the SF-36, HADS and PCFS scores. SF-36 QoL scores were low, especially in the domains of physical functioning, vitality, social functioning and emotional role. The SF-36 score of DB patients stratified by gender contrasted with healthy never-smokers of a comparable age in Switzerland and showed an important decrease in the QoL score compared with age-matched controls (figure 2).29 62.5% of patients had a high risk for anxiety and/or depression (HADS≥15). Almost all (97.9%) patients had functional repercussions related to COVID-19. Among these, 31.9% reported a PCFS of 2 (equivalent to the presence of limitations in everyday life that lead to the avoidance/reduction of usual duties/activities due to symptoms, pain, depression or anxiety), and 40.4% a PCFS of 3 (incapacity to perform some usual duties/activities due to symptoms, pain, depression or anxiety, but without the need of external help). Patients with a mixed type were significantly more impaired than other subgroups (75% with a PCFS of 3 (online supplemental table S6). Otherwise, there was no significant difference in HADS, SF-36 and PCFS scores between groups.

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Table 5 shows PFTs, CPET and arterial blood gases before and after exercise. On average, PFTs were within the normal range and did not differ between groups. No individual had obstructive spirometry (defined as an FEV₁/FVC<−1.64 Z score). One patient had a restrictive pattern (defined as a TLC<−1.64 Z score). Five patients had an abnormal TLCO (defined as a TLCO <−1.64 Z score). Using predetermined criteria, CPET were maximal in 42 patients (87.5%) with an average normal peak V’O₂ of 87% and a normal predicted peak work of 92%. The V’E/V’CO₂ slope was higher in the HVS group and mixed group (38.9 and 36.4, respectively) compared with the EB/PDS group (24.9). The HVS group had a normal mean pH (7.37) at the end of exercise, despite a high lactate (8.6 mmol/L) due to a relatively low end-exercise PaCO₂ (3.7 kPa) representing disproportionate hyperventilation. Laboratory tests and radiological examinations were within reference values for most patients (table 6). An abnormal NT proBNP was found in 1 patient (2.2%). Chest CT or chest X-ray identified abnormalities in five patients (four post-COVID-19 lung interstitial anomalies of a limited extent and one segmental pulmonary embolism).

Discussion

Our study found that previously healthy, long COVID patients diagnosed with DB lived with a high burden of symptoms, poor QoL and a high level of post-COVID functional impact, despite a long delay between acute COVID-19 infection and assessment (median, 7 months). The clinical impact of long COVID-associated DB is worrisome. First, the long delay between the acute infection and assessment suggests an ongoing active process. Second, there is currently no therapy for long COVID-associated DB that has proved effective in controlled trials. Third, the working and living capacity of long COVID patients with DB may be durably reduced, posing a societal problem given the high number of individuals infected by SARS-CoV-2. To our knowledge, this study analysed the largest case series of long COVID patients diagnosed with new onset DB. DB was diagnosed in 32.4% of our ambulatory patients presenting with unexplained dyspnoea and this finding adds to the growing evidence that it seems to be a common condition among long COVID patients.14–17 In addition, we provide a detailed assessment of symptoms, QoL and functional repercussions.

Our findings showed that in addition to dyspnoea, the five most frequently selected items from the Nijmegen scale were faster or deeper breathing, palpitations, sighs, inability to breathe deeply and yawning. Other symptoms reported by more than 50% of patients were fatigue, myalgia, trouble sleeping, chest tightness, headache, vertigo, change of mood, memory loss, concentration difficulties and cough. Compared with the measured value in a similar control group of healthy never-smokers in Switzerland,29 SF-36 scores were markedly reduced in most domains, largely more than the minimal clinical important difference (MCID) of 10 points,19 suggesting not only an important physical impact with limiting symptoms, but also a significant impact in multiple QoL domains. The low SF-36 scores in our study are preoccupying as it has been shown in population and clinical studies that reduced physical functioning, chronic pain and reduced mental health were strongly associated with the working disability rate.30 31 The functional impact was high with a PCFS of 2 and 3 in most patients (73.9%), representing either a limitation or an impossibility to perform some daily tasks/activities. Together with poor QoL, high PCFS scores in a middle-aged population of previously active workers with only initial mild infection may be an important concern for the long-term work capacity of long COVID patients with DB.

More than 60% of patients with DB exhibited severe anxiety and/or depression symptoms. Anxiety and depression could be the consequences of DB, but also contributing factors to DB. Indeed, anxiety disorders have been linked to DB.9 In this context, the exact number of symptoms, functional repercussions and impact on QoL that can be attributed to DB, anxiety or depression is unclear. However, we think that the most important aspect is not to fully understand the causality between these different conditions, but to recognise that anxiety and depression are frequent in patients diagnosed with DB and should be systematically screened. This offers clinicians the possibility to have a multimodal approach with their patients, targeting both the DB with specific physiotherapy and the anxiety/depression if present with both non pharmaceutical and pharmaceutical approaches.

Although patients with EB/PDS reported a history of asthma more frequently, this association might be spurious in the context of multiple subgroup analyses. In this case series, patients were predominantly female which is in concordance with data showing the female sex is a risk factor for persisting symptoms after SARS-CoV-2 infection.32

The physiopathology of DB after SARS-CoV-2 remains to be elucidated, but an active process affecting the respiratory centres might be present. Importantly, recent data showed that even mild COVID was associated with changes in brain structure, including brainstem mass loss.33 Of note, a large majority of our patients reported neurocognitive symptoms, with 85.1% and 78.7% reporting difficulty focusing and forgetfulness, respectively. Whether specific damage to respiratory centres is present in patients with DB remains unknown and needs to be investigated. Another possible explanation for hyperventilation could be local muscular mechanisms with increased sensitive afferents signals to the respiratory centre leading to higher ventilation.34

Interestingly, PFTs (including a systematic measurement of TLCO) and overall exercise capacity were preserved in our patients. These results speak against a significant contribution of the lung parenchyma to explain their respiratory symptoms. A concomitant O₂ utilisation/delivery limitation was present in 11 patients (22.9%). After exclusion of main causes, including cardiac pathologies, abnormal arterial desaturation and anaemia, this pattern suggests an abnormal cardiac output due to deconditioning or abnormal muscle O₂ uptake.35 Our patients had a systematic measurement of haemoglobin and NT-proBNP before CPET. The single patient included with an NT-proBNP >125 ng/L had a normal transthoracic echocardiography. No anaemia was diagnosed. Our study design did not allow to differentiate between central (cardiac output) or peripheral oxygen extraction as the cause of the observed limitation. While the presence of concomitant deconditioning could explain the level of dyspnoea to some extent, it cannot explain the other associated respiratory and extrarespiratory symptoms reported by all included patients.

RL patterns during CPET were present in two patients due to a breathing reserve <15%. Both had mild COVID-19 infection with normal PFTs and imaging. They were diagnosed with an important HVS with a severe elevation of V’E/V’CO₂ slope and respiratory alkalosis at the end of exercise, despite a normal VD/VT ratio, causing the exhaustion of breathing reserve. Five patients had an abnormal TLCO, one patient had a restriction, four patients had mild residual interstitial abnormalities and one patient had a segmental pulmonary embolism. At exercise, none of these patients had gas exchange abnormalities or obvious ventilatory constraints, including VT plateau or exhaustion of breathing reserve. Symptoms, VD/VT and other criteria of ventilatory inefficiency were carefully investigated before hyperventilation was diagnosed.12 36 We also excluded SARS-CoV-2-induced vascular sequelae in patients with low TLCO due to a low transfer coefficient of the lung for carbon monoxide (KCO) without interstitial abnormalities or in those with a history of pulmonary embolism during SARS-CoV-2 with a diagnostic algorithm suggested elsewhere.37 Seven patients (14.6%) with concomitant controlled asthma were included. None had obstructive spirometry and all patients described their symptoms as different from those of asthma.

Online supplemental material 1 describes in detail our diagnostic process, including objective definitions (when applicable) of the different CPET patterns, as well as a description of some patients in our case series. Although inspiratory capacity measurements are recommended in respiratory diseases,25 we considered that it could modify our interpretation of DB (including sighs and subjective analysis of the VT variability) and it was not performed.

The strengths of the study are the size of the case series, the systematic assessment of symptoms, QoL and functional repercussions, and the complete approach to diagnose DB, including a detailed analysis of CPET with supplementary slopes and continuous flow-over-volume and volume-over-time graphs. Limitations are: (1) the absence of CPET and PFT before acute COVID-19 to evaluate for pre-existing abnormal breathing patterns and to assess PFT and exercise capacity change, (2) the monocentric evaluation that may limit the generalisability of our findings, (3) the lack of consensus objective criteria to diagnose DB, (4) the absence of a control group of healthy individuals or of post-COVID patients with respiratory symptoms but without DB and (5) the lack of a measurement that depicted the time from onset of long COVID symptoms to first assessment in the study. Therefore, we cannot assure that the full extent of symptoms, QoL and post-COVID functional impact were not evolving before the clinical evaluation.

While objective criteria to help the diagnosis of HVS have been described,12 there are no validated objective criteria for the diagnosis of EB/PDS. Hence, we probably used the most appropriate diagnostic approach, which is a combined approach of clinical symptoms and evaluation of breathing pattern at rest and during exercise after exclusion of other possible causes for the symptoms.9 The lack of a control group is a limitation that precludes the understanding of the exact extent of symptoms attributable to the diagnosis of DB. However, we believe that this case series is still of great value to highlight the major impact associated with the diagnosis of DB that concerned 32.4% of our ambulatory patients presenting with unexplained dyspnoea.

Conclusion

One-third of patients with long COVID-associated dyspnoea presented with HVS, EB/PDS or a mix of these two patterns. Patients with DB had a high burden of respiratory and general symptoms, with a high functional impact and a low QoL. Recognition of DB associated with long COVID is important for the design of therapeutic trials and to foster research on the potential mechanisms of its occurrence.