Persisting exercise ventilatory inefficiency in subjects recovering from COVID-19. Longitudinal data analysis 34 months post-discharge, 2024, Dorelli+

[SNT Gatchaman]

Persisting exercise ventilatory inefficiency in subjects recovering from COVID-19. Longitudinal data analysis 34 months post-discharge
Dorelli, Gianluigi; Sartori, Giulia; Fasoli, Giulia; Ridella, Nicolò; Bianchini, Nicola; Braggio, Michele; Ferrari, Marcello; Venturelli, Massimo; Carbonare, Luca Dalle; Capelli, Carlo; Grassi, Bruno; Crisafulli, Ernesto

SARS-CoV-2 infection has raised concerns about long-term health repercussions. Exercise ventilatory inefficiency (EVin) has emerged as a notable long-term sequela, potentially impacting respiratory and cardiovascular health. This study aims to assess the long-term presence of EVin after 34 months and its association with cardiorespiratory health in post-COVID patients. In a longitudinal study on 32 selected post-COVID subjects, we performed two cardiopulmonary exercise tests (CPETs) at 6 months (T0) and 34 months (T1) after hospital discharge. The study sought to explore the long-term persistence of EVin and its correlation with respiratory and cardiovascular responses during exercise.

Measurements included also VO2peak, end-tidal pressure of CO2 (PETCO2) levels, oxygen uptake efficiency slope (OUES) and other cardiorespiratory parameters, with statistical significance set at p < 0.05. The presence of EVin at both T0 and T1 defines a persisting EVin (pEVin). Out of the cohort, five subjects (16%) have pEVin at 34 months.

Subjects with pEVin, compared to those with ventilatory efficiency (Evef) have lower values of PETCO2 throughout exercise, showing hyperventilation. Evef subjects demonstrated selective improvements in DLCO and oxygen pulse, suggesting a recovery in cardiorespiratory function over time.

In contrast, those with pEvin did not exhibit these improvements. Notably, significant correlations were found between hyperventilation (measured by PETCO2), oxygen pulse and OUES, indicating the potential prognostic value of OUES and Evin in post-COVID follow-ups.

The study highlights the clinical importance of long-term follow-up for post-COVID patients, as a significant group exhibit persistent EVin, which correlates with altered and potentially unfavorable cardiovascular responses to exercise. These findings advocate for the continued investigation into the long-term health impacts of COVID-19, especially regarding persistent ventilatory inefficiencies and their implications on patient health outcomes.

Link | PDF (BMC Pulmonary Medicine) [Open Access]

 

[SNT Gatchaman]

Selected summary quotes from introduction —

CPET has highlighted a reduction of maximal exercise capacity and oxygen uptake (VO2peak) [...] demonstrated that exercise hyperventilation and ventilatory inefficiency (Evin) are a contributor to numerous disabling signs and symptoms

Exercise ventilation efficiency is assessed by examining how minute ventilation (V̇E) correlates with the amount of carbon dioxide produced (V̇CO2 ). This relationship is quantified using three metrics: the slope of V̇E against V̇CO2 (V̇E/V̇CO2 slope), the lowest value observed (nadir) for this ratio, and the carbon dioxide ventilatory equivalent at the first ventilatory threshold (V̇E/V̇CO2 ̇ at θL). These metrics are well-established for evaluating mismatches in ventilation and pulmonary perfusion during exercise in patients with heart and lung conditions

EVin is also a hallmark of pulmonary vascular diseases, such as pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension where it is an excellent prognostic marker

A significant amount of evidence indicates that a subset of asymptomatic COVID-19 survivors exhibits EVin, with prevalences reported at 29% and 17% at 6 and 12 months post-discharge, respectively. Compared to those without exercise ventilatory inefficiency, those with ventilatory efficiency (EVef), postCOVID patients with Evin show lower values of end-tidal pressure of CO2 (PETCO2) throughout the exercise and display hypocapnia and respiratory alkalosis, which may correlate with an impairment in diffusing capacity (DLCO)

evidence at 12 months following severe COVID-19 infections indicates that numerous patients despite achieving normal VO2peak ̇ levels, exhibit signs of Evin, notably linked to signs of underlying pulmonary microvascular disease and increased dead space ventilation [...] believed to stem from endothelial dysfunction and a hypercoagulable state

An invasive CPET study documents that symptomatic long-COVID patients with reduced exercise capacity have a blunted peripheral oxygen extraction

In addition to V̇O2peak ̇ and V̇E ̇V̇CO2 relationship, impairments of the respiratory and cardiovascular response to exercise, could be also evaluated through the oxygen pulse (O2pulse), aerobic efficiency slope (V̇O2/W slope ) and oxygen uptake efficiency slope (OUES) which also estimates the cardiovascular risk in certain populations. O2pulse is the ratio between oxygen uptake and heart rate (HR): it reflects the amount of oxygen extracted by the tissue per heartbeat and could be used as a non-invasive estimator of stroke volume, or peripheral oxygen utilization.

Our first hypothesis is that EVin may persist chronically

We also hypothesized that EVin is a sign of a broader dysfunction in the cardiorespiratory response

 

[SNT Gatchaman]

Selected summary quotes from methods —

We evaluated the resting and exercise ventilatory and cardiovascular responses in a cohort of selected postCOVID patients at 34 months from hospitalization, comparing data with a previous evaluation performed 6 months after discharge. [...] involving patients h pitalized for COVID-19 pneumonia during the first two waves

We have then excluded subjects meeting the following criteria: (a) age exceeding 65 years; (b) concurrent presence of respiratory and non-respiratory chronic diseases (including the suspected clinical presentation of newonset), respiratory failure, or need for long-term oxygen therapy; (c) a body mass index (BMI) ≥ 35 kg/m2 ; (d) an inability to perform a CPET with a peak respiratory exchange ratio (RER) < 1.05 (to exclude poor motivation); and (e) psychiatric disorders in order to avoid psychogenic hyperventilation. Among chronic diseases, only stable systemic arterial hypertension was accepted.

 

[SNT Gatchaman]

Selected summary quotes from discussion —

Our study starts from the hypothesis that EVin may be a persistent ventilo-perfusory alteration after COVID

In a selected cohort of post-COVID patients, at almost three years of follow-up, we demonstrated that a pEVin is present in 16% of subjects. These subjects showed the phenomenon of exercise hyperventilation, documented by lower levels of PETCO2, and variables related to hospitalization do not seem to have a role in this alteration.

Our patient cohort, comprising individuals with both EVef and EVin, exhibited consistently normal maximal exercise capacity, as well as normal levels of FEV1, FVC, TLC at both 6 months (T0) and 34 months after discharge (T1). This persistent exercise hyperventilation correlates with an exacerbated cardiovascular response to exercise, which was the second hypothesis of this study.

A reduction in maximal exercise capacity and VO2peak ̇ has been reported as the main CPET feature of symptomatic post-COVID patients. However, most of the asymptomatic post-COVID patients, despite maintaining preserved lung functionality, maximal exercise capacity and VO2peak, exhibit EVin. Research has indicated that exercise ventilatory inefficiency may be a significant feature also in apparently healthy COVID-19 survivors: however, its clinical role has not yet been fully elucidated, as well as its pathophysiological cause.

EVin in cardiopulmonary chronic conditions is a very common alteration and may be caused mainly by two reasons: (1) An altered arterial partial carbon dioxide pressure (PaCO2) set-point and chemosensitivity (usually a consequence of chronic hypoxemia), and (2) an abnormally high dead space fraction during exercise caused by a ventilatory-perfusion mismatch, which could involve the ventilation, or the pulmonary perfusion

The exact cause of this hyperventilation remains unknown. As a consequence of SARS-CoV-2 infection, an imbalance in the ventilatory control has been hypothesized as a mechanism, related to either heightened activation of activator systems (including automatic and cortical ventilatory control, peripheral afferents, and sensory cortex) or suppression of inhibitory systems (endorphins)

Our study reports a close association between exercise hyperventilation and EVin as a permanent and distinctive sign of a proportion of asymptomatic survivors after 34 months. Even if this phenomenon has been documented, the pathophysiological mechanism is still unclear.

Now, we document a selective improvement of diffusion capacity only in EVef subjects, compared to pEvin subjects. Even if our study was not designed to explain the physiopathology of pEvin, the DLCO behavior of our pEVin subjects after 3 years is a novel finding that merit notice as an indirect sign of subclinical damage of the cardio-respiratory system leading to an increase of dead space ventilation during exercise.

 

[Sean]

A golden opportunity missed:

According to our own @Snow Leopard, reduction in power at the ventilatory threshold on the 2nd day is the primary finding in 2-day CPET tests in ME/CFS.

This study only did single tests at each time point.

Still, a useful paper.

 

[EndME]

Some other LC studies that also used a CPET:

• Use of Cardiopulmonary Exercise Testing to Evaluate Long COVID-19 Symptoms in Adults - A Systematic Review and Meta-analysis
• Reduced exercise capacity, chronotropic incompetence, early systematic inflammation in cardiopulmonary phenotype Long COVID
• Cardiopulmonary testing in long COVID-19 versus non-COVID-19 patients with undifferentiated Dyspnea on exertion
  

 

[EndME]

Cohort characteristics:

32 LC patients (tested at 6 months and 34 months). These patients had all been hospitalized due to COVID-19 pneumonia during the first two waves of the pandemic in Italy.

Patients above the age of 65, a BMI above 35 and with pre-existing illnesses were mostly excluded.

Other than that I didn't see any details on the patients.

In that sense it is not clear whether this has much relevance to "Long-Covid" and indeed as the title suggests is rather a study of patients after they had Covid-19 pneumonia.

As such I don't think it's really much of a missed opportunity to not have conducted a 2-day CPET as the authors seem to be studying something else entirely (rather than ME/CFS or syndromic LC) with a focus on breathlessness in people that experienced pneumonia during a severe infection, an interesting field in its own right. The ventilo-perfusory alteration after COVID-19 references which the authors cite are mostly related to severe acute infections as far as I can see.

If anything this study once again shows that if you want to study phenomena that might not be a direct consequence of a severe acute infection it's most sensible to exclude such people from your study or even better have different cohorts with different acute infection statuses. It could be interesting to compare this data to some of the LC-CPET studies above which also included non-hospitalised patients as far as I remember.

Could be interesting to know what percentage of people are currently exercising or had undergone physical therapy as this would probably apply to most of these patients and suggest that these problems are indeed non-resolving for a subset of people who have a severe acute infection but who are considered "physically fit".

 

[Mij]

I have dyspnoea when walking at a slow pace during viral infections.

 

[Turtle]

Can hypervertilation, more Co2, in exercise help to remove lactate?